Integration of Peripheral and Central Systems in Control of Ingestive and Reproductive Behavior
Summary and Keywords
During the evolution of animals, survival and reproduction depended upon mechanisms that maintained internal homeostasis in the face of environmental change. These environmental changes included fluctuations in ambient temperature, food availability, humidity, day length, and population density. Most, if not all, of these variables have effects on the availability of energy, and most vertebrate species have mechanisms that sense energy availability and adjust behavioral priorities accordingly. For example, when the availability of food and potential mating partners is stable and abundant, brain mechanisms often inhibit ingestive behavior, increase energy expenditure, and give priority to courtship and mating. In response to severe energy shortages, brain mechanisms are likely to stimulate foraging, food hoarding, and overeating. These same deficits often delay reproductive development or inhibit adult reproductive behavior. Such adaptations involve the integration of sensory signals with peripheral hormone signals and central effectors, and they are key to understanding health and disease, particularly obesity, eating disorders, and diabetes.
The link between energy balance and reproduction recurs repeatedly, whether in the context of the sensory-somatic system, the autonomic nervous system, or the neuroendocrine cascades. Peripheral signals that are detected by receptors on vagal and splanchnic nerves are relayed to the caudal hindbrain. This brain area contains the effectors for peripheral hormone secretion and for chewing and swallowing, and this same brain area contains receptors for humoral and metabolic signals from peripheral circulation. The caudal hindbrain is therefore a strong candidate for integration of multiple signals that control the initiation of meals, meal size, energy storage, and energy expenditure, including the energy expended on reproduction. There are some differences between the reproductive and ingestive mechanisms, but there are also many striking similarities. There are still gaps in our knowledge about the nature and location of metabolic receptors and the pathways to their effectors. Some of the most promising research is designed to shed light on how hormonal signals might be enhanced or modulated by the peripheral energetic condition (e.g., the level of oxidizable metabolic fuels).
Keywords: agouti-related protein, estrous cycle, ghrelin, glucoprivation, hypothalamic-pituitary-gonadal system, ingestive behavior, kisspeptin, leptin, lipoprivation, metabolic fuels, nucleus of the solitary tract, RFamide-related peptide, satiation, sex behavior, splanchnic nerve, vagus nerve
The central nervous system (CNS) is affected by peripheral events, both metabolic and endocrine, that occur in response to environmental change. These peripheral–central interactions are critical for the maintenance of internal homeostasis in the face of environmental change, including perturbations in ambient temperature, humidity, day length, the availability of potential mating partners and competitors, and the availability of calories and nutrients (Abdulhay et al., 2014; Cools et al., 2018; Fantino & Cabanac, 1984; Gao et al., 2019; Paul et al., 2010; Schneider et al., 2013; Silver & Kriegsfeld, 2014; Wade & Jones, 2004; Woodside, 2016). In recent years, neuroendocrinologists have added endocrine-disrupting compounds, dim light at night, and the gut microbiome to a growing list of environmental factors that influence motivation and behavior (reviewed by Fonken & Nelson, 2014; Heiss & Olofsson, 2019; Ley et al., 2006; Nesan et al., 2018; Schneider et al., 2014; Vitetta et al., 2014). For all species with a nervous system, central–peripheral connections are essential for survival in an ever-changing environment. For human beings, they are central for understanding health and disease.
Central–peripheral communication is reciprocal. In one direction, changes in diet lead to gastric, metabolic, and endocrine events that influence mood, motivation, and behavior (reviewed by Baker et al., 2017; Schneider, 2006). Furthermore, peripheral hormone concentrations fluctuate over the estrous or menstrual cycle, pregnancy, lactation, and menopause, and these changes have profound effects on ingestion, mood states, sexual motivation, and general activity. They also influence energy expenditure, energy storage, and body fat distribution. In the other direction, mood states and behavior affect the gastric, metabolic, and endocrine processes in peripheral organs. For example, anxiety and depression are linked to elevated inflammation, obesity, and heart disease (Celano et al., 2016). Controlling for other variables, anxiety leads to a 26% increase in the incidence of coronary artery disease (Roest et al., 2010). In addition, chronic social stress is reciprocally linked to disorders, including insulin resistance, diabetes, visceral adiposity, obesity, infertility, and diminished libido (Scott et al., 2012). Mood and motivation are clearly linked to diverse treatments for obesity (Liu et al., 2014). Thus, the popular notion of a “mind–body connection” might be oversimplified, but the foundation of this idea is based on a century of evidence for reciprocal brain–body communication, and this communication is almost always involved with internal and external energy availability. Two-way, central–peripheral communication is therefore highly relevant to drug development, dietary guidelines, and treatments for obesity and eating disorders.
Ingestion and reproduction are two behaviors that are most often studied in isolation, even though both vary predictably with external conditions. In particular, they vary with the availability of calories and nutrients and with factors that alter energetic demands, including ambient temperature, food availability, foraging requirements, and population density. Most environmental variables have direct or indirect effects on the availability of energy, and energy is required for most behaviors and physiological processes. Thus, it is not surprising that most behaviors are controlled by energy availability, including energetically expensive reproductive behaviors. It is therefore unfortunate that most researchers who study ingestive behavior typically study laboratory subjects isolated from potential mating partners. Conversely, those who study reproductive behavior typically focus on subjects with continuous, unlimited access to standard laboratory chow. This article highlights the links between ingestive and reproductive mechanisms and the research of scientists who study both ingestive and reproductive behaviors simultaneously. Given the importance of ingestive and reproductive behavior in evolutionary adaptation, knowledge of the underlying mechanisms is likely to provide a starting point for understanding many different phenotypes that rely on peripheral–central integration, including the stress response, anxiety, insecurity, affiliation, and cognition.
Modes of Communication Between Brain and Periphery
Most communication between the brain and periphery falls into one of two major categories, both of which are essential for metabolic control of ingestion and reproduction (Figure 1). First, the brain communicates with other organs via the peripheral nervous system, which is comprised of the somatic and autonomic branches. The somatic system sends signals from the brain to the skeletal muscles that control voluntary action and the somatic reflexes. The autonomic system controls the involuntary actions of cardiac muscle, smooth muscle, and exocrine and endocrine glands. These effects extend to aspects of sexuality. For example, the autonomic nervous system controls the involuntary action of smooth muscle relaxation during penile and clitoral erection. Furthermore, the autonomic nervous system controls secretions of the gut that influence sexual motivation; for example, secretion of the stomach hormone ghrelin is influenced by the autonomic nervous system (Hosoda & Kangawa, 2008), and increases in ghrelin secretion are inhibitory for sexual motivation, behavior, and hypothalamic-pituitary-gonadal (HPG) secretion (Burroughs et al., 2018; Egecioglu et al., 2016). In addition, ghrelin increases the appetite for food and food intake (Abizaid & Horvath, 2012; Cummings, 2006). The autonomic nervous system also senses dangerous drops in glucose in the caudal hindbrain and, in response, stimulates the adrenal catecholamine secretion necessary for the compensatory release of glucose (e.g., by the breakdown of stored glycogen); this same pathway is necessary and sufficient for increases in food intake in response to hindbrain glucose deficits (reviewed by Ritter, Li, & Wang, 2019). Thus, the autonomic nervous system controls both sex and ingestive behavior.
In addition to the somatic and autonomic nervous systems, the brain communicates with other organs via neuroendocrine cascades, chains of hormone secretion from two or more endocrine organs (Figure 1). Three types of neuroendocrine cascades include those that involve hypothalamic hormone secretions that reach the anterior pituitary, those that involve hypothalamic neural projections to the posterior pituitary, and those that are independent of the pituitary gland. These cascades are intertwined with the peripheral nervous system. For example, the hormones of the pituitary-independent cascades are often directly controlled by the autonomic nervous system. All the cascades affect ingestion and reproduction and are discussed in detail in this article.
In addition, the brain receives critical cues via chemical messengers from the immune system, cues that allow organisms to respond to parasitic, bacterial, and viral infections (Balmer & Hess, 2017). These processes are affected by seasonal cues, energy availability, and reproductive phase (Kriegsfeld et al., 2003; Nelson et al., 1995; Sylvia & Demas, 2018). Finally, coordination occurs between the master circadian oscillator in the brain (in mammals, the suprachiasmatic nucleus [SCN]) and peripheral oscillators. The SCN receives information about day length from the melanopsin retinal ganglion cells via the retino-hypothalamic tract. In addition, the SCN receives neural and humoral signals from the peripheral organs (e.g., the pineal gland, stomach, and liver), and these signals provide information about the internal state of the animal. These clocks are key to synchronization of internal processes to cyclic changes in the environment (e.g., daily, lunar, and annual cycles; reviewed by Silver & Kriegsfeld, 2014). Via these communication systems, ingestive and sexual processes are synchronized with geophysical events.
The Somatic System
The somatic system controls both voluntary motor movements and some important reflex arcs. With regard to sexuality, genital stimulation leads to arousal via afferents to the secondary somatosensory cortex and the posterior insula. At peak arousal, efferent transmission leads to the ejaculatory reflex. Another excellent example is the arched-back lordosis reflex that occurs during copulation in females of many mammalian species. The arched-back posture, lordosis, is a spinal reflex in which male stimuli are integrated with steroid-binding circuits in the CNS. Integration of many environmental cues determines whether this spinal reflex will occur. For example, the reflex occurs only in well-fed and well-nourished females during the evening of estrus in the presence of an adult male housed in relative safety from predators and weather extremes. The reflex is inhibited by prior food deprivation and other stressors via detectors discussed elsewhere in this article. During the nonfertile phase of the estrous cycle, when circulating levels of estradiol are low, the lordosis reflex is inhibited by projections from the hypothalamus. The somatic reflex is linked to the HPG cascade. For example, at the time of estrus, the lordosis reflex is disinhibited when elevated secretion of ovarian estradiol leads to estradiol binding to its receptor, estrogen receptor-alpha (ER-α), in specific brain areas, for example, the preoptic area (POA), anterior hypothalamus, the ventromedial nucleus of the hypothalamus (VMN), and periaqueductal gray (PAG). Estradiol binding to its receptor leads to transcription of the gene for progestin receptor (PR) and subsequent binding of progesterone to PR. Disinhibition of the lordosis reflex occurs when estradiol and progesterone binding coincides with afferent stimuli generated by olfactory and tactile cues from the male. The lordosis reflex includes projections from the hypothalamic VMN to the PAG to the median reticular formation. Projections from this area reach the motor neurons of the spinal cord, which in turn innervate the lumbar epaxial muscles that produce the lordosis posture (reviewed by Daniels et al., 1999; Pfaff & Modianos, 1985). Even if an adult male is present and levels of ovarian steroids are optimal, the lordosis reflex might be inhibited in malnourished females. This might occur via effects of decreased availability of glucose and free fatty acids and the neuroendocrine sequelae, one of which is a decrease in VMN estradiol receptors (reviewed by Wade et al., 1996; Wade & Jones, 2004). The lordosis reflex is a canonical example of the complex interaction between brain and peripheral gonadal steroids to control sex behavior and of metabolic control of reproduction.
The Autonomic System
The cell bodies of the sympathetic nervous system reside in the intermediolateral cell columns of the lateral horn of the spinal cord. From here, preganglionic fibers of the sympathetic system target cells in ganglia located close to the thoracic and lumbar vertebral columns. The preganglionic cells of the sympathetic nervous system secrete acetylcholine (Ach), which binds to nicotinic Ach receptors, whereas the postganglionic cells secrete norepinephrine (with some exceptions) at their myriad targets. Many of these peripheral targets contain noradrenergic receptors. Sympathetic noradrenergic communication with the abdominal viscera occurs mainly via the various branches of the splanchnic nerve (Shechter & Schwartz, 2016). In addition, efferent sympathetic signals trigger release of epinephrine from the adrenal medulla to increase respiration, heart rate, blood pressure, and piloerection (Dalal & Grujic, 2019). Other processes are frankly inhibited by sympathetic activation. For example, sympathetic activation causes constriction of blood vessels in smooth muscle and therefore loss of penile erection. On the other hand, once smooth muscle vasodilation and erection are obtained, emission and ejaculation require sympathetic activation. This reflex also includes somatic activation of motor neurons in the spinal cord and resulting excitation of the bulbocavernosus and ischiocavernosus muscles of the penis and of the pelvic floor muscles in both males and females. In addition to these sexual responses, stress-induced vasoconstriction inhibits digestion and some aspects of the immune system, processes that can be delayed during a life-threatening stress response. Sympathetic afferent and efferent projections connect the CNS to adipose tissue, and sympathetic activation stimulates glycolysis, the oxidation of glucose, and lipolysis, the process whereby free fatty acids are released along with glycerol from triglycerides mobilized from adipocytes (Bartness et al., 2014). Thus, sympathetic activation is an important means of procuring the two most important oxidizable fuels, glucose and free fatty acids, which are critical for eventual formation of adenosine triphosohate, ATP, the energy currency of the cell. These and other sympathetic connections to liver and muscle are involved in the sympathoadrenal response to glucoprivation. Glucoprivation is a deficit in the availability of oxidizable glucose, a condition that can be experimentally induced by treatments with agents that block glycolysis or by treatment with insulin, which removes glucose from circulation. Glucoprivation is detected in the ventrolateral medulla, and catecholaminergic projections from the ventrolateral medulla are sent via the hypothalamus to the adrenal medulla. In response to signals from glucoprivation in the ventrolateral medulla, the adrenal secretes catecholamines, which promote glycogenolysis and lipolysis. The free fatty acids and glucose released are the oxidizable fuels critical for the mental and physical responses to any stressor. In addition, sympathetic responses are one arm of the two-arm “freeze-fight-or-flight” response, which leads to an abundance of metabolic fuels to support a complex, energetically expensive, largely unconscious response to aversive stimuli (LeDoux et al., 2017). The other arm of the stress response is the hypothalamic-pituitary-adrenal (HPA) cascade.
The parasympathetic system connects the brain to the peripheral organs through various cranial, sacral, and pelvic efferent and afferent fibers and targets postganglionic cells located close to the organs they innervate (Figure 1). Ach is the parasympathetic neurotransmitter at both the ganglion and the target organ. One important exception occurs when the target organ is the genital region. Penile and clitoral erection are mediated by parasympathetic ganglia that secrete nitric oxide (NO), and thus, pharmaceutical products that address erectile dysfunction enhance the effects of NO. Where there is a sexual response, we can expect a food-related response. With regard to digestion of food and food intake, parasympathetic innervation reaches the viscera from the vagus, the tenth cranial nerve. In contrast to the sympathetic “freeze-flight-or-fight” system, the parasympathetic system is sometimes known as the “rest-and-digest” system. Parasympathetic activation includes decreased heart rate, respiration, and blood pressure, and increased blood flow to the intestines. The parasympathetic nervous system sends and receives signals from adipose tissue to promote lipogenesis in response to the aftermath of the stress response (Bartness et al., 2014). In the long term, parasympathetic activation increases food intake, fat storage, and myriad processes involved in healing and recovery from trauma.
Most important in this article, visceral sensory information is received in various areas of the gut, including the duodenum-jejunal juncture, the hepatic portal vein, and stomach. Visceral sensory information is carried by the vagus and splanchnic nerves through two important areas in the caudal hindbrain, the area postrema (AP) and nucleus of the solitary tract (NTS) in the dorsomedial medulla (Loewy, 1990). From the AP/NTS, signals are relayed to the lateral parabrachial nucleus and to forebrain areas, such as the paraventricular nucleus of the hypothalamus (PVH). In addition, parallel pathways are critical for the counterregulatory responses to glucoprivation (Ritter et al., 2019). They reach the forebrain directly from the AP/NTS projections (Loewy, 1990), including the aforementioned catecholaminergic pathway from the ventrolateral medulla, These are the primary autonomic routes by which information about the availability of oxidizable fuels reaches the brain, and these routes are likely the primary mediators of the metabolic effects on ingestive and reproductive behavior.
In addition to the sympathetic and parasympathetic branches, the enteric nervous system forms a flat sheet of interwoven neurons that surrounds the esophagus, stomach, and intestines (Figure 1). In humans, about 2,000 autonomic fibers connect the brain to the enteric nervous system, a relatively large neural matrix of over 100 million neurons. Although the enteric system is in contact with the brain, it can monitor the internal milieu and modulate gut function independently. The enteric nervous system shares many traits in common with the brain. For example, serotonin (5-HT) is an important neurotransmitter in the CNS and a pharmaceutical target for depression (many antidepressant medications act by increasing availability of serotonin at CNS synapses), and yet, 95% of the 5-HT in the body is secreted from cells in the enteric nervous system. Furthermore, the enteric nervous system can function both in response to, and independent of, the CNS, and has been called, the “gut brain” or the “second brain.” The enteric nervous system is not divorced from the mechanisms that control realms of mind, i.e., mood, affect, depression, memory, learning, and motivation, and might be involved in the development of obesity (Baudry et al., 2012; Heiss & Olofsson, 2019). A fruitful avenue of future research is the role of the enteric nervous system in ingestive behavior and obesity. Its role in reproduction is less well studied.
In vertebrate species, several neuroendocrine cascades link the brain to peripheral organs, but this statement should not be taken to imply that the brain is not an endocrine organ. Neural and endocrine are convenient categories, but in reality, the two systems are not separate. The nervous system is characterized by its electrical properties, synapses between cells, and neurotransmitters secreted from presynaptic cells, whereas the endocrine system is characterized by its ductless glands that secrete hormones, chemical messengers that act at a relatively long distance from the site of secretion. The anterior pituitary, for example, is an endocrine organ (a ductless gland), and is therefore known as the adenohypophysis (adeno is Latin for endocrine). Like the anterior pituitary, some cells of the CNS secrete hormones, and those hormones are called neurohormones. Neurohormones are secreted by specialized CNS cells known as neurosecretory cells. Neurosecretory cells are located in the brain and neurohypophysis, and they have axons, dendrites, and receptors for neurotransmitters. Their membranes propagate action potentials, and their circuits show long- and short-term potentiation and depression. Despite all these neural characteristics, the chemical messengers they secrete are true hormones that travel long distances through the circulatory system.
Examples of neurohormones include the releasing factors, gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GHRH), all of which act on receptors located far away from their site of secretion. These neurohormones are secreted from axon terminals and travel from the ventral-most layer of the brain, the median eminence, to the anterior pituitary via the pituitary-portal plexus (the hypophyseal portal system), an intricate system of capillaries. The neurohormones form the first part of the three-link neuroendocrine cascades.
Neurohormones act on receptors found in many peripheral organs, including the anterior pituitary. When neurohormones bind to their specific receptors in the anterior pituitary, they stimulate the release of their respective trophic hormones. GnRH binds to its receptors on pituitary luteotrophs to stimulate the secretion of luteinizing hormone (LH). CRH binds to its receptors on pituitary corticotrophs to stimulate the secretion of adrenocorticotropic hormone (ACTH). TRH binds to its receptors on pituitary thyrotrophs to stimulate the secretion of thyroid-stimulating hormone (TSH). The trophic secretions from the anterior pituitary travel in the general circulation to their specific peripheral target organs.
In the HPG cascade, GnRH, secreted in discrete pulses, stimulates the pulsatile secretion of gonadotropins, LH and follicle stimulating hormone (FSH), which in turn stimulate gametogenesis and the synthesis and secretion of the gonadal steroids. The rise in the circulating levels of gonadal steroids provides a relatively rapid negative-feedback signal to hypothalamus and pituitary to inhibit secretion of GnRH and gonadotropins. This steroid negative feedback prevents the otherwise infinite increases in GnRH and gonadotropin secretion. In contrast to the negative-feedback effects of low levels of steroids, estradiol at prolonged, high concentrations has positive feedback on GnRH secretion, thereby generating the ovulatory LH surge via ER-α in the anteroventral periventricular nucleus (AVPV), a cluster of cells located in the caudal POA. The GnRH cells are not rich in receptors for ER-α, and therefore estradiol feedback likely occurs via other cells that express the gene for ER-α and synapse on GnRH terminals. In particular, three types of cells that are rich in ER-α respond to estradiol and project to GnRH terminals. These three cell types secrete either kisspeptin, RFamide-related peptide 3 (RFRP-3), or glutamate. RFRP-3 is synthesized in cells of the dorsomedial nucleus of the hypothalamus (DMH), binds to the G-protein-coupled receptor 147 (Gpr147) on GnRH cells, and has inhibitory effects on GnRH and LH secretion, at least in females. Kisspeptin, by contrast, has stimulatory effects on GnRH secretion in both sexes (Clarke et al., 2012b; Khan & Kauffman, 2012; Kriegsfeld, 2006; Smith et al., 2006; Tsutsui et al., 2015). Kisspeptin is synthesized in two clusters, one in the AVPV and the other in the arcuate nucleus, where it is synthesized along with neurokinin B and dynorphin. These cells therefore are known as KNDy cells. They generate the species-specific pulsatile rhythm of GnRH secretion (Clarkson et al., 2017; Goodman et al., 2013), and when they are inhibited by estradiol, they are one factor that accounts for steroid negative feedback on GnRH secretion. Kisspeptin binds to the Gpr54 on GnRH and other cells (Clarke et al., 2012b; Khan & Kauffman, 2012; Kriegsfeld, 2006; Smith et al., 2006; Tsutsui et al., 2015). In addition to providing feedback to GnRH cells, kisspeptin, RFRP-3, and gonadal steroids affect courtship and copulatory behavior (Benton et al., 2018; Clarke et al., 2012b; Piekarski et al., 2013; Schneider et al., 2017). In male laboratory rodents, sexual motivation is influenced by the circadian-timed increase in testosterone and/or its metabolite, estradiol, whereas sexual performance is influenced by testosterone and/or its metabolite, dihydrotestosterone (Everitt, 1990). In females of many species, including women, sexual motivation and ovulation are associated with a periovulatory increase in the concentrations of circulating estradiol (Pfaus et al., 1999; Roney & Simmons, 2008; Zehr et al., 1998), and in laboratory rodents, copulatory performance (the lordosis posture) requires estradiol-dependent synthesis of neural progestin receptors, followed by binding of progesterone to those receptors (Delville & Blaustein 1991). In females of many species with spontaneous ovulatory cycles, the increases in sexual motivation and performance are synchronized with the time of peaks in circulating estradiol concentrations and fertility (Ball & Hartman, 1935; Bonsall et al., 1978; Czaja & Bielert, 1975; Komisaruk & Diakow, 1973; Roney & Simmons, 2013). The HPG cascade exemplifies peripheral endocrine interaction with the brain to control a myriad of behavioral and physiological processes.
These reproductive activities do not occur in a vacuum; rather, they occur in environments with many other challenges, demands, and distractions. Reproduction requires energy above and beyond the energy required for other activity. Changes in season, weather, food availability, shelter, and competitors must all be integrated with reproductive activity. The hormones of the HPG cascade respond to changes in energy availability and control energy intake, storage, and expenditure (Wade & Schneider, 1992). In many species, the HPG system is inhibited by a wide array of energetic challenges, including food deprivation, housing at cold ambient temperatures, excess exercise, and treatment with inhibitors of metabolic fuels (reviewed by Bronson, 1989; Schneider et al., 2012; Wade & Schneider, 1992; Wade et al., 1996). The ubiquitous effects of energy on reproduction led Bronson to declare that, among the environmental factors that control mammalian reproduction, energy availability is the most important (Bronson, 1989). Changes in the availability of fuels affect the adult HPG cascade by a variety of mechanisms that include inhibition of expression of the genes for kisspeptin, RFRP-3, or their receptors (Clarke & Arbabi, 2016; De Bond & Smith, 2014; Leon et al., 2014; Padilla et al., 2017; Smith et al., 2010a; Tena-Sempere, 2010; True et al., 2011c). In addition, low food availability delays puberty and prolongs the postlactation onset of estrous cycles (Foster & Olster, 1985; Woodside, 1991), and these effects have been linked to kisspeptin (Ladyman & Woodside, 2014; Roa et al., 2018; True et al., 2011c). Furthermore, decreases in the peripheral availability of metabolic fuels affect the activation of GnRH cells (Berriman et al., 1992) and the number of estradiol receptors (ER-α) in brain areas involved in control of the HPG system and reproductive behavior (reviewed by Wade et al., 1996; Wade & Jones, 2004).
The energetic challenges that decrease reproductive behavior increase ingestive behavior (Table 1). Conversely, the periovulatory increase in sexual behavior is coupled with a suppression of ingestive behavior (Abdulhay et al., 2014; Attah & Besch, 1977; Gilbert & Gillman, 1956; Petersen, 1976; Roney & Simmons, 2017). In fact, all the hormones in the HPG cascade have both direct and indirect effects on ingestion. Estradiol treatment, in the absence of potential mating partners, decreases food intake in a variety of species (Rivera & Stincic, 2018; Santollo & Daniels 2015, 2019; Santollo & Eckel, 2008; Santollo et al., 2011, 2013), including human females (see Fowler et al., 2019). Conversely, removal of the ovarian steroids by ovariectomy or mutations in the gene that encode ER-α result in obesity (Heine et al., 2000; Ohlsson et al., 2000). The GnRH cells are traditionally associated with reproductive processes, and yet some forms of GnRH have direct or indirect effects on ingestive behavior (Hoskins et al., 2008; Kauffman et al., 2005). GnRH-II, for example, has inhibitory effect on food intake (Kauffman & Rissman, 2004). Similarly, the gonadotropins are well known for their effects on reproductive processes, but FSH is implicated in postmenopausal symptoms, including obesity and its sequelae. Loss of estradiol negative feedback on FSH after menopause is correlated with the metabolic syndrome characterized by insulin resistance and increased visceral adiposity (Stefanska et al., 2014). Furthermore, kisspeptin is implicated in the inhibitory effects of estradiol on food intake because ablation of KNDy neurons prevents the weight gain that results from removal of the ovary, the main source of estradiol. Treatment with RFRP-3 increases food intake and food hoarding in a wide variety of species (Benton et al., 2018; Clarke et al., 2012a; Schneider et al., 2017). Thus, it appears that the hormones and receptors of the HPG system have a multiple effects that are critical for setting behavioral priorities in environments where energy availability fluctuates (reviewed by Schneider et al., 2013, 2017). Whereas many other hormones and neural events control energy balance, energy balance is affected directly by hormones of the HPG system.
Table 1. Effects of Various Central–Peripheral Communication Systems and Some of Their Chemical Messengers on Ingestive Behaviors, Energy Storage and Expenditure, and Reproductive Processes
Control of Ingestion
Control of Energy Storage/Expenditure
Control of Reproduction
Compensatory increases in food intake occur in the sympathoadrenal response to glucoprivation.
Activation of this system increases lipolysis and glycogenolysis.
Activation of this system is critical for ejaculation. Over-activation during the stress response can result in erectile dysfunction and inhibition of the HPG system.
Acetylcholine in the nucleus accumbens increases the rewarding aspects of eating food.
Activation of this system increases lipogenesis and glycogenesis.
Activation of this system is critical for smooth muscle relaxation and erectile function.
Food intake is increased by gonadectomy and normalized by treatment with estradiol but not progesterone.
Estradiol increases energy expenditure, whereas progesterone counters this effect and promotes energy storage, usually without affecting food intake.
Estradiol and testosterone facilitate sexual motivation and behavior. In rodents, estradiol plus progesterone is necessary for the lordosis reflex.
Inhibition of eating, digestion, and gastric distension occurs during the stress response.
Body weight and fat are lost during acute stress response. Visceral adipose tissue is accumulated after chronic stress.
Baseline levels are important for fertilization, implantation, and maintenance of pregnancy.
Inhibition of the HPG system occurs during the acute response to a stressor.
THRH decreases food intake, whereas T3 in the ventromedial hypothalamus increases food intake.
T3 increases metabolic rate and energy expenditure.
T3 is permissive for seasonal gonadal regression.
Prolactin is stimulatory for food intake.
Prolactin is necessary for crop milk production in birds and milk production in mammals.
Prolactin is one of many signals for lactational diestrus. Prolactin inhibits the HPG system in males as well.
Oxytocin and vasopressin inhibit food intake.
Oxytocin increases energy expenditure and lipolysis.
Oxytocin and vasopressin facilitate affiliation, partner preference, and mother–infant bonding.
Leptin inhibits food intake.
Leptin increases glycolysis and lipolysis and energy expenditure.
In the presence of an abundance of metabolic fuels, leptin facilitates courtship, mating, and the preference for sexual partners vs. food items.
Ghrelin stimulates food intake, whereas CCK and GLP-1 decrease food intake.
Ghrelin promotes energy storage and decreases energy expenditure, whereas CCK and GLP-1 have the opposite effects.
Ghrelin inhibits sex behavior and the HPG system in females, whereas CCK and GLP-1 have the opposite effects.
Note: References appear in the text. Abbreviations are defined in the text.
The dual effect of estradiol on ingestive and reproductive behavior is more than a coincidence, and there is reason to believe that the choice between food and sex might be the phenotype most closely aligned with the neuropeptide mechanisms that allow organisms to survive in an energetically labile environment. For example, when ad libitum-fed female hamsters are given a choice between spending time with food or spending time with an adult male hamster, they spend more than 50% of their time with male hamsters. When females are subjected to 25% food restriction, their preference is reversed. They now prefer to spend time hoarding food on every day of the estrous cycle, with the exception of the day of estrus (Klingerman et al., 2010). The increases in food hoarding are accompanied by a significant increase in the activation of RFRP-3 cells, again except for the day of estrus. The trends in preference for food vs. sex and in activation of RFRP-3 cells are reversed at the time of estrus or in response to treatment with estrus-inducing doses of estradiol plus progesterone (Benton et al., 2018). In fact, the level of activation of RFRP-3 cells increases as a function of the duration of food restriction and continues and falls again after refeeding. What’s more, there is a striking match between levels of RFRP-3 cellular activation and the preference for spending time with food vs. spending time with males (Klingerman et al., 2011). By contrast, there is little or no concordance between the level of RFRP-3 activation and food intake or between the level of RFRP-3 activation and lordosis duration in the absence of food (Benton et al., 2018; Klingerman et al., 2011; Schneider et al., 2017). Together, these results emphasize the importance of measuring the preference for food vs. sex in an energetic context. The effects of steroids on preference for food vs. sex are not limited to hamsters. For example, when ovariectomized rats were trained to give an operant response (lever-pressing) to food reward or sexual reward, treatment with estrus-inducing levels of estradiol and progesterone increased responding for sex and decreased responding for food (Yoest et al., 2019). The link between food availability and behavioral priorities is not limited to females. Whereas males of some species are less sensitive to reproductive inhibition by food restriction, nevertheless, their priorities are closely matched to the peripheral hormones and central neuropeptides that respond to energetic status (Ammar et al., 2000). Together, these lines of research point to the need to use the choice between food and sex as a window into peripheral–central integration (Schneider et al., 2017).
Other neuroendocrine cascades follow this pattern. In the HPA cascade, CRH stimulates the secretion of anterior pituitary ACTH, which stimulates the secretion of adrenal glucocorticoids. Glucocorticoids are part of the system that helps organisms react to physical and psychological stressors (Angelier & Wingfield, 2013), and these steroids from the adrenal cortex have important effects on reproduction and energy intake, storage, and expenditure (reviewed by Berthon et al., 2014; Whirledge & Cidlowski, 2013). For example, during the stress response, glucocorticoids bind to their receptors in adipocytes, increasing lipolysis (Mattsson & Olsson, 2007). In contrast to their acute effects, chronically elevated circulating glucocorticoids alter the distribution of adipose tissue, i.e., they increase the accumulation of abdominal visceral adipose tissue (Lee et al., 2014). These changes are linked to increases in the incidence of insulin resistance and the development of type 2 diabetes (Lee et al., 2014). This system is important because natural and synthetic glucocorticoids are widely prescribed in medicine to treat bone and joint pain/injury, arthritis, asthma, and other inflammatory diseases, and synthetic glucocorticoids are used in organ transplantation and cancer treatments. Furthermore, stress-induced increases in levels of CRH and glucocorticoids are inhibitory for the reproductive system prior to, during, and after pregnancy (reviewed by Vrekoussis et al., 2010; Whirledge & Cidlowski, 2013), and these effects often involve gonadotropin-inhibiting hormone (GnIH) or its mammalian ortholog, RFRP-3 (Calisi et al., 2008; Ernst et al., 2016; Geraghty et al., 2015; Kirby et al., 2009). Without a doubt, the HPA system is involved in the orchestration of energy intake and storage, as well as the energy expended on reproduction (Table 1).
The hypothalamic-pituitary-thyroid (HPT) cascade has taken center stage in recent years with regard to control of seasonal changes in body weight and reproduction. This system has long been associated with alterations in energy expenditure required for growth, development, and the thermogenic response to changes in environmental temperature (lower ambient temperatures require higher levels of energy expenditure on thermogenesis; reviewed by Herwig et al., 2008; Laurberg et al., 2005). TRH synthesized in the PVH is released into the pituitary portal plexus, enters the circulation, and reaches the pituitary, where it stimulates the secretion of TSH, which in turn stimulates the secretion and metabolism of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). When TSH binds to its receptor, it initiates the expression of an enzyme, deiodinase 2 (DIO2), which catalyzes the conversion of the inactive T4 to the biologically active T3. DIO2 is present in brain, adipose tissue, and skeletal muscle. Excess levels of T3 (e.g., in hyperthyroid patients) increase metabolic rate and energy expenditure and result in a net loss of body fat. The effects on food intake are unclear because hypothalamic treatment with T3 increases food intake, whereas treatment with THRH decreases food intake (reviewed by Herwig et al., 2008).
Independent of the HPT system and under control of melatonin, the metabolism of thyroid hormones in the brain is involved in seasonal changes in reproduction, food intake, body fat storage, and energy expenditure in Siberian hamsters (Barrett et al., 2007; Dardente et al., 2014, 2019). Seasonal changes in this species include reproductive inhibition and a significant loss of body weight and adiposity in response to short-day photoperiods. These responses are initiated by signals that arise from day length detected by retinal ganglion cells that send signals to the SCN, which, via sympathetic activation, alters the duration of the nocturnal secretion of melatonin by the pineal gland. A long-day melatonin signal (a short duration of elevated melatonin during the dark period) is detected in the pars tuberalis, the most rostral part of the anterior pituitary, where it increases secretion of TSH. Thus, in this system TSH is under control of melatonin rather than THRH. In Siberian hamsters, TSH binds to its receptors on nonneural CNS cells, tanycytes, located near the third ventricular area of the hypothalamus. The biologically inactive T4 is transported into tanycytes, where TSH binding to its receptor increases expression of DIO2. DIO2 deiodinates T4 to the active T3. There is evidence that tanycyte control of thyroid hormone metabolism mediates the effects of day length. For example, implantation of T3 into the hypothalamus of short-day-housed Siberian hamsters prevents the body weight loss, hypophagia, and gonadal regression that is normally associated with being housed on short-day photoperiods. Implantation of TSH increases expression of the gene for DIO2 and mimics the effects of long days on body weight (reviewed by Barrett et al., 2007; Dardente et al., 2014). This is a fascinating cascade because CNS T3 levels are regulated in a manner that does not reflect peripheral circulating T3 levels. Rather, changes in day length alter transporters in tanycytes and activity of the deiodinase enzymes (reviewed by Barrett et al., 2007; Dardente et al., 2014). Furthermore, the effect of elevated TSH and T3 on reproduction involves an interaction between the thyroid system and RFRP-3 and kisspeptin control of the HPG system (reviewed by Dardente et al., 2019). HPT control of energy balance and reproduction involves a ping-pong game between the CNS and periphery. Beginning with the peripheral detectors of light, the signal is relayed to the central circadian oscillator, then out to the peripheral endocrine glands, the pineal and then the pituitary, and then back to the CNS tanycytes, and out again to peripheral secretion of T3, which finally acts in brain and periphery to control energy balance and reproduction (Table 1).
In the hypothalamic-pituitary-somatic (HPS) cascade, GHRH stimulates the secretion of growth hormone (GH) from the anterior pituitary and this in turn stimulates somatic growth and differentiation, partly by direct effects on its targets and partly by its stimulatory effects on other peripheral hormones, such as insulin-like growth factor (IGF; Veldhuis et al., 2001). IGF is produced in the liver, but also in many other GH targets. In general, GH and IGF are required for optimal growth and fertility. The GH secretagogue ghrelin increases appetite and food intake, but these effects do not require increases in GH secretion. The HPS system is an important node of peripheral–central integration. Though it is critical for somatic growth, development, and fertility, it has interesting and less well-understood effects on mood, memory, and motivation (Bonthuis & Rissman, 2013; Butler et al., 2019; Chaplin et al., 2011; Jorgensen et al., 1991; Leone et al., 2018).
Yet another neuroendocrine cascade controls prolactin secretion from the anterior pituitary. Prolactin secretion is subject to inhibitory control by hypothalamic dopamine and regulates its own release via a short feedback loop through autoreceptors on the hypothalamic tuberoinfundibular dopaminergic neurons. Prolactin is also subject to stimulatory influence by prolactin-releasing peptide, serotonin, and other hormones, neuropeptides, and environmental factors. Circulating levels of this protein hormone increase during the periovulatory period of the estrous cycle, immediately after mating, at the end of pregnancy, and in response to suckling stimulation from the offspring during lactation. Prolactin is critical for mothers’ milk production, decreases in mating and courtship, and increases in maternal food intake, responses that are necessary to support growth and development of offspring (Gerardo-Gettens et al., 1989a, 1989b; Sauve & Woodside, 1996, 2000). Pregnant and lactating females of some species develop resistance to signals that terminate meals and limit food intake in nonpregnant females, and this adaptation to the energetic demands of reproduction is attributable to increased secretion of prolactin/placental lactogen (Augustine et al., 2008; Augustine & Grattan, 2008; Grattan & Kokay, 2008).
Other neuroendocrine cascades control the secretion of neuropeptides from the posterior pituitary. Unlike the anterior pituitary, the posterior pituitary is a collection of axons from cells in the hypothalamus, and it is therefore known as the neurohypophysis. For example, neurosecretory cells that originate in areas like the supraoptic nucleus (SON) and PVH send projections to the posterior pituitary. The axon terminals of these cells secrete the nonapeptides oxytocin and vasopressin. In addition, oxytocin and vasopressin are released in other specific CNS nuclei. Oxytocin acts on various tissues, including the uterus, mammary gland, caudal hindbrain, and hypothalamic areas, to stimulate uterine contractions, orgasm, milk letdown, maternal care, and affiliation (Stoop, 2012). Vasopressin increases water retention, either increases or decreases aggression depending on the sex, and, in male prairie voles, facilitates monogamous pair-bonds (Carter, 2017; Lim et al., 2004; Renaud, 2006). In addition, activation of vasopressin and oxytocin neurons inhibits food intake (Skinner et al., 2019; Spetter & Hallschmid, 2017; Yoshimura et al., 2017). In the past, the posterior pituitary peptides have been associated with affiliative and agonistic behavior, whereas in recent years they have been revealed as peptides that orchestrate the appetites for food and reproduction.
In summary, via these cascades, the brain reacts to sensory information from the changing environment and stimulates the secretion of peripheral hormones that affect gamete production, reproductive behaviors, energy metabolism, ingestive behavior, and many other physiological and behavioral responses. The communication is not one way. Peripheral hormones travel back to modulate the hormonal output of the neurosecretory cells in the brain and to affect behavior. These neuroendocrine feedback loops illustrate that the CNS is not separate from the endocrine system—rather, the CNS is an endocrine organ making reciprocal connections with the rest of the body.
Many other hormonal cascades influence energy intake, expenditure, and storage via neuroendocrine cascades, and, in some cases, they do not require participation of the pituitary and the secretion of its trophic hormones. Insulin and glucagon, for example, are protein hormones secreted by the pancreas. In most peripheral tissues, insulin increases, and glucagon decreases, the uptake of circulating metabolic fuels. As a result of insulin-induced hypoglycemia, treatment with high doses of insulin can increase the appetite for food, increase food intake, and inhibit the HPG system to conserve energy for survival (reviewed by Wade et al., 1996). Insulin secretion is under the influence of the brain, and insulin secretion affects the brain and behavior. In contrast to high doses of insulin in the periphery, low doses of insulin treatment in the brain are associated with decreases in food intake and facilitation of the HPG system (Benoit et al., 2004; Miller et al., 1995). Another peripheral hormone involved in energy intake, storage, and expenditure is leptin, a protein hormone secreted primarily by adipocytes. In ad libitum-fed animals, the circulating concentrations of leptin are positively correlated with the level of body adiposity, but after food deprivation or fasting, plasma concentrations of leptin fall rapidly (Maffei et al., 1995). Low fasting levels of leptin are associated with high food intake, delayed puberty, or inhibition of the adult HPG system and reproductive behavior (Ahima et al., 1996). Conversely, ghrelin is a protein hormone secreted primarily by cells of the stomach, and increased ghrelin secretion is stimulatory for ingestive behavior and inhibitory for reproductive processes (Burroughs et al., 2018; Fernandez-Fernandez et al., 2004; Furuta et al., 2001; Hyland et al., 2018; Tschop et al., 2000; Wren et al., 2000). The effects of peripheral hormones like insulin, leptin, and ghrelin are mediated at least in part by hormone receptors on neurons that secrete two neuropeptides, neuropeptide Y (NPY) and agouti-related protein (AgRP). The ways that these hormone cascades act on the HPG, HPA, and HPT system to influence reproduction are discussed in detail later in this article.
Integration of CNS with periphery is illustrated by research on ingestive and reproductive behavior, traits that contribute to survival and reproductive success and therefore are subject to strong natural selection. The next sections lay out the evidence that both reproduction and ingestive behavior are modulated by metabolic signals from the periphery carried by the vagus and splanchnic nerves, as well as by hormones that fluctuate with changes in peripheral metabolic fuels.
Ingestive Behavior Cascade
Ingestive behavior is controlled by an interaction between brain and periphery and is one part of a system that maintains homeostasis in the availability of oxidizable metabolic fuels. The availability of fuels must be maintained within a relatively narrow range, and therefore levels of food intake fluctuate to meet the minimal need and to prevent an excess of fuels in circulation. First, a sufficient level of fuels is required to produce ATP, and ingestion of food is the primary means by which fuels are acquired. Second, an excess of fuels damages cells of the nervous and circulatory systems. The level of food intake rises and falls to meet the demand for fuels (reviewed by Friedman, 2008). For example, food intake increases markedly when animals are housed in a cold environment (which requires increased energy expenditure for heat production) or when female mammals are lactating (which requires increased energy expenditure on milk production; Cripps & Williams, 1975). In many different species, food intake decreases or halts altogether during the mating season, whereas in others, food intake decreases during phases of the ovulatory cycle when mating behavior is highest (e.g., in seals, deer, mice, rats, and hamsters; reviewed by Schneider et al., 2013). Holding food intake to strict levels is therefore contrary to survival and reproductive success. Rather, food intake fluctuates, often wildly, to maintain homeostasis in the availability of fuels, to allow animals to engage in other behaviors, and to prevent the excess of fuels that can damage tissues.
Like food intake, body weight cannot be held in narrow homeostasis if the individual is to survive in a dynamic energetic environment. For example, when population size outstrips the availability of food in the environment, fuels must be derived from body fat stores. Survival depends upon the ability to increase lipolysis, to break down triglycerides released from adipose tissue, and to mobilize the fatty acids to muscle and other organs. This in turn conserved available glucose, which is shunted to fuel the CNS. This leads to sharp decreases in body weight, not in maintenance of a set point for body weight. Homeostasis in circulating fuels is maintained, while a set point for body weight is not reliably defended. Conversely, when food becomes available after a period of starvation, body weight and adiposity do not often remain low without cognitive restraint. Rather, they rise and often increase beyond their original level. Body weight seldom reaches a plateau that is maintained over a lifetime. Contrary to the notion of a body weight set point, laboratory rodents fed standard laboratory chow for more than 6 weeks (longer than the typical laboratory experiment) develop hyperphagia, obesity, and insulin resistance (Martin et al., 2010). This process can be accelerated by high-calorie diets, but it occurs even in the animals fed standard laboratory chow ad libitum. In summary, food intake and body weight must rise and fall to meet the demand for a continuous supply of metabolic fuels (reviewed by Friedman, 2008).
Why is there so much fat storage? For one, lipid and glycogen stores provide a sink for any potentially damaging levels of glucose and fatty acids in circulation. Excess glucose, for example, is toxic to the nervous and circulatory system. Most vertebrate species have the ability to remove glucose from circulation and transform it into glycogen and triglycerides, which can be stored in tissues. When glucose is safely locked away in these tissues, storage molecules delay the acute oxidative damage associated with hyperglycemia (excess glucose in circulation; Vincent et al., 2004). In addition, in times of high energetic demand, the storage molecules can be broken down to supply precious fuels. Glycogenolysis and lipolysis are critical sources of energy whenever food is not being ingested. On a day-to-day basis, this includes periods of sleep, mating, and parental care. On a long-term basis, this includes seasonal or unexpected food shortages.
To gain weight and to create the necessary safety net for future food shortages and high energetic demands, control of ingestion involves not only satiation (termination of meals) and satiety (inhibition of long-term food intake), but also appetition, the process whereby food intake is enhanced, for example by experience with highly palatable, calorically dense foods. The following discussion therefore covers peripheral–central integration and satiation, satiety, and appetition.
Meals cannot go on forever. Satiation is important because animals must engage in many important activities other than eating food. Reproductive activities are not the least of these. Termination of meals is accomplished in part by communication between the digestive system and the CNS. When food is ingested, three types of satiation signals are created: mechanical, nutrient-related, and chemical. Mechanical signals are created by distension of the stomach, which activates receptors on vagal afferent neurons. Vagal cell bodies are located in the nodose ganglion and project to neurons in subnuclei of the NTS (reviewed by Loewy, 1990; Schwartz, 2018). The stomach contents are emptied into the intestines at a rate determined by the size and type of meal, and the presence of digested food in the small intestine produces another type of signal that reduces food intake in a calorie-dependent manner (McHugh & Moran, 1978). Nutrient-related metabolic signals are produced by chemical interaction with the gut and changes in the availability of oxidizable fuels, and therefore gastric preloads with glucose or lipids decrease food intake. Conversely, peripheral treatment with agents that inhibit the oxidation of glucose and/or free fatty acids increases food intake (reviewed by Friedman, 2008; Ritter et al., 2019). Ultimately, the critical peripheral signal might be the availability of ATP or the ratio of ATP to the other adenine nucleotides, which is affected by the availability of oxidizable fuels and is transmitted vagally to the caudal hindbrain (reviewed by Friedman, 2008). Some of the greatest gaps in our knowledge are related to the specific nature of the metabolic stimuli, the location of their detectors, and the function and relative importance of the different signals.
Different fuels might be detected via different detectors. Detection of changes in ATP likely occurs in the hepatic portal vein (Friedman, 2008; Friedman et al., 2005). Availability of glucose can be detected by specific groups of highly sensitive cells in the hindbrain, a circumventricular area with access to circulating metabolic fuels (Ritter et al., 2000). In addition, the reduction in food intake in response to nutrient signals involves hormonal signals from the stomach and intestine, which include increases in amylin, cholecystokinin (CCK), enterostatin, pancreatic peptide YY (PYY), glucagon-like peptide-1 (GLP-1), gastrin-releasing peptide (GRP), obestatin, and oxyntomodulin (reviewed by Cummings & Overduin, 2007). Concomitantly, peripheral treatment with any one of these inhibits food intake. There is a gap in our knowledge of the mechanism by which energy deficits lead to changes in levels of hormone secretion. Another important area of future research is how peripheral hormones and neuropeptides cause changes in the disposition of metabolic fuels and can act as modulators of the metabolic stimulus.
For the most part, ending meals early results in a compensatory decrease in intermeal interval, thereby preventing the loss of body fat that might otherwise be expected to result from smaller meals (reviewed by Schwartz, 2018). In other words, the meal-ending mechanisms have so far not provided a useful target for reversing obesity. More recent experimental results implicate the vagus nerve in processes other than meal termination, such as thermogenesis and glucose homeostasis, and these processes play an equal if not more important role in the development of obesity or leanness (reviewed by Schwartz, 2018). Perhaps more important, mechanisms that end meals have other critical functions. For example, the termination of meals is typically a prerequisite for engaging in other behaviors that increase reproductive success and the genetic contribution to future generations (reviewed by Schneider et al., 2013).
In any case, the motor program for eating is affected by three general types of satiation signals, mechanical, nutrient, and hormonal. These signals are relayed by different pathways. The signals are received by gastrointestinal and hepatic vagal and/or splanchnic afferents that promote digestion and gastric emptying and inhibit food intake (cause satiation). Signals detected by visceral afferents are conveyed to the CNS by the vagus and splanchnic afferents to the caudal hindbrain, specifically to brain areas in the dorsomedial medulla, the AP/NTS (reviewed by Loewy, 1990; Schwartz, 2018).
In this context, it is worth noting that the forebrain is not necessary for the effects of many peripheral factors on the termination of meals (reviewed by Grill, 2006; Grill & Hayes, 2009). For example, in rats that have all neural communication to the forebrain severed, consummatory ingestive behavior increases in response to peripheral deficits in oxidizable metabolic fuels, such as glucose (glucoprivation), and consummatory ingestive behavior decreases in response to peripheral hormones like CCK, GLP-1, or leptin (Flynn & Grill, 1983; Grill, 2010). When rats lacking all neural communication between the caudal hindbrain and hypothalamus are treated with different doses of a GLP-1R agonist, they show a dose-dependent decrease in food intake and rate of gastric emptying that do not differ from those in neurologically intact control rats (reviewed by Grill, 2010). The effects of GLP-1 are eliminated by vagotomy (Imeryuz et al., 1997). A similar pattern occurs with regard to hunger signals from energy deficit. When glucoprivation or infusions of ghrelin are restricted to the caudal hindbrain, food intake increases (Faulconbridge et al., 2003; Ritter et al., 1981), and when leptin treatment is restricted to the caudal hindbrain, food intake decreases (see Skibicka & Grill, 2009, and reviewed by Grill, 2010). Receptors for leptin and ghrelin abound in the caudal brainstem. In the context of meal termination, it is worth noting that the AP/NTS is a circumventricular organ, lies outside the blood–brain barrier, and has glucose-sensitive neurons and neurons with receptors for gut hormones. The effectors for eating are close by. The physical act of eating involves licking, chewing, and swallowing. These processes are controlled by muscles of the face, jaw, and tongue, which are innervated by the lower brainstem, including the NTS (Travers, 2015). Given that the caudal hindbrain can detect levels of glucose, controls licking, chewing, and swallowing, and receives neural input from the vagus and splanchnic nerves and hormonal input from the periphery, this area is a strong candidate for the integration of multiple signals (reviewed by Grill, 2010). It is likely that these signals are important not only for control of hunger for food, but also for desire for sex.
It is clear that the forebrain receives input from the viscera via the hindbrain, and many mid- and forebrain areas eventually participate in termination of meals. Mid- and forebrain areas have receptors for various gut peptides that affect meal size, and many of these peptides are synthesized and released within the brain in addition to being released in the gut. For example, the PVH receives projections from the caudal hindbrain via the parabrachial nucleus and parallel projections (Loewy, 1990). The hypothalamic area that has received by far the most attention, however, is the arcuate nucleus (Barsh & Schwartz, 2002; Cowley et al., 2001). The arcuate nucleus is a ventral, circumventricular brain area reciprocally connected to the PVH and caudal hindbrain. The arcuate nucleus is diverse, but contains two dense populations of cells that have received a great deal of attention. One arcuate population synthesizes proopiomelanocortin (POMC), which can be cleaved to produce alpha-melanocyte-stimulating hormone (α-MSH), a melanocortin, which is secreted after meals. α-MSH treatment decreases food intake and increases energy expenditure when infused into the brain (reviewed by Anderson et al., 2016; Vergoni & Bertolini, 2000). Another arcuate population synthesizes both NPY and another melanocortin, AgRP. NPY and AgRP are secreted during fasting and increase meal size when infused into the brain (Alex Thomas et al., 2018, and reviewed by Morton & Schwartz, 2001). For example, arcuate nucleus AgRP cells are activated prior to meals and are required to prevent starvation in adult mice (Luquet et al., 2005). There are redundant and parallel projections of AgRP neurons to many brain areas (Betley et al., 2013), which secrete other orexigenic peptides (e.g., orexin and melanin-concentrating hormone, MCH) and anorectic peptides (e.g., cocaine-and-amphetamine-related transcript, CART; Betley et al., 2013). Thus, it is hypothesized that meal termination requires inhibition of cells that secrete AgRP. Consistent with this idea, meals are terminated and these AgRP cells are silenced by gastric infusions of either glucose, lipids, amino acids, amylin, CCK, or PYY or a cocktail of the latter three hormones (Su et al., 2017). Thus, the termination of meals can be linked to calorie-specific signals from the periphery to neural activation in the arcuate nucleus of the hypothalamus (most likely via vagal and/or splanchnic afferent projections through the caudal hindbrain). Of note, termination of meals by this mechanism might be expected to promote reproduction, indirectly by decreasing interest in food, and directly by preventing the well-known inhibitory effects of AgRP on reproductive processes (Dietrich & Horvath, 2012; Egan et al., 2017; Padilla et al., 2017).
Hunger and Satiety
Hunger and the initiation of eating are, at least in part, adaptive responses to a deficit in the availability of internal fuels for the formation of ATP. Cells in the CNS use glucose as the primary fuel and, compared to the peripheral organs, the brain has a very low capacity for glycogen storage. Thus, low levels of oxidizable glucose—glucoprivation—triggers an emergency counterregulatory response that requires central and peripheral communication. This survival response is clearly a purview of the autonomic nervous system, but in addition, it involves the motor control of eating, courtship, and sexual behavior. In studies of the sympathoadrenal response, food intake, and sex behavior, glucoprivation can be induced by agents like 2-deoxy-d-glucose (2DG), which inhibits glycolysis and can be administered in periphery or in the brain. A similar lack of available glucose is induced by treatment with hypoglycemia-inducing doses of insulin. The response to glucoprivation or hypoglycemia involves sympathetic activation of the adrenal medulla to promote the secretion of epinephrine, which in turn stimulates secretion of glucagon from the pancreas. The role of glucagon is to mobilize glucose from stored glycogen in muscle and liver. In addition, glucoprivation promotes the secretion of glucocorticoids from the adrenal cortex. Increases in the levels of glucocorticoids increase lipolysis and mobilization of fatty acids, which can be used for fuel in the periphery, sparing fuel for the brain. Finally, glucoprivation increases compensatory increases in food intake to increase incoming glucose concentrations (reviewed by Ritter et al., 2011), without increases in plasma leptin concentrations (Barb et al., 2001), and, as is discussed below, inhibits sex behavior. Glucoprivation is detected by cells in the dorsomedial and ventrolateral medulla (Ritter et al., 2019). The ventrolateral medulla contains the most glucose-sensitive cells. It must be noted that several forebrain areas are somewhat glucose sensitive, although not as sensitive as hindbrain cells. It is important to realize, however, that not all glucose-sensitive neurons are involved in counterregulatory response, and the forebrain glucose-sensitive cells are most likely involved in other functions, such as neuroprotection (Levin et al., 1999). Highly glucose-sensitive cells in the ventrolateral medulla send catecholaminergic projections to the PVH. These projections can be selectively destroyed by “DSAP lesions,” wherein a toxin (saporin) is directed at nondopaminergic cells that express the enzyme necessary for synthesis of epinephrine and norepinephrine (the enzyme is dopamine beta hydroxylase). DSAP experiments show that catecholaminergic projections from glucose-sensitive cells in the ventrolateral medulla are necessary for all responses to glucoprivation, including increases in epinephrine secretion, glucocorticoid secretion, sex behavior, and food intake (reviewed by Ritter et al., 2019). Selective activation of this same catecholaminergic pathway is sufficient to induce all counterregulatory responses (reviewed by Ritter et al., 2019). Of note, the critical signal is generated by a change in oxidative metabolism, not in glucose concentrations per se. For example, treatment with 2DG increases circulating levels of glucose, increases food intake, and provokes a counterregulatory increase in glucocorticoid and epinephrine secretion. The response to 2DG is therefore a response to decreased glucose metabolism, not decreases in glucose in circulation. The glucoprivic circuitry is an excellent example of the bidirectional communication between brain and periphery. In this case, the drop in glucose oxidation in peripheral circulation is detected in the circumventricular areas of the hindbrain, and the drop in glucose oxidation activates an endocrine cascade that begins in the hindbrain, alters a central neural circuit, and leads to changes in peripheral hormone secretion from the adrenal gland.
In addition, hunger and eating are elicited by lipoprivation, i.e., decreases in the oxidation of free fatty acids by treatment with mercaptoacetate (MA), methyl palmoxirate (MP), or etomoxir (Friedman & Tordoff, 1986; Friedman et al., 1986; Horn et al., 2004; Ritter & Taylor, 1989). Conversely, increasing the availability of free fatty acids decreases food intake (Aja et al., 2008; Loftus et al., 2000). Lipoprivic agents have potent and reliable effects on food intake without decreasing plasma leptin concentrations (Hudson et al., 2010). The eating response to lipoprivic agents is exaggerated in animals that are more dependent on fatty acids for fuels. For example, food intake in response to MP or MA is greater in rats that have been food deprived (and are therefore getting their oxidizable fuels via lipolysis and fatty acid oxidation), treated with a glucoprivic agent, or fed a diet high in fat (Friedman & Tordoff, 1986; Friedman et al., 1986). Lipoprivic, but not glucoprivic overeating is mediated by vagal afferents from viscera to the caudal hindbrain (Ritter & Taylor, 1990).
The peripheral tissues oxidize either glucose or free fatty acids, and therefore it is possible that central processes are activated by decreases in the overall availability of fuels or substrates that are synthesized downstream. In fact, many years of work on metabolic control of food intake is consistent with the idea that food intake is controlled by changes in the availability of oxidizable fuels and the metabolic sequalae, such as the availability of ATP (Friedman, 1998; Friedman et al., 1999; Ji & Friedman, 1999; Ji et al., 2000; Koch et al., 1998; Rawson et al., 1994; Rawson & Friedman, 1994). Many of these signals clearly originate in the periphery (Friedman et al., 2005; Horn et al., 2001; La Fleur et al., 2003) and activate canonical food intake circuits in the CNS (Horn et al., 1999).
So-called satiety signals that influence ingestion might be created by changes in adiposity and diet that occur over longer time periods (periods that are longer than a single meal). Many of these signals alter meal size, but their effects can lead to obesity or leanness. One hormonal candidate is leptin, a protein hormone secreted from adipocytes and other tissues after meals and in proportion to overall levels of adiposity (Frederich et al., 1995; Maffei et al., 1995). Leptin treatment was first touted as a satiety hormone because it has clear inhibitory influences on food intake as well as stimulatory effects on fuel oxidation and energy expenditure in a wide range of species (Zhang et al., 1994, and reviewed by Ahima & Flier, 2000, and Reidy & Weber, 2000). It is important to note, however, that in most instances chronically high levels of leptin are ineffective in decreasing food intake, maintaining a low body weight, and curtailing obesity (reviewed by Flier & Maratos-Flier, 2017). The higher the level of adiposity, the higher the level of plasma leptin, and most species studied rapidly develop a resistance to leptin inhibition of food intake and body fat accumulation. Contrary to the idea that the main role of leptin is to decrease meal size and thereby prevent obesity, most data support the idea that the fall in plasma leptin concentrations is part of an adaptive response to starvation that includes intensified hunger and increased food intake, elevated secretion of glucocorticoids, and inhibited reproduction (Flier, 1998). These responses to starvation can be temporarily prevented by peripheral or central treatment with leptin, whereas continued treatment with leptin fails to prevent overeating and body fat accumulation (reviewed by Flier, 1998; Flier & Maratos-Flier, 2017). It is often posited that signals from increasing adiposity produce satiety and prevent obesity, but this notion is based on conflicting evidence. By contrast, a large body of data consistently supports the hypothesis that many redundant and synergistic signals from food deprivation and loss of adiposity promote hunger, foraging, hoarding, eating, and body fat accumulation (Schwartz et al., 2003). Not the least important of the energy-conserving responses is the inhibition of the HPG system and reproductive behavior, as is discussed below.
Receptors for leptin are distributed in the caudal hindbrain, midbrain, many peripheral tissues (e.g., pancreas, liver, adrenal, and gonads), and hypothalamus (reviewed by Cottrell & Mercer, 2012). A great deal of research is focused on effects of leptin on the orexigenic (NPY/AgRP) and anorectic (POMC) cells in the arcuate nucleus of the hypothalamus (reviewed by Barsh & Schwartz, 2002, Cowley et al., 2001, and Yeo & Heisler, 2012). Over the years, the accumulated evidence suggested a role for these neurons in glucose homeostasis, but the evidence for a role in satiety is inconsistent (reviewed by Williams & Elmquist, 2012). In various mouse models, arcuate nucleus leptin signaling is required for glucose homeostasis, whereas elimination of arcuate leptin signaling has only minimal effects on food intake and body weight. This is true whether leptin signaling is ablated in either the POMC cells alone or the arcuate alone. Similarly, in leptin-receptor-mutant mice, arcuate reactivation of leptin receptors is not sufficient to reverse obesity. It is interesting in light of the intense focus on the arcuate nucleus that leptin action in the caudal hindbrain is sufficient for significant decreases in food intake in rats. It is also interesting that, despite clear decreases in food intake, body weight is maintained in these rats (reviewed by Grill, 2010). Dense populations of leptin receptors in the caudal brainstem and ventral premammillary nucleus suggest a role for leptin in extrahypothalamic areas in control of ingestion and reproduction (see Donato et al., 2009). Together, these results show that leptin can be characterized as a central modulator of peripheral energy disposition (which includes the energy available for reproduction). In the academic laboratory, pharmaceutical development laboratory, and clinical trials, leptin fails to meet the standards of an effective “satiety signal” or a “regulator” of body weight.
Ghrelin is a gut hormone secreted by the oxyntic cells of the stomach and is implicated in hunger and increased food intake. Ghrelin levels are lowest after meals, and circulating levels of ghrelin gradually rise as the duration of fasting increases. Treatment with ghrelin increases appetite, food intake, and body fat accumulation (reviewed by Cummings, 2006; Abizaid & Horvath, 2012). Receptors for ghrelin reside in the peripheral viscera, hindbrain, midbrain, and forebrain. Ghrelin therefore is often characterized as a “hunger” hormone, or an orexigen, but it is much more. Ghrelin-secreting cells of the stomach produce intrinsic rhythmic output that serves as a signal in the brain and periphery to entrain food-anticipatory behavior (LeSauter et al., 2009). The appetite for food and the propensity to eat are not simply responses to energy deficit. Rather, they are influenced by central and peripheral circadian clocks and experience with meal timing. Thus, the role of ghrelin in circadian entrainment of eating is an important area for future investigation.
Most readers will have noticed that many individuals seem predisposed toward overeating and body fat accumulation. One hypothesis is that satiation signals that terminate meals might be overridden by appetition, the process whereby future food intake is increased after experience with a flavor associated with a caloric value (Sclafani, 2013). For example, when novel flavors are associated with a peripheral metabolic stimulus, such as an increase in the availability of glucose, central synapses are potentiated in brain circuits like the mesolimbic dopamine system. Ghrelin is implicated (Skibicka et al., 2013), but, in mice, ghrelin is not required for appetition (Sclafani et al., 2015). Recent evidence shows that the connection between the novel flavor and the availability of fuels requires the detection of fuels in the viscera. In these experiments, rats were conditioned to drink a nonnutritive sweet cherry flavor by pairing of that flavor with infusion of glucose directly into the stomach or upper intestine (the duodenum). After pairing of the conditioned flavor (cherry) with the unconditioned stimulus (duodenal glucose infusion), the rats were allowed to choose between flavored and unflavored solutions. After presentation of the cherry flavor paired with the glucose infusion, laboratory rats invariably preferred the flavor that had been paired with the glucose infusion. The conditioning process was accompanied by increased dopaminergic activity in the mesolimbic system (Han et al., 2016). Striatal dopamine release is induced by portal-mesenteric glucose infusion, but not a similar jugular infusion, which suggests that the primary signal for condition is not systemic, but rather specific for glucose absorption in the duodenum. Conditioned flavor preference does not require either the vagal or splanchnic nerves to be intact, but conditioned flavor preference requires an intact upper intestine near the exit of contents from the stomach (the duodenum-jejunal juncture). For example, gastric bypass surgeries that prevent nutrients from reaching the duodenum-jejunal area decrease the appetite for food and prevent conditioned preferences for sweet flavors. Infusion of glucose, but not nonnutritive control solutions, into the duodenum-jejunal area increases dopamine release in the ventral striatum of the brain, and the effect on dopamine release is absent in animals with duodenal-jejunal bypass surgery (reviewed by Shechter & Schwartz, 2016). Thus, learning to love highly palatable, calorically dense foods involves linked mechanisms in brain and periphery. Research on peripheral–central communication will be critical for understanding overeating and might aid in preventing or reversing obesity.
In summary, ingestive behavior is a multifaceted process that can be parsed into satiety, satiation, and appetition, and these facets are controlled by a distributed neural network that involves the autonomic nervous system, caudal hindbrain, midbrain, and forebrain in communication with the peripheral organs via metabolic and humoral factors that provide information about the availability of oxidizable glucose, free fatty acids, levels of adiposity, and times since the last meal. Ingestion has many components that serve various functions in different environmental contexts. Direct detection of a glucoprivic emergency can occur in the hindbrain and initiate a four-pronged counterregulatory response that includes increases in food intake. By contrast, the caloric information that terminates meals is detected in the gut and is carried to the brain by the vagus and splanchnic nerves. In addition, important signals are generated by changes in ATP relative to the other adenine nucleotides, and changes in ATP are proxy for overall fuel availability from the digestive system and storage as glycogen or lipids in adipose tissue. Detection of overall fuel availability is hypothesized to occur in the hepatic vagus and the signal is carried to the brain by the vagus. From the vagus, the signals are sent via the caudal hindbrain to the CNS areas involved in control of ingestion that matches intake to energetic requirements. Finally, information about caloric availability involved in appetition might be detected at the duodenal-jejunal juncture, carried humorally or by the vagus, and received eventually by AgRP neurons in the CNS. This system is hypothesized to be involved in learning the sensory cues associated with calorically dense food. There is no consensus about whether or how these different signals might lead to “regulation of body weight” or “prevention of obesity”; however, there is a striking degree of overlap among the systems that affect ingestion and those that affect reproduction.
Integration of Reproduction and Energy Balance
It is no coincidence that virtually every chemical messenger and metabolic signal mentioned so far has effects on both reproduction and energy balance. Energy balance refers to energy intake, storage, and expenditure. The energy expended on reproduction is substantial in both males and females of many species, but reproduction is particularly expensive for female mammals because of the high energetic cost of lactation (reviewed by Gittleman & Thompson, 1988). The energy-balancing systems seen in organisms today are the result of the forces of evolution, and one important evolutionary force is natural selection. For heritable traits that have been under natural selection, those most likely to appear in successive generations are those that were proven adaptive. Adaptive traits are those that confer survival and reproductive success in a particular environment. Traits that are directly related to reproductive success include fertility, fecundity, and behaviors related to courtship, mating, and parenting. Thus, the energy-balancing system must contain two types of mechanisms. The first type of mechanism ensures anticipatory overeating and body fat accumulation prior to reproduction and inhibits eating for periods of time long enough to engage in courtship, mating, and offspring care. The second type of mechanism allows for inhibition of reproduction and stimulation of ingestion whenever environmental energy availability is critically low (reviewed by Bronson, 1989; Schneider et al., 2013). Reproduction is inhibited whenever energetic demands cannot be met by increased energy intake. In the laboratory, energetic challenges include food deprivation or restriction, treatment with pharmacological inhibitors of fuel oxidation, or treatment with hormones that induce hypoglycemia. Thus, mechanisms that control ingestive behavior must do more than keep body weight at a healthy and fashionable set point. They set behavioral priorities to optimize reproductive success in environments where energy availability fluctuates or is unpredictable (Bronson, 1989; Schneider et al., 2013).
The reproductive system is responsive to energy availability at many different stages of the life cycle. The reproductive system can be inhibited prior to puberty, in adulthood, prior to mating, during pregnancy, and during lactation. At these different stages, the effects occur at many levels, including the hypothalamic GnRH cell, the anterior pituitary cells that secrete LH, the gonadal cells that secrete gonadal steroids, and CNS areas that express steroid receptors. When signals for energy deficit inhibit the hypothalamic GnRH cell, the consequence is immediate inhibition of LH secretion and eventual decreases in gonadal steroid secretion.
The HPG System, Puberty, and Estrous Cyclicity
Whereas motor control of food intake lies in the brainstem, the primary effector for reproduction is the GnRH pulse generator, now thought to be located in the arcuate nucleus kisspeptin cells (at least in mice; Clarkson et al., 2017). The GnRH pulse generator is thought to be the primary locus of effect because, in food-deprived females, the percent of activation GnRH cells is reduced (Berriman et al., 1992), and the entire neuroendocrine cascade, including estrous cycles, ovulation, and successful fertilization, can be restored by infusion of species-specific frequency of pulses of GnRH (Armstrong & Britt, 1987; Bronson, 1986; Campbell et al., 1977; Manning & Bronson, 1991). Thus, food deprivation preserves pituitary and gonadal responsiveness while inhibiting GnRH secretion. This inhibitory mechanism might involve increased steroid negative feedback in kisspeptin cells of the mediobasal hypothalamus and/or RFRP-3 cells from the DMH that project to GnRH cells (Benton et al., 2018; Castellano et al., 2010; De Bond & Smith, 2014; Fergani et al., 2014; Klingerman et al., 2011; Ladyman & Woodside, 2014; Messager, 2005; Nestor et al., 2014; Sanchez-Garrido & Tena-Sempere, 2013; Schneider et al., 2017; Smith et al., 2010a; Tena-Sempere, 2010; Wahab et al., 2013).
Direct effects on other components of the HPG system are possible, especially if the metabolic challenge is prolonged and/or severe. For example, long-term starvation can decrease the pituitary response to exogenously applied GnRH and gonadal steroid secretion in response to gonadotropin treatment (Knuth & Friesen, 1983).
The mechanisms that control reproduction are sensitive to the same signals that control food intake, especially the nutrient-related signals generated by changes in the availability of oxidizable fuels and peripheral hormone secretion. In addition, the signals for reproductive inhibition are detected in a similar location and transmitted by similar pathways as signals for food intake.
First, body fat can protect against the inhibitory effects of fasting on estrous cyclicity by virtue of the oxidizable free fatty acids that are released during lipolysis. Fasting-induced anestrus (inhibition of the estrous cycle by 48 hours of food deprivation) is induced in lean female Syrian hamsters, but not in females that were fattened prior to food deprivation. This result suggests that estrous cycles are protected by the ability to oxidize free fatty acids mobilized from the lipids in adipose tissue. Consistent with this hypothesis, estrous cycles are not protected from fasting-induced anestrus when the ability to oxidize fatty acids is blocked by treatment with an inhibitor of fatty acid oxidation (lipoprivation; Schneider & Wade, 1990). In fasted hamsters, estrous cycles are protected by feeding either pure sugar or pure fat, but not by distension of the gut with nonnutritive filler (Szymanski et al., 2009).
The critical fuel required for normal estrous cyclicity depends on the species and level of the reproductive system affected. In ad libitum-fed Syrian hamsters, estrous cycles are inhibited by simultaneous glucoprivation plus lipoprivation and by glucoprivation alone, but not by lipoprivation alone (Schneider & Wade, 1989). In adult rats, pulsatile LH secretion is inhibited in a dose-dependent manner by acute glucoprivation alone (I’Anson et al., 2003a) or lipoprivation alone induced by intraperitoneal or cerebroventricular injection (Sajapitak et al., 2008; Shahab et al., 2006). Similarly, in prepubertal lambs, pulsatile LH secretion is inhibited by intracerebral glucoprivation alone (Foster et al., 1995). As with food intake, the effects are not mediated by circulating levels of a particular fuel (e.g., glucose), but by the availability of oxidizable fuels. For example, treatment with 2DG causes compensatory increases in the circulating levels of blood glucose even as it blocks glycolysis. Despite high levels of circulating glucose, 2DG treatment inhibits estrous cycles and pulsatile LH secretion in female rodents, sheep, and pigs. Thus, the critical signal comes from less glucose metabolism and/or less oxidizable glucose, not lower levels of glucose in circulation. Furthermore, glucoprivic treatments that inhibit pulsatile LH secretion do not produce significant changes in pulsatile leptin secretion; thus, a decrease in leptin cannot explain glucoprivic inhibition of reproduction (Barb et al., 2001). Furthermore, after food deprivation-induced inhibition of pulsatile LH secretion or estrous cyclicity, LH pulses and estrous cyclicity resume rapidly after refeeding with no change in plasma leptin concentrations in female hamsters and ewes (Schneider et al., 2000; Szymanski et al., 2007). Pulsatile LH secretion can be restored temporarily in food-restricted females by mesenteric infusion of free fatty acids, suggesting that the mechanisms that control LH pulses are directly affected by the availability of oxidizable metabolic fuels (Szymanski et al., 2011). Thus, although some details differ, the mechanisms that control food intake and reproduction are both responsive to metabolic fuel oxidation and its downstream biochemical effects.
Like glucoprivic control of food intake, glucoprivic control of the estrous cycle involves the caudal hindbrain and its catecholaminergic projections to the forebrain. Brain glucoprivation elicits a counterregulatory response that includes increased food intake and inhibition of processes unnecessary for immediate survival. Reproduction is an energetic, long-term investment that can be delayed when energy must be conserved for survival. Treatment with drugs that inhibit the oxidation of glucose inhibits estrous cycles in rats and Syrian hamsters, inhibits pulsatile LH secretion in rats and sheep, and increases cellular activation in the AP/NTS. In hamsters and rats, lesions of the AP/NTS do not inhibit estrous cycles or sex behavior (lordosis), but the lesions prevent the inhibitory effects of glucoprivation on estrous cycles (Nagatani et al., 1995; Schneider & Zhu, 1994). In rats, selective destruction of catecholaminergic projections from the caudal hindbrain to the PVH has no effect on normal estrous cycles, but prevents the glucoprivic inhibition of estrous cycles (I’Anson et al., 2003b). These experiments reveal that glucoprivic control of reproduction is a structural and functional part of the emergency response that increases food intake while conserving energy by inhibiting reproduction.
In addition to direct detection of fuel deficits by the hindbrain, some metabolic signals might be transmitted via the vagus nerve, whereas most signals for reproduction so far do not require an intact vagus. This might be a point of departure for the mechanisms that control meal size and those that control the HPG system. With regard to metabolic control of pulsatile LH secretion in rats and sheep and estrous cycles in Syrian hamsters, most studies show that the effects of fasting or metabolic inhibitor treatment are not blocked by total subdiaphragmatic vagotomy (Schneider et al., 1997a, 1997b). In rats, however, total subdiaphragmatic vagotomy prevents the inhibitory effect of food deprivation on estrous cycles (Cagampang et al., 1992), and it is therefore possible that, depending on the species and reproductive output, signals about energy deficits are carried by the vagus nerve. Together, these data suggest that controls of food intake and controls of reproduction, although overlapping, are somewhat dissociable. Classic, vagally transmitted metabolic signals are required for meal termination, but not for estrous cycles and pulsatile LH secretion. In addition, signals generated by deficits in glucose availability do not require an intact vagus nerve to increase food intake and inhibit these aspects of reproduction.
Reproductive inhibition of estrous cyclicity and the HPG system might involve hormonal signals secreted from adipose tissue, such as a rise in adiponectin and a fall in leptin concentrations (Ahima et al., 1997; Angelidis et al., 2013; Barash et al., 1996; Barbe et al., 2019; Clarke & Henry, 1999; Conway & Jacobs, 1997; Elias & Purohit, 2013; Michalakis & Segars, 2010; Schneider et al., 1997c, 2007). During food deprivation-induced inhibition of the HPG system, plasma leptin concentrations fall, and plasma adiponectin concentrations rise. Inhibition of gonadotropin secretion or delay of puberty occurs when increases in plasma adiponectin or decreases in plasma leptin are experimentally or genetically induced, and these effects can be prevented with leptin treatment (Ahima et al., 1996, 1997; Barbe et al., 2019; Chehab, 2014; Cheung et al., 2001). Peripheral or central treatment with leptin prevents the effects of fasting on pulsatile LH secretion (Henry et al., 2004; Nagatani et al., 1998), but the doses of leptin used might have exceeded those present during basal, ad libitum-fed conditions. In three different model systems of energetic challenge, replacement of leptin at basal physiological levels failed to prevent fasting-induced inhibition of the HPG system (True et al., 2011a). The low circulating concentrations of leptin might provide one inhibitory signal for GnRH secretion, but, if so, the effects likely occur indirectly via kisspeptin and other cells that project to GnRH cells, because GnRH cells lack leptin receptors (Clarke & Smith, 2010; Quennell et al., 2009). It has been noted that there is a dense population of leptin receptors in the ventral premammillary nucleus, which projects to brain areas that control GnRH secretion, and lesions of this area block effects of leptin on LH secretion and pubertal development (reviewed by Donato et al., 2011). An additional effect of leptin might be to disinhibit the negative effects of AgRP on the HPG system; knockout of leptin receptor on AgRP neurons delayed pubertal development, and rescue of leptin receptor only on AgRP cells restored pubertal development (Egan et al., 2017).
Whereas low leptin might contribute to the inhibition of the HPG system during fasting, leptin is not critical for the rapid re-initiation of the HPG system upon refeeding (Schneider et al., 2000; Szymanski et al., 2007). Rapid, temporary re-initiation of gonadotropin secretion occurs in response to infusion of essential free fatty acids into the hepatic portal vein (Szymanski et al., 2011). Furthermore, the stimulatory effects of high concentrations of leptin might depend upon the availability of oxidizable metabolic fuels (Schneider et al., 1998; Wade et al., 1997), as discussed in the final section of this article. Together, these results suggest that the restoration of a healthy reproductive system requires healthy adipocytes that provide not only leptin, but also an abundance of fuels in the form of free fatty acids.
Leptin is not the only hormone that fluctuates with energy availability and affects reproduction. The orexigenic stomach hormone ghrelin is another peripherally secreted hormone implicated in control of reproduction (Babaei-Balderlou & Khazali, 2016; Barreiro & Tena-Sempere, 2004; Burroughs et al., 2018; Egecioglu et al., 2016; Fernandez-Fernandez et al., 2005; Shah & Nyby, 2010). Plasma concentrations of ghrelin are inhibitory for the HPG system (Furuta et al., 2001; Iqbal et al., 2006) and sexual motivation (Burroughs et al., 2018). The effect on the HPG system occurs primarily at the level of kisspeptin control of GnRH secretion but also involves pituitary responsiveness to GnRH (Fernandez-Fernandez et al., 2005).
In addition, the list of peripheral hormones that affect the HPG system includes amylin, bombesin, CCK, PYY, GLP-1, GRP, and oxyntomodulin (Baranowska et al., 2006; Beak et al., 1998; Chmielowska et al., 2005; Comninos et al., 2014; Jeibmann et al., 2005; Michalakis & Segars, 2010; Pinilla et al., 2006; Pinski et al., 1992; Schreihofer et al., 1993). Again, sensitivity to these hormones differs with the species and the reproductive phase (e.g., prepubertal, the time of the estrous cycle, pregnancy, or lactation), and sex differences in response to these hormones is an important avenue for future research.
The same central messengers that stimulate food intake inhibit estrous cycles and the HPG system in females, including AgRP, MCH, NPY, and RFRP-3 (Benton et al., 2018; Canepa et al., 2008; Castellano et al., 2010; Clarke et al., 2009; Dietrich & Horvath, 2012; Egan et al., 2017; Henningsen et al., 2016; Jones et al., 2004; Kalra et al., 1987, 1988; Keene et al., 2003; Khan & Kauffman, 2012; Leon et al., 2014; Qi et al., 2009; Schneider et al., 2017; Skrapits et al., 2015; Wu et al., 2009; Zhang et al., 2012; Zhong et al., 2013). Those that inhibit food intake stimulate reproductive processes, including CART and kisspeptin (Backholer et al., 2009, 2010; Baranowska et al., 2004; Castellano et al., 2010; Crown et al., 2007; Fernandez-Fernandez et al., 2006; Hill et al., 2008; Kriegsfeld, 2006; Parent et al., 2000; Smith et al., 2010a; Tena-Sempere, 2006, 2010; Verma et al., 2014). In most cases, the chemical messengers that inhibit food intake stimulate reproductive processes and vice versa. An exception is orexin, which is stimulatory for both food intake and reproductive processes, possibly owing to its increase in the duration of wakefulness and decrease in the duration of sleep (Backholer et al., 2009; Hoskins et al., 2008; Martynska et al., 2006; Pu et al., 1998).
Pregnancy and Lactation
Pregnancy and lactation are two energetically expensive processes, and their success is linked to increases in energy intake and body weight gain. There are some similarities, but many differences, between pregnant/lactating females and estrous-cycling females. First, the mechanisms differ during pregnancy because gonadotropin support of reproduction is assumed by the placenta, not the anterior pituitary. Metabolic challenges that inhibit LH secretion do not interrupt pregnancy, although effects on offspring might appear at birth, during development, in adulthood, and in future generations. Another metabolic buffer for pregnancy is the maternal resistance to the effects of leptin on food intake and body weight gain. Resistance to the anorectic effects of leptin might be an important adaptation that allows pregnant and lactating female rats to maintain increased food intake and body fat accumulation. The adaptation is achieved in part because the hormones of pregnancy and lactation (prolactin and oxytocin) promote continuous appetite, overeating, and resistance to the weight reducing effects of leptin (Crowley, 2015; Ladyman et al., 2009, 2016; Woodside et al., 2012).
During lactation, the HPG system and estrous cyclicity are blocked, mainly by suckling stimulation from offspring, but also by the increased energetic demand for milk production. As a consequence, the onset of estrous cyclicity can be delayed by food restriction or by the energetic drain of having to feed previously undernourished offspring (Leon & Woodside, 1983; Woodside, 1991; Woodside & Jans, 1995). Unlike effects of food restriction on estrous cyclicity, effects of food restriction on lactation might not involve direct detection of diminished glycolysis or fatty acid oxidation. In lactating rats, the duration of lactational anestrus is prolonged by food restriction but not by treatment with metabolic inhibitors alone or in combination (Abizaid et al., 2001; Abizaid & Woodside, 2002). Thus, lactating females might be buffered from acute decreases in the availability of oxidizable glucose and free fatty acids.
During lactation, females typically shunt available fuels toward milk production, lose body fat, decrease plasma leptin concentrations, decrease the synthesis of POMC, and increase the synthesis of the CNS orexigenic peptides NPY, AgRP, orexin, and MCH (Smith et al., 2010b). Inhibition of pulsatile GnRH secretion is mediated by kisspeptin cells in the arcuate nucleus that project to GnRH nerve terminals in the median eminence (True et al., 2011b). Treatment with leptin at pharmacological levels can decrease the inhibitory effects of lactation and food restriction on estrous cyclicity (Woodside et al., 1998), but restoration of prepregnant levels of circulating leptin is not sufficient to reverse the effects of food restriction on kisspeptin cells in the arcuate nucleus (True et al., 2011c). Thus, low leptin might be a contributing factor to the mechanisms that inhibit GnRH secretion, but not the only factor. The role of NPY is another point of difference between estrous-cycling females and lactating females. Whereas in estrous-cycling females NPY infusion stimulates food intake and body weight gain and inhibits estrous cyclicity, in lactating females, NPY infusion stimulates the onset of the estrous cycle, bringing an early end to the usual period of lactational anestrus (Woodside et al., 2002). The integration of peripheral and central signals during this phase of reproduction is not fully characterized. Although they are less well characterized, they might have been central to the evolution of energy-balancing mechanisms because traits related to birth interval are very closely related to Darwinian fitness. The fitness value of mechanisms that link energy to birth interval might therefore have constrained the evolution of mechanisms in males and estrous-cycling females.
Consummatory Sex Behavior
In addition to the HPG system, the brain mechanisms that control sexual motivation and performance are quite sensitive to energetic status. In laboratory rodent females, sexual performance (the consummatory aspect of sex) is measured by the duration of lordosis, a stiff, arched-back posture that normally occurs in well-fed females within minutes of an encounter with an adult, gonadally intact, sexually experienced male. Lordosis is required for successful intromission by the male and requires priming in the ventromedial hypothalamus (VMH) with estradiol followed 24 to 48 hours later by progesterone. In ovariectomized female rodents treated with estrus-inducing doses of estradiol and progesterone, food deprivation decreases the duration of lordosis (Dickerman et al., 1993). Thus, even in the presence of estrus-inducing hormones, female sexual performance is diminished by prior food deprivation. This is likely related to food deprivation-induced decreases in the number of ER-α receptors in the VMH. These experiments employed relatively severe metabolic challenges (total food deprivation), but in nature these responses to lack of food might be adaptive in the long run if reproductive responses return when food becomes available.
In ovariectomized Syrian hamsters treated with estradiol plus progesterone, lordosis duration is unaffected by glucoprivation or lipoprivation alone, but is significantly decreased by either food deprivation or simultaneous glucoprivation plus lipoprivation in ad libitum-fed females (Dickerman et al., 1993). Lesions of the AP/NTS, but not vagotomy, prevent both the inhibitory effects of glucoprivation plus lipoprivation on lordosis in ovariectomized hamsters treated with estradiol and progesterone and the effects of glucoprivation plus lipoprivation on ER-α in the VMH (reviewed by Wade & Jones, 2004). Ingestion and reproduction are similar in their dependence on the AP/NTS, but different in that reproduction does not depend upon the vagus.
Leptin is stimulatory and inhibitory for estrous behavior in ovariectomized females treated with estrus-inducing doses of estradiol and progesterone (Wade et al., 1997). Leptin treatment lengthens lordosis duration in ad libitum-fed females and decreases lordosis duration in food-deprived females. As will be noted in the final section of this article, these results are consistent with the view that metabolic fuel availability and leptin interact to influence reproductive outcomes.
In addition, CRH can be inhibitory for both ingestion and estrous behavior (reviewed by Wade & Jones, 2004). In most species examined, AgRP, NPY, kisspeptin, and RFRP-3 have opposite effects on reproductive behavior and ingestion, i.e., if they are stimulatory for ingestion, they are inhibitory for reproduction (Clark et al., 1985; Kalra et al., 1988; Keene et al., 2003; Marin-Bivens et al., 1998).
Increases in levels of ghrelin are inhibitory for sex behavior in female mice (Bertoldi et al., 2011) but have the opposite effects in male mice depending on the site of action (Egecioglu et al., 2016; Hyland et al., 2018). In the field of metabolic control of reproduction, most work is focused on female mammals, but sex differences in the response to metabolic fuels and peripheral hormones have ecological and evolutionary implications. In some mammalian species, males are less sensitive than females to energetic challenges, and if those species are short-lived, the males are likely to increase reproductive efforts in response to energetic challenges because reproductive success cannot be optimized by delaying reproductive efforts (reviewed by Schneider et al., 2013). In any case, the sex differences in response to ghrelin and other factors, such as RFRP-3 (Ancel et al., 2012), might underlie differential sensitivity of males and females to energetic challenges.
Appetitive Behavior and Sexual Motivation
Even mild metabolic challenges affect sexual motivation (the appetitive aspect of sex behavior). Appetitive behavior is defined as the percurrent behaviors that lead to consummation of the desire for the object of the behavior (Craig, 1917; Everitt, 1990). In laboratory rodents, lordosis is the consummatory aspect of copulation, whereas sexual desire and interest are reflected in appetitive behaviors, including vaginal scent marking (which attracts mating partners), approach to an opposite-sex conspecific, and a preference for sexual stimuli vs. food stimuli. Appetitive behavior is more sensitive than consummatory behavior to energetic challenges and is inhibited by dieting or food restriction long before effects on plasma levels of ovarian hormones are significant.
As noted early in this article, appetitive sex behavior of females is inhibited by mild metabolic challenges, such as restricting daily food intake by 25% for one week in Syrian hamsters (Klingerman et al., 2010; Schneider et al., 2007). This inhibition occurs even though plasma levels of estradiol and progesterone are unaffected. Inhibition of appetitive sex behavior by mild energetic challenges involves increases in activation of cells that secrete RFRP-3 in a dose-dependent manner (Benton et al., 2018; Klingerman et al., 2011; Schneider et al., 2017), and intracerebral treatment with RFRP-3 inhibits appetitive, but not consummatory, sex behavior in ad libitum-fed females (Benton et al., 2018; Piekarski et al., 2013). The sensitive response of the mechanisms that control appetitive sex behaviors might prevent investment in reproduction prior to the accumulation of adequate food reserves. In fact, the same treatments that inhibit appetitive sex behavior in hamsters tend to increase food hoarding but not food intake (Benton et al., 2018; Klingerman et al., 2010, 2011). This model system has been used to explore hormonal–energetic interactions.
Treatment with leptin during food deprivation or food restriction prevents reproductive inhibition at many stages, including courtship, sexual solicitation, and the choice between food and sex (see Schneider et al., 2007). Ad libitum-fed female hamsters prefer to visit adult male hamsters instead of food on every day of their estrous cycle, whereas mildly food-restricted females confine their visits to males to the fertile, estrous period of the ovulatory cycle. Treatment of food-restricted females with leptin (Schneider et al., 2007) or the hypothalamic/gut protein prokineticin (Burroughs et al., 2018) reverses the effects of food restriction, causing a significant increase in preference for a male hamsters vs. food. Conversely, ad libitum-fed females treated with ghrelin or RFRP-3 decrease visits to males and increase visits to food (Benton et al., 2018; Burroughs et al., 2018). These results serve as a reminder that in nature, food intake does not occur in isolation from potential mating partners and reproduction does not take place in the context of unlimited food availability. Thus, various hormones and metabolic signals work in the context of behavioral priorities.
Very few investigators study the choice between food and a mating partner, but this phenotype (the choice itself) might be closely linked to the brain–periphery mechanisms that control meal size. One of the most important functions of the termination of meals is to free time for reproductive activity. If so, it might be predicted that the choice between food and a mating partner might be swayed toward food by pretreatment with glucoprivic or lipoprivic agents, and swayed toward sex by infusion of glucose, lipids, amino acids, amylin, CCK, GLP-1, or PYY(3-36). The roles of the vagus and caudal hindbrain in metabolic control of motivation are unknown.
In summary, effects of energy deficits on reproduction occur at all levels of the HPG system; in addition, they have direct effects on sexual motivation, courtship, mating, and parental behavior (Table 1). Each of these different effects might be mediated by different types of metabolic stimuli and brain circuits. Each of these circuits might be more or less overlapping with circuits for ingestion. For example, in ovariectomized females treated with estrus-inducing doses of estradiol and progesterone, lordosis duration can be shortened by simultaneous treatment with inhibitors of glucose and fatty acid oxidation, but not by glucoprivation alone, whereas ingestion, the HPG system, and the estrous cycle are inhibited by treatment with glucoprivation alone. Our understanding of the adaptive function of satiation factors might be facilitated by future research on the effects of these factors on the choice between food and sex.
Integration of Fuels and Hormones in Ingestion and Reproduction
Signals from the periphery reach the brain via neural and humoral routes and provide information about energy availability. This information sets behavioral priorities to optimize survival and reproductive success in environments where energy availability fluctuates. In environments with low food availability and high energetic demands, changes in the periphery reach the brain to make food intake a priority over reproductive activity. When ingestion is studied in the laboratory divorced from reproductive context, the expectation seems to be that these mechanisms “regulate” food intake to maintain a particular body weight. For example, one hypothesis posits that satiation signals are modulated by adiposity signals so as to decrease meal size and body fat accumulation (Smith, 1996). It is unlikely, however, that ingestive behavior evolved in a vacuum to produce individuals that all maintain a healthy and fashionable body weight. Evolutionary adaptation is closely related to reproductive success, and reproductive processes are energetically expensive. For females of many species, successful reproduction requires a period of energy storage prior to courtship, copulation, and parental care. The mechanisms of appetition and the ability to overeat and store energy as adipose tissue are required for survival and reproductive success during famine or seasonal changes in food availability and ambient temperature. Thus, the separation of the reproductive system from the ingestive system is an artificial construct, as is the separation of the CNS from the peripheral endocrine system. Peripheral–central mechanisms are likely to have increased survival in environments in which food and potential mating partners coexisted simultaneously. In this context, the most relevant question is not “Do adiposity signals and meal termination signals interact?” but, “How are humoral and metabolic signals integrated to set behavioral priorities?” For example, energetic challenges deplete the availability of specific fuels, and it is therefore possible that humoral signals for hunger are amplified and humoral signals for sexual motivation are modulated by a metabolic deficit. Indeed, when leptin-treated rats are simultaneously treated with lipoprivic agents, leptin fails to decrease food intake (Hudson et al., 2010). Similarly, when female Syrian hamsters are treated with either lipoprivic or glucoprivic agents, leptin fails to prevent fasting-induced inhibition of the estrous cycle, even when the doses of the gluco- and lipoprivic agents are too low to inhibit estrous cycles on their own (Schneider et al., 1998). In male mice, pretreatment with glucose decreases ghrelin-induced ingestive behavior and CNS NPY expression, whereas pretreatment with a glucoprivic agent potentiates these ghrelin-induced effects (Lockie et al., 2018). Whether ghrelin and metabolic fuels interact in the same way to control reproduction is under investigation. If so, this would provide more evidence that the level of metabolic fuel availability can interact with hormonal action on behavior. The integration of metabolic and hormonal signals is an important area of research for the future.
It is possible that humoral and metabolic signals act via parallel pathways; however, another possibility is that hormones act intracellularly to alter the metabolic stimulus (Hwa et al., 1997; Minokoshi et al., 2002; Pinkney, 2014; Reidy & Weber, 2000; Steinberg et al., 2002). The latter possibility might occur when hormones and fuels both affect intracellular metabolism in the same cell. This provides a mechanism that might explain different effects of hormones depending on the availability of oxidizable fuels and/or ATP. For example, in the CNS, hormones and oxidizable fuels affect intracellular enzymes, such as AMP-activated protein kinase (AMPK). AMPK is a ubiquitous and evolutionarily ancient enzyme that, when activated, switches off ATP-consuming pathways in response to a drop in the ratio of ATP to AMP. AMPK is activated by deficits in ATP in response to food deprivation or in response to treatment with inhibitors of fuel oxidation. In the brain, AMPK is also phosphorylated and activated in response to treatment with orexigenic hormones, such as ghrelin. AMPK is inactivated by peripheral or central infusion of glucose, or by treatment with anorectic hormones, such as insulin or leptin (reviewed by Lim et al., 2010). AMPK is therefore a potential site of integration of metabolic signals, and, concomitantly, AMPK mediates effects of glucose and ghrelin on reproduction. For example, in juvenile rats, food restriction delays the onset of puberty and phosphorylates and activates hypothalamic AMPK. In immature female rats, activation of AMPK causes a significant delay in puberty onset. The effect likely occurs in the arcuate nucleus. Viral overexpression of a constitutively active form of AMPK in the arcuate causes a significant delay in puberty onset; the delay in pubertal onset is prevented by ablation of the AMPKγ1 subunit in kisspeptin cells of the arcuate (Roa et al., 2018). Furthermore, GnRH neurons are responsive to glucose, and these effects are mediated by AMPK (Roland & Moenter, 2011). These results in the arcuate nucleus, while interesting, conflict with data that demonstrate that glucoprivic control of the pulsatile LH secretion and estrous behavior are prevented by lesions of the AP/NTS (Cates & O’Byrne, 2000; Murahashi et al., 1996; Panicker et al., 1998) or by selective immunotoxic destruction of NE/NPY neurons from the brainstem to the PVH (I’Anson et al., 2003b). Nevertheless, activation of intracellular “energy sensors,” such as AMPK, mammalian target of rapamycin (mTOR), carnitine palmitoyl transferase-1 (CPT-1), and SGLUT, are potential sites of integration of metabolic and hormonal signals for ingestive behavior and reproduction (reviewed by Andrews, 2011; Schneider et al., 2012). Compared to their effects in the CNS, in peripheral organs, the availabilities of metabolic fuels and hormones have the opposite effect on AMPK and other fuel-detecting enzymes. Furthermore, these effects in the periphery might vary with internal energy storage and expenditure. The results obtained via manipulation of hypothalamic AMPK are often not well integrated with results that emphasize detection of fuels in the caudal brainstem and in the periphery.
There are still many gaps in our knowledge of the nature and location of metabolic detectors and the pathways to their effectors. In addition, different aspects of behavior and physiology might employ different fuels, detectors, and pathways. One untested hypothesis is that the effect of satiety signals from the gut might be more relevant for appetitive aspects of sex behavior, whereas signals from adiposity or from the overall availability of fuels might be more relevant for consummatory behavior and/or the HPG system. Current and future research will shed light on how hormonal signals are enhanced or modulated by the peripheral energetic condition (e.g., the level of oxidizable metabolic fuels).
The author thanks Attilio Ceretti, Sophie Antonioli, Michael Mobarakai, Jeremy Brozek, and Alexa Bennetch for proofreading various drafts of this manuscript. This research was supported by IOS-1257638 and IOS-1257876 from the National Science Foundation.
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