Abstract
In the past decades, it has become clear that the brain plays a key role in the control of feeding and energy homeostasis. These are complex systems that require the integration of diverse physiological components, from sensing energy demands and storage to behavioral responses, motor function, and reflex adjustments. Studies in different organisms from worms to flies and rodents to humans have identified key molecular pathways, conserved genes, and neural circuits crucial for the understanding of the control of distinct components of energy homeostasis. Among them, the brain plays a fundamental role in food intake (e.g., meal frequency and size), energy expenditure, body weight and body composition, feeding behavior, satiety, reward or hedonic consumption, and glucose homeostasis. Although the brain function in metabolic control has been explored for almost a century, the discovery of leptin and its cognate receptor in the mid-1990s and advances in molecular and genetic tools propelled the field toward an unprecedented development. In this chapter, we will highlight the main findings in recent years using these scientific tools with emphasis on the brain pathways and circuitry associated with the control of the metabolic function.
Access provided by Autonomous University of Puebla. Download reference work entry PDF
Similar content being viewed by others
Keywords
- Hypothalamus
- Neuroendocrinology
- Autonomic nervous system
- Melanocortin
- Lateral parabrachial nucleus
- Paraventricular nucleus of the hypothalamus
- Arcuate nucleus
- Mesolimbic dopaminergic system
Introduction
The fundamental role of the central nervous system (CNS) in the regulation of feeding and energy homeostasis has been known for decades. Clinical observations in patients with Fröhlich’s syndrome (adiposogenital dystrophy) displaying excessive subcutaneous fat due to adenopituitary tumors gave rise to an important debate on the relative contributions of the pituitary gland versus the overlying hypothalamus in the genesis of the metabolic aspects of the syndrome (Fröhlich 1901). While Fröhlich, Crowe, and Cushing supported the importance of the pituitary gland in the adiposity, Aschner, a few years later, demonstrated that removal of the pituitary gland alone did not affect adiposity in dogs, suggesting that damage of the hypothalamus was the main cause of the obese phenotype seen in Fröhlich’s syndrome (Crowe et al. 1910; Aschner 1912; Elmquist et al. 1999). With the development of experimental tools to lesion restricted areas of the brain, Hetherington and Ranson reinforced Aschner’s findings and proposed a crucial role for the hypothalamus in food intake and body weight regulation (Hetherington and Ranson 1940). They observed that bilateral lesions of the medial hypothalamus of rats (without disturbing the pituitary gland) produced a profound increase in body weight and adiposity. On the other hand, lesions of the lateral hypothalamic area induced hypophagia leading to death by starvation, in some cases (Anand and Brobeck 1951). Together, these observations gave rise to the classic “dual center” model proposed by Stellar in 1954, comprised of a “satiety center” (i.e., the ventromedial nucleus of the hypothalamus, the VMH) and a “feeding center” (i.e., the lateral hypothalamic area, the LHA) (Stellar 1954).
These ideas were later revised with the development of more refined and precise techniques. For example, small electrolytic or excitotoxic lesions of the VMH and adjacent areas, knife cuts of projecting fibers, and subdiaphragmatic vagotomy challenged the concept of the VMH as the satiety center (King 2006; Gold 1973; Cox and Powley 1981). Concurrently, others questioned the interpretation of data from lesions of the LHA due to the potential interruption of the medial forebrain bundle (which contains the ascending dopaminergic system), which might cause movement disorders or other behavioral changes (Stricker and Verbalis 1990; Bernardis and Bellinger 1996).
The discovery of the adipocyte-derived hormone leptin and its cognate receptor (LepRb) in the mid-1990s, together with the development of new molecular and genetic tools, has permitted the identification of chemically defined neuronal populations associated with specific physiological components of energy homeostasis and the molecular dissection of relevant neural circuits (Zhang et al. 1994; Tartaglia et al. 1995; Chua et al. 1996; Lee et al. 1999; Myers and Leibel 2015).
As a starting point, the neural control of metabolic function recapitulates the basic organizational principles of the CNS in general. The sensory (input) arm perceives and conveys information on nutritional state and energy stores to specific brain nuclei (integrative centers) that integrate multiple physiological signals and orchestrate a coordinated response via the motor (output) arm. The sensory arm relies on hormones, peptides, and other signals from peripheral organs and tissues that function as “metabolic cues.” In this chapter, we will summarize what we have learned in the past decade or so with the use of animal models and genetic tools. We will give special emphasis to the brain circuitry unraveled by studies performed in rodents, the preclinical animal model of choice in the field.
Sensing Metabolic Cues: Humoral and Neural Components
The sensory (input) arm of the neural control of the metabolic function may be subdivided in humoral and neural components, according to the route used by the metabolic cues to access the CNS. Most of these signals enter the CNS via the hypothalamus (mostly humoral signals) and brain stem (humoral and neural signals).
Humoral Components
Most metabolic cues derived from peripheral tissues are released into the circulation and directly act in specific hypothalamic and brain stem nuclei to control food intake, energy expenditure, and glucose homeostasis. Among them, hormones secreted by adipocytes (e.g., leptin), endocrine pancreas (e.g., insulin), and gut (e.g., ghrelin) have been widely investigated in the context of the neural control of the metabolic function.
Leptin, encoded by the Lep/LEP gene (previously called ob for obese), is primarily synthesized and secreted by white adipose tissue (Zhang et al. 1994). During negative energy balance, the fall in leptin levels represents a key signal for the neuroendocrine adaptations prompted by states of energy insufficiency (Flier 1998; Chan and Mantzoros 2005; Ahima et al. 2000; Casanueva and Dieguez 1999). These adaptive responses include decreased locomotor activity and thermogenesis, increased appetite and motivation for food, inhibition of the thyroid and reproductive axes, and activation of the adrenal axis (Ahima 2006). Leptin acts via LepRb (encoded by the Lepr/LEPR gene), which is highly expressed in several regions of the hypothalamus, including the arcuate nucleus (Arc), the VMH, the dorsomedial nucleus (DMH), and the LHA. In the brain stem, the ventral tegmental area (VTA), the periaqueductal gray matter, the lateral parabrachial nucleus (lPBN), and the nucleus of the solitary tract (NTS) also express LepRb (Tartaglia et al. 1995; Chua et al. 1996; Mercer et al. 1996; Fei et al. 1997; Elmquist et al. 1998a; Scott et al. 2009; Myers et al. 2009).
Insulin, produced by the pancreatic β cells, is crucial for the control of blood glucose; it stimulates glucose uptake by peripheral organs including liver, muscle, and adipose tissue (Weyer et al. 1999; Biddinger and Kahn 2006). Glucose uptake by neurons and glia is mediated by insulin-insensitive glucose transporters; hence, the acquisition and use of glucose by the brain are independent of insulin action (McEwen and Reagan 2004; Banks et al. 2012). Insulin receptors are widespread in the CNS, however, and growing evidence supports a role for brain insulin action in the control of energy balance (along with peripheral glucose homeostasis). For example, mice with neuronal deletion of insulin receptor display increased adiposity and higher susceptibility to obesogenic diet (Plum et al. 2006; Kleinridders et al. 2014; Bruning et al. 2000).
Ghrelin is primarily produced and released by endocrine cells of the stomach and small intestine (Kojima et al. 1999). It was initially described as a potent growth hormone (GH) secretagogue, acting via the GH secretagogue receptor (GHSR). Soon after its discovery, several laboratories reported that peripheral or central injections of ghrelin potently stimulate food intake and decrease energy expenditure, leading to weight gain (Nakazato et al. 2001). Ghrelin is also an important modulator of glucose homeostasis. Loss-of-function mutations in the ghrelin gene (Ghrl) increase glucose-stimulated insulin secretion, as well as insulin sensitivity (Sun et al. 2006). Similarly, ghrelin infusion reduces insulin sensitivity and increases glucose levels. Some of ghrelin’s actions may be mediated by direct effects in pancreatic islets (Dezaki et al. 2006), but many lines of evidence demonstrate major roles for GHSR in the brain (Nogueiras et al. 2008). GHSR is abundant in the Arc and VMH, as well as relevant brain stem sites, including the VTA, lPBN, and NTS (Nakazato et al. 2001; Zigman et al. 2006).
To exert their effects, circulating hormones must pass the blood–brain barrier (BBB) to access their receptors in the brain parenchyma. The BBB is composed of closely adjoined endothelial cells, glia, and (in some areas) tanycytes. It is present in the entire brain with the exception of small areas located adjacent to the cerebral ventricles, called circumventricular organs (CVOs). The CVOs contain fenestrated blood vessels that allow diffusion and interchange of bigger molecules (peptides and hormones) between the brain parenchyma and the bloodstream, presumably without the need for active transport across the BBB (Ganong 2000; Johnson and Gross 1993; Broadwell and Brightman 1976). Among the seven well-described CVOs, the median eminence and the area postrema are of particular interest here, given their proximity to metabolic sensing neurons in the Arc and the NTS, respectively. These are sites where metabolic signals may passively penetrate the brain and bind to receptors. Alternatively, hormones in the circulation may cross the BBB by two mechanisms: (a) via lipid-mediated free diffusion or (b) via carrier- or receptor-mediated active transport. Most of the metabolic hormones (e.g., leptin, insulin, and ghrelin) have BBB transporters that permit access to deep structures in the brain, not just CVO-adjacent regions (Banks et al. 1996, 2012; Balland et al. 2014; Banks 2008).
Neural Components: Visceral Inputs
The CNS control of energy homeostasis also relies on information conveyed by visceral inputs. Sensory information is generated in each segment of the alimentary tract, from food taste, temperature, and texture in the mouth to mechanical and chemical signals in the stomach and intestine. These signals are conveyed by several cranial nerves carrying different modalities of sensory inputs. The upper segments of the alimentary tract (mouth and tongue) convey gustatory inputs (taste signals) to the rostral subdivision of the NTS via the facial (VII) and glossopharyngeal (IX) cranial nerves; the mid- and lower segments (pharynx, larynx, esophagus, stomach, and intestine, as well as the liver and the portal vein) transmit mechanical and chemical inputs to the intermediary and caudal subdivisions of the NTS via the vagus (cranial nerve X). The different modalities of sensory inputs convey distinct information to the brain. For example, while gustatory inputs are associated with food selection and hedonic responses, mechano- and chemoreceptors signal nutritional content. In this regard, the vagus nerve is the primary neural component in the transmission of visceral inputs to the CNS (Chung and Andrea 2011; Pavlov and Tracey 2012).
The vagus nerve is comprised of afferent (sensory) and efferent (motor) fibers. The afferent vagal branch is organized as a typical sensory nerve, i.e., pseudounipolar neurons with cell bodies located in a ganglion outside the CNS, the nodose ganglion (aka inferior ganglion of the vagus nerve (Fig. 1)). Vagal dendrites, which contain specialized receptors, are distributed in a topographic manner along the mid- and lower segments of the alimentary tract. The mechanoreceptors are concentrated in the pharynx, esophagus, and stomach, and the chemoreceptors are more abundant in the stomach, liver, and intestine (Berthoud 2002). The mechanoreceptors are found throughout the myenteric plexus and external smooth muscle layers. In the stomach, they sense gastric distension and provide signals that promote satiation (Fox et al. 2001). The chemoreceptors are distributed in the mucosal and submucosal layers of the gastrointestinal (GI) tract and in the liver and portal vein; these may sense changes in glucose, amino acids, and fatty acids. The chemoreceptor cells are also responsive to peptides produced in the GI mucosa in response to food intake, including ghrelin, cholecystokinin (CCK), amylin, peptide YY, and glucagon-like peptide-1 (GLP-1) among others in response to food intake (Berthoud 2002; Chaudhri et al. 2008). The viscerosensory inputs (via the vagus nerve) and humoral signals (via the area postrema) reach the CNS via direct actions upon NTS neurons. This neuronal relay functions as the primary brain stem entry site in metabolic regulation.
Brain Stem Pathways: Transducing Visceral and Humoral Inputs
Many humoral and neural signals of energy balance, including a variety of gut-derived signals, converge on the NTS (Fig. 2; Grill and Hayes 2012; Myers and Olson 2014). In addition to receiving the vagally encoded information from gut distension, a variety of humorally conveyed signals (including gut peptides, such as amylin and CCK) activate cells in the area postrema that project onto an overlapping set of neurons in the medial NTS; medial NTS responses contribute to short-term satiety. Additionally, many of the neurons in the medial NTS that receive vagal and area postrema-derived information also express LepRb and respond to leptin (Huo et al. 2008). Leptin augments the response of these cells to gut peptide- and vagally encoded signals, thus amplifying the effects of feeding on these satiety-promoting circuits (Huo et al. 2008; Morton et al. 2005).
The gut- and nutrient-responsive neurons of the medial NTS contain a variety of neurotransmitters; most are glutamatergic, but many also contain neuropeptide transmitters including proopiomelanocortin (POMC)-derived peptides, CCK, and GLP-1 (Huo et al. 2008; Garfield et al. 2012). Subpopulations of these cells express the transcription factor Phox2B, and Phox2b-Cre-mediated deletion of LepRb interferes with satiety signaling, as does virally mediated suppression of NTS LepRb expression (Aponte et al. 2011). Medial NTS neurons project to a variety of regions, including the adjacent dorsal motor nucleus of the vagus (DMV) – where they mediate gut reflexes that alter peristalsis, etc. (Grill and Hayes 2012). Medial NTS cells also project to the lPBN, where they synapse on neurons that contain calcitonin gene-related peptide (CGRP), among others (Wu et al. 2012). lPBN CGRP neurons project to the central nucleus of the amygdala to promote anorexia. Medial NTS neurons also make direct projections into more rostral areas, including hypothalamic sites (such as the paraventricular nucleus of the hypothalamus, the PVH), the amygdala, and the thalamus.
Importantly, in addition to roles played by brain stem nuclei in conveying gut- and nutrient-derived information rostrally, the NTS and lPBN receive information from hypothalamic structures and play an important role in mediating the control of food intake by these sites (Grill and Hayes 2012; Myers and Olson 2014). Both the NTS and lPBN receive direct inputs from the hypothalamus – especially from the PVH and the Arc nuclei; the lPBN plays prominent roles in the control of food intake by cells in both of these areas. Indeed, the lPBN also plays important roles in the anorexia associated with gut sickness-derived signals, as well as normal satiety signals.
Hypothalamic Systems that Control Energy Balance
Overall Organization
Many of the neural systems that control energy balance lie in the hypothalamus. Like the brain stem (and unlike more recently developed brain areas such as the neocortex and hippocampus), the hypothalamus is not organized in a laminar manner but rather consists of clusters of neuronal soma (nuclei). The cells within each nucleus connect to other cells in the same region and/or other nuclei to generate an integrated signal, which is then passed to output nuclei that ultimately relay the signal to motor neurons that control autonomic and endocrine systems or influence feeding behavior. While each of these nuclei contains heterogeneous (and even oppositely acting) types of neurons, the neurons of each nucleus often control related functions. While many hypothalamic nuclei contribute to the control of energy balance at some level, several of these nuclei play defined and especially important roles.
Within the medial region, the Arc, which lies immediately above the median eminence, enjoys rapid access to circulating factors (see Humoral Components discussed above) that mediate important signals of energy balance (Myers and Olson 2014). The Arc makes strong reciprocal connections with the dorsomedial nucleus of the hypothalamus (DMH), which integrates the Arc-derived signals with information (e.g., circadian cues, body temperature) from other hypothalamic regions (Fig. 3). The Arc and DMH each also make strong reciprocal connections with the PVH, which lies anterior to these other structures. As noted above, the PVH also receives direct input from the brain stem. The PVH represents a crucial output nucleus for the hypothalamus: PVH efferents to the brain stem and spinal cord control autonomic function, projections to the median eminence and posterior pituitary control endocrine function, and projections to the brain stem regulate feeding.
The VMH, especially the dorsomedial VMH (dmVMH, which mediates most of the energy balance function of the VMH), though nestled between the anterior portions of the Arc and DMH, makes relatively few connections with these two nuclei but rather projects to rostral and brain stem regions associated with autonomic function (e.g., the bed nucleus of the stria terminalis and the periaqueductal gray matter) (Canteras et al. 1994). Lateral to the Arc, VMH, and DMH lies a more loosely defined structure, the lateral hypothalamic area (LHA), through which course projections among several limbic regions rostral and caudal to the hypothalamus. The LHA contains many cell bodies, as well; many of these receive metabolic signals and project to the midbrain (including the dopaminergic ventral tegmental area or VTA) or to rostral limbic regions (such as the nucleus accumbens). The LHA represents a major conduit linking the hypothalamus to the mesolimbic dopamine system and other circuits that control motivation (Opland et al. 2010).
Arcuate Nucleus
The Arc in rodents (tuberal nucleus in humans) is located in the medioventral portion of the hypothalamus surrounding the third ventricle and intimately connected to the median eminence and hypophyseal portal vascular system by the infundibular stalk. It contains a heterogeneous group of projection neurons producing proopiomelanocortin (POMC), agouti-related peptide (AgRP), or Kisspeptin, hypophysiotropic neurons producing growth-hormone-releasing hormone (GHRH), somatostatin, or dopamine, plus glial-like tanycytes (in addition to astrocytes and microglia). A Golgi impregnation study showed that the majority of Arc neurons are bipolar with two major, relatively aspiny dendrites (van den Pol and Cassidy 1982). Tanycyte cell bodies are located in the ventral-most ependymal lining of the third ventricle and elaborate their characteristic arching projections laterally and ventrally (Langlet 2014). The median eminence is one of the circumventricular organs with fenestrated capillaries and therefore provides neurons of the Arc with relatively unfettered access to circulating hormones, cytokines, nutrients, and metabolites. Modulation of tanycytes by peripheral signals, including leptin, appears to be capable of further opening the blood–brain barrier to allow access of circulating factors deeper into the Arc parenchyma (Balland et al. 2014; Mullier et al. 2010).
Neuropeptidergic neurons of the Arc, including those that contain POMC and somatostatin, are among the earliest differentiated neurons of the CNS, at E10.5 in the mouse. The homeodomain transcription factor Isl1 has recently been shown to be essential for the specification of POMC neuron identity and transcription of the Pomc gene by its interaction with two distinct neural-specific enhancers (Lam et al. 2015; Nasif et al. 2015). Similarly, the homeodomain transcription factor Bsx has been implicated in transcription of the Agrp gene (Sakkou et al. 2007). The early POMC-positive neurons in the developing Arc appear to be intermediate progenitors that ultimately give rise to mature POMC neurons, as well as subpopulations of mature AgRP and Kisspeptin neurons (Padilla et al. 2010; Sanz et al. 2015). Another defining feature of the developing Arc is the trophic action of the postnatal surge in leptin secretion to stimulate neural projections from the Arc to other hypothalamic nuclei (Bouret et al. 2004). There is increasing evidence that the epithelial lining of the third ventricle contains a stem cell population that together with tanycytes is capable of generating newly born and differentiated Arc neurons in the adult mouse brain (Kokoeva et al. 2007; McNay et al. 2012; Lee et al. 2012), although the physiological significance of these discoveries remains to be fully defined. Excitingly, recent reports have outlined the in vitro conditions essential to generate differentiated cells representative of the full range of Arc neurons from either human ES (embryonic stem) cells or IPSC (induced puripotential stem cells) cells (Merkle et al. 2015; Wang et al. 2015a). These groundbreaking findings will likely permit a more complete analysis of the factors underlying the development of the Arc and exploration of the genetic disturbances associated with Arc dysfunction in hereditary hypothalamic obesity syndromes.
Abundant genetic evidence from the clinic, together with animal studies, has identified the CNS melanocortin system, including POMC and AgRP neurons and their projections to distal neurons expressing the melanocortin MC3 and MC4 receptors, as a critical component of the homeostatic neural circuitry regulating energy balance (Cone 2005). Melanocortin peptides (α-, β-, and γ-MSH in humans, only α- and γ-MSH in rodents) are endogenous agonists of the two CNS receptors, while AgRP is a competitive antagonist/inverse agonist at both receptors (Ollmann et al. 1997). The remainder of this section will therefore focus on the dyad of Arc POMC and AgRP neurons.
A study by Cowley et al. (2001) first proposed a model to explain the homeostatic basis of body weight control, whereby leptin stimulation of POMC neurons is balanced by their inhibition from nearby AgRP neurons. In this useful (albeit simplistic) model, the two subpopulations of neurons largely project to similar sites in the CNS (Bagnol et al. 1999; Wang et al. 2015b) but have opposing actions, α-MSH ultimately leading to decreased food intake and increased energy expenditure and AgRP increasing food intake and decreasing energy expenditure. The model is conceptually very similar to the earlier, but now debatable, notion of opposing mediobasal hypothalamic anorexigenic and lateral hypothalamic orexigenic zones. More recent evidence has greatly elaborated on the dyadic model without nullifying its heuristic value.
AgRP neurons also produce neuropeptide Y (NPY) (Hahn et al. 1998) and the fast inhibitory neurotransmitter GABA (Cowley et al. 2001). Although AgRP and NPY both stimulate food intake following injection into the cerebrospinal fluid or specific hypothalamic nuclei, this pharmacological action does not fully reflect the complexity of endogenous AgRP neuron function. Researchers were puzzled by the demonstration that mutant mice engineered to lack AgRP and/or NPY did not exhibit the predicted phenotype of decreased body weight, adiposity, and food intake (Qian et al. 2002). However, ablation of AgRP neurons in the adult, but not in neonatal mouse, causes starvation and death, and this phenotype is independent of melanocortin signaling (Luquet et al. 2005; Wu et al. 2008). These paradoxical findings have at least been partially explained by the primary role of GABA signaling from AgRP neurons in their acute actions to stimulate feeding, with the neuropeptides playing accessory or modulatory roles (Tong et al. 2008; Wu et al. 2009). Stimulation of AgRP neurons by either optogenetic or chemogenetic technology leads to the rapid onset of feeding behavior, even in sated mice (Aponte et al. 2011; Krashes et al. 2011). However, further experiments have demonstrated that endogenous AgRP release does indeed stimulate feeding but on a longer time scale than either GABA or NPY release (Krashes et al. 2013). There are apparently at least two parallel neural pathways mediating these effects, one a direct projection of AgRP neurons to the lPBN (Wu et al. 2012; Betley et al. 2013) and a second polysynaptic circuit involving an inhibitory AgRP projection to MC4R-expressing glutamatergic neurons within the PVH that in turn project by a descending pathway to the lPBN (Garfield et al. 2015). It is not yet known if the latter target neurons are identical to each other for both pathways originating from the Arc.
Like AgRP neurons, subpopulations of Arc POMC neurons are characterized by diverse afferent signaling pathways, including activation by the humoral factors leptin and insulin via LepRb and InsR (Qiu et al. 2010, 2014), respectively, either direct activation or inhibition by glucose (Ibrahim et al. 2003; Parton et al. 2007), transsynaptic excitation by glutamatergic inputs (Kiss et al. 2005; Sternson and Shepherd 2005), and transsynaptic inhibition by GABAergic inputs (including those from local AgRP/NPY/GABA neurons), opioid peptides via μ-opioid receptors (Pennock and Hentges 2011), and serotonin via 5-HT2C receptors (Berglund et al. 2013). POMC neurons also synthesize cocaine- and amphetamine-regulated transcript (CART) and dynorphin peptides and are capable of the synaptic release of both GABA and glutamate (Hentges et al. 2009; Jarvie and Hentges 2012), although the physiological importance of these co-modulators and co-transmitters is still unknown. However, there is abundant and unequivocal evidence from pharmacological, genetic, and electrophysiological experiments that melanocortin peptides derived from POMC neurons play a critical physiological role in the reduction of food intake by promoting early satiation and in the reduction of energy expenditure via effects on the autonomic nervous system (Yaswen et al. 1999; Huszar et al. 1997; Butler et al. 2000; Chen et al. 2000; Xu et al. 2011). The actions of β-endorphin, an opioid peptide that is generated stoichiometrically with melanocortins during posttranslational processing of the prohormone, are less certain (Wardlaw 2011). β-Endorphin injected into the nucleus accumbens acutely stimulates feeding, particularly of highly palatable food (Majeed et al. 1986; Will et al. 2003); however, mice with a specific genetic loss of β-endorphin exhibit a mild obesity phenotype with increased food intake (Appleyard et al. 2003). The explanation for these contradictory findings has not been adequately explained.
Unlike the rapid stimulatory effects on food intake produced by the remote activation of AgRP neurons, activation of Arc POMC neurons has only produced delayed inhibitory effects on food intake after as much as 24 h (Aponte et al. 2011; Atasoy et al. 2012; Zhan et al. 2013). Similarly, only long-term inhibition of POMC neurons was capable of increasing food intake (Atasoy et al. 2012). Because the feeding inhibitory effects from optogenetic activation of POMC neurons were blocked by a melanocortin antagonist and POMC neuron activation could overcome coincident inhibition from AgRP neurons, the most parsimonious explanation for the delayed response is that melanocortin peptide release, and not the other putative peptide and amino acid transmitters produced in POMC neurons, is of principal importance to POMC neuron function in the control of energy homeostasis. However, it is worth noting that the loss of Pomc gene expression selectively from the Arc has no detectable effect on body weight in mice until they are weaned at age 3 weeks (Bumaschny et al. 2012). The absence of Pomc expression also does not prevent the maturation of POMC neurons and the development of their widespread axonal projections throughout the brain.
The most recent advances in our understanding of the intrinsic activity of POMC and AgRP neurons and their role in energy balance come from a pair of elegant studies using in vivo Ca2+ imaging of the Arc with either fiber photometry or miniaturized confocal optics in freely behaving mice (Chen et al. 2015; Betley et al. 2015). These experiments revealed unexpected aspects of neuronal activity that have not been possible to assess using ex vivo slice electrophysiology. Fasted mice were shown to have tonically active AgRP neurons and tonically inhibited POMC neurons. Food presentation alone or even olfactory cues from a hidden food pellet were sufficient to immediately reverse the activity state of the two populations of Arc neurons. Furthermore, the magnitude of these responses was increased directly with the hedonic value of the presented food, and, conversely, food removal slowly restored the original activation states. Extrinsic excitation of the AgRP neurons conditioned mice to avoid a previously associated neutral flavor or preferred chamber in a place preference test. These results suggest that AgRP neuron activation has a negative valence, and, as a corollary, the state of food deprivation associated with tonically active AgRP neuron firing is intrinsically aversive. Therefore, the natural drive to eat, with consequent achievement of reward, may be motivated not only by the positive hedonic reinforcement from food but also by the reduction of negative reinforcement encoded by AgRP neuron activity. Although not explicitly tested, it is logical to propose that POMC neuron activation may have an opposing positive valence that is unrelated to its induction of satiation. Finally, these demonstrations of rapid alterations in Arc neuronal firing in anticipation of food consumption, rather than as a response to it, provide new insights concerning the role of the melanocortin system in both homeostatic and non-homeostatic control of energy balance.
Dorsomedial Nucleus
Even among the complex nuclei of the hypothalamus, the size and functional diversity of the DMH is substantial (Fontes et al. 2011; Dimicco et al. 2007). While there are many recognized subdivisions of the DMH, it is probably most useful to distinguish among the dorsal component (DMHd, which borders the dorsal hypothalamic area or DHA), the compact central zone, and the ventral region (DMHv). The DMH plays a role in the control of many autonomic functions, including thermogenesis, heart rate, and blood pressure. Like the Arc, the DMH contains a substantial number of LepRb-expressing cells (Scott et al. 2009; Patterson et al. 2011). Dorsal DMH/DHA LepRb neurons interact with the thermal control systems of the medial preoptic area and PVH and play an important role in the control of body temperature by leptin (Rezai-Zadeh et al. 2014). Consistently, deletion of LepRb in the prolactin-releasing hormone-expressing neurons of this region decreases body temperature and energy expenditure, promoting obesity in high-fat-fed animals (Dodd et al. 2014). A variety of data also suggest that the LepRb neurons in this region modulate blood pressure and contribute to the increase in blood pressure associated with the hyperleptinemia of obesity (Simonds et al. 2014).
Some brain lesion experiments also suggest a role for the DMH in the control of food intake. It is possible that the DMH contains oppositely acting sets of neurons (similar to the POMC and AgRP neurons of the Arc but more evenly balanced), which could limit the ability to detect roles in the control of food intake following traditional lesioning. It is also possible that the variable effects on feeding that result from DMH lesions may reflect differences in the subregions of the DMH targeted in various studies; certainly, DMHd/DHA LepRb neurons control autonomic output but do not modulate feeding (Rezai-Zadeh et al. 2014). Correlative evidence suggests the potential for DMH leptin action (presumably the ventral DMH) in the control of feeding, however. The deletion of LepRb from distributed populations of hypothalamic cells that express the vesicular GABA transporter (vGat, Slc32a1 gene) or neuronal nitric oxide synthase (nNOS, Nos1 gene) each produces dramatic hyperphagia and obesity (Leshan et al. 2012; Vong et al. 2011). The distributions of these cells overlap mainly in the DMH, suggesting a potential role for DMH LepRb neurons in the suppression of feeding.
Paraventricular Nucleus: Hypothalamic Output
The PVH is a critical hypothalamic center that receives and integrates energy balance signals from a variety of brain regions and coordinates physiologic responses to maintain energy homeostasis predominantly through the autonomic nervous system. The PVH is a complex structure composed of a heterogeneous group of mostly glutamatergic neurons that have been classically described as parvocellular or magnocellular based on cell size and axonal projection patterns. The magnocellular neurons in the PVH, including those that express oxytocin (OXT) or vasopressin (AVP), project primarily to the posterior pituitary and release their contents directly into the general circulation to regulate peripheral tissue function. Importantly, however, dendritic release of these neuropeptides has been implicated in the overall control and coordination of PVH function.
The PVH parvocellular cells are more diverse and send projections within the central nervous system to three main areas: (1) the median eminence where secreted factors (e.g., corticotropin-releasing hormone or CRH) enter the portal hypophyseal circulation and regulate pituitary function; (2) the brain stem, including the dorsal vagal complex (composed of the NTS and DMV) and the lPBN – both of which have been implicated in feeding (Wu et al. 2009; Wan et al. 2008; Wu and Palmiter 2011; Zheng et al. 2005; Berthoud et al. 2006); and (3) the preganglionic, sympathetic output centers such as the intermediolateral cell column of the spinal cord (Sawchenko and Swanson 1982; Swanson et al. 1980; Biag et al. 2012). Parvocellular PVH neurons that respond to satiety signals, such as leptin, have been proposed to regulate feeding by modulating hindbrain responses to ascending feeding signals from the gut and periphery (Morton et al. 2005; Atasoy et al. 2012; Blevins et al. 2004, 2009). However, it is important to point out that hypothalamic factors secreted into the portal hypophyseal circulation at the median eminence undoubtedly contribute to both energy and metabolic homeostasis via regulation of pituitary function.
The overall importance of the PVH in the regulation of energy balance is underscored by the massive obesity and metabolic abnormalities associated with alterations in PVH development or function. Rodents and humans harboring deleterious mutations in the hypothalamic transcription factor single minded-1 (Sim1) develop a hypocellular PVH and hyperphagic obesity. Moreover, lesions of the PVH also result in hyperphagic obesity and glucose dysregulation. Neither the neural architecture nor the molecular mechanisms used by the PVH to maintain energy and metabolic homeostasis are well understood. This is in large part due to the cellular heterogeneity of the PVH, the density of its projection targets, and the array of PVH afferent inputs from different brain regions (Sawchenko and Swanson 1983; Ferguson et al. 2008).
The PVH serves as an important regulatory output center for peptides and conditions known to modulate food intake, including leptin, melanocortins (from the Arc), GLP-1 (presumably from the NTS), GLP-1 agonists, and dehydration (Tung et al. 2008; Acuna-Goycolea and van den Pol 2004; Baraboi et al. 2011; Dalvi et al. 2012; Salter-Venzon et al. 2008). The melanocortin system is perhaps the best studied of these pathways, as it is essential for energy balance in rodents and humans and is directly linked to PVH function (Cone 2005; Garfield et al. 2015; Farooqi and O’Rahilly 2006; Farooqi et al. 2003). POMC and AgRP neurons in the Arc produce melanocortin agonists and antagonists, respectively, and project to PVH neurons that express melanocortin receptors (Ellacott and Cone 2004; Kishi et al. 2003; Mountjoy 2010). Endogenous and pharmacologic melanocortin agonists stimulate melanocortin receptor-bearing neurons to activate effector pathways that inhibit food intake and stimulate energy expenditure. Melanocortin action in PVH Sim1 neurons suppresses food intake (Balthasar et al. 2005; Shah et al. 2014), and ablation of most Sim1 neurons in adult mice results in profound hyperphagic obesity with decreased energy expenditure and altered locomotor activity (Xi et al. 2012). In addition, selective deletion of MC4R from Sim1 cells leads to hyperphagic obesity (Shah et al. 2014).
Subsets of PVH neurons contain a variety of neuropeptides implicated in neuroendocrine and energy balance control, including OXT, CRH, AVP, thyrotropin-releasing hormone, and somatostatin. The anorectic effects of pharmacologic doses of OXT and CRH agonists generated a great deal of interest in PVH OXT and CRH neurons as potential regulators of energy balance. At odds with this formulation are the findings that rodents lacking OXT or OXT neurons (or CRH/CRH receptors) demonstrate minimal energy balance phenotypes; neither does the activation of PVH OXT or CRH neurons alter feeding (Sutton et al. 2014). Whether the contradiction between pharmacologic studies and genetic approaches reflects developmental compensation to the systemic inactivation of these neuropeptides is not clear, but the profound effects of Sim1 neuron (pan-PVH) manipulation suggest that yet-to-be-defined PVH neurons distinct from OXT and CRH cells represent crucial mediators of energy balance.
With the recent development of an array of genetic tools, cell-specific genetic changes in PVH cells have confirmed the critical role of the PVH in feeding regulation and have extended our understanding of the molecular components and neural circuitry of PVH function/action. MC4R action on Sim1 cells in the PVH is sufficient to normalize feeding in animals that lack MC4Rs elsewhere, and this is not attributable to direct MC4R action on OXT, CRH, or AVP neurons. Moreover, MC4R expression in Sim1 PVH neurons is required for body weight maintenance, indicating that PVH MC4R action is both necessary and sufficient for normal energy homeostasis (Balthasar et al. 2005; Shah et al. 2014). Remote activation of Sim1 PVH neurons using chemogenetic approaches suppresses feeding and increases energy utilization (Garfield et al. 2015; Sutton et al. 2014). The effects of pan-PVH activation on parameters of energy balance are not assignable to PVH OXT, CRH, or AVP neurons, since chemogenetic manipulation of these populations had minor (if any) effects on energy balance. In contrast, cell-specific activation of neuronal nitric oxidase synthase (NOS1)-expressing PVH neurons (a subset of Sim1 PVH cells) alters feeding to a similar extent as pan-PVH activation, suggesting that PVH NOS1 neurons play an important role in feeding.
The PVH sends projections to a variety of brain regions within the central nervous system. For the purposes of this discussion, we will highlight the functional roles of PVH projections to brain areas known to be important for food intake/energy expenditure, including the lPBN (feeding), NTS, and spinal cord (autonomic control). The importance of these specific PVH projections has been inferred based on published data demonstrating the importance of these target regions in energy balance. The combination of stereotaxic delivery of cell-specific viral tools into transgenic animals with technologies such as light-dependent neural activation (optogenetics) has made it possible to interrogate the physiologic function of specific PVH neuronal projections. Indeed, recent studies using these technologies have revealed a PVH → Arc orexigenic circuit and established the importance of PVH → lPBN projections for melanocortin action in the CNS (Garfield et al. 2015; Krashes et al. 2014). Similar approaches targeting other PVH projections will undoubtedly uncover additional important biological mechanisms underpinning energy balance regulation.
Ventromedial Nucleus
For several decades following the seminal studies of Hetherington and Ranson, in which the bilateral medial hypothalamic lesions (that included the VMH) produced hyperphagic obesity, the VMH was the main focus of attention regarding the neural control of energy homeostasis (Hetherington and Ranson 1940). Following intense debate, these studies were dismissed by findings suggesting that the electrolytic lesions likely disrupted the neural connections of the medial hypothalamus, including projections from the Arc to and from the PVH (Elmquist et al. 1999; King 2006). While still not completely resolved, the role for the VMH in energy balance has been clarified by recent studies using more specific molecular and cellular methods.
The VMH contains glucose-sensing neurons that are highly responsive to changes in glucose levels, as well as those that express receptors for metabolic hormones (e.g., leptin and insulin) or for neuropeptides associated with energy balance (Scott et al. 2009; Elmquist et al. 1997; Routh 2003; Song et al. 2001; Kang et al. 2004). However, the VMH, like most hypothalamic nuclei, is not a homogeneous structure, and it is comprised of neurons with distinct neurochemical identities and characteristic projection patterns. For example, the ventrolateral subdivision (VMHvl) expresses sex steroid receptors and projects to sites related to behavioral control, whereas neurons in the dorsomedial subdivision (VMHdm) respond to metabolic cues (e.g., glucose, leptin, and insulin) and innervate areas associated with autonomic and circadian regulation (Canteras et al. 1994; Kim et al. 2011a; Elmquist et al. 1998b; Klockener et al. 2011). Among these, VMHdm projects densely to the lateral aspect of the bed nucleus of the stria terminalis and to the subparaventricular zone of the hypothalamus (Canteras et al. 1994; Elmquist et al. 1998b; Dong and Swanson 2004). The lateral bed nucleus of stria terminalis is part of the central autonomic circuitry preferentially innervating the central amygdala, periaqueductal gray matter, lPBN, and NTS (Dong and Swanson 2004). On the other hand, the subparaventricular zone receives dense innervation from the suprachiasmatic nucleus, the main circadian clock of the mammalian brain (Moore 1983; Watts et al. 1987). The neuroanatomical organization of the VMHdm suggests roles in energy balance by the control of autonomic function (e.g., thermogenesis, hepatic glucose production, glucose utilization, and secretion of insulin and glucagon) and the circadian oscillations of circulating hormones (e.g., corticosterone) in response to changes in energy stores (Kim et al. 2011a; Bernardis and Frohman 1971; Luo et al. 1999; Niijima et al. 1984; Krieger 1980; Choi et al. 1996).
To better understand the regulation and function of VMH circuits, several groups examined the temporal and anatomic distribution of gene expression in the VMH. Of the identified genes, steroidogenic factor 1 (SF1, Nr5a1 gene) received a great deal of attention due to its VMH-specific expression within the CNS (Ikeda et al. 1995; Segal et al. 2005). The restricted expression of SF1 has allowed the development of a series of genetically modified mouse models to interrogate VMHdm function. Mice with global loss-of-function mutations in the SF1 gene show disrupted VMH development (Ikeda et al. 1995; Sadovsky et al. 1995; Luo et al. 1994; Shinoda et al. 1995), and neuron-specific deletion of SF1 results in morbid obesity – primarily due to decreased energy expenditure (Kim et al. 2011a, b; Majdic et al. 2002). Two independent groups also demonstrated that leptin signaling in VMH SF1 neurons is required for energy expenditure, glucose homeostasis, and adaptive thermogenesis and hence for the control of body weight (Dhillon et al. 2006; Bingham et al. 2008). On the other hand, selective deletion of insulin receptor from SF1 neurons induced resistance to obesogenic diet and altered glucose metabolism (Klockener et al. 2011).
The VMH also plays a prominent role in the control of glucose homeostasis (Routh 2003). VMH neuron responses to glucose are heterogenous: Glucose-excited (GE) VMH neurons increase and glucose-inhibited (GI) VMH neurons decrease their firing rate when glucose rises (Song et al. 2001). Intra-VMH 2-deoxyglucose (a non-metabolizable glucose analog that mimics low glucose) injection increases plasma glucose, glucagon, noradrenaline, and adrenaline, suggesting a role in the counter-regulatory response to hypoglycemia, presumably by activating GI neurons. Recent studies have also suggested that VMH innervation by brain stem sites also plays a role in this response (Garfield Alastair et al. 2014; Flak et al. 2014). Conversely, leptin or melanocortin action in the VMH increases glucose uptake into tissues and/or decreases blood glucose (presumably via GE neurons). These findings support the notion that the VMH is a key component in the control of glucose homeostasis via sensing changes in glucose levels and modulation of autonomic responses (Routh 2003).
Targeted deletion of leptin- or insulin-regulated intracellular signaling pathways has unraveled some of the molecular mechanisms involved in the humoral control of the VMH function. For example, reduced activity of phosphatidylinositol 3-kinase (PI3K) in SF1 neurons decreased the adaptive autonomic response to high caloric intake without changes in glucose homeostasis (Xu et al. 2010). In addition, deletion of FOXO1 (a transcription factor downstream of PI3K signaling) resulted in improved insulin sensitivity and in a lean phenotype due to increase in energy expenditure (Kim et al. 2011b).
Non-SF1 neurons (such as those that contain brain-derived neurotrophic factor or BDNF) may also play an important role in metabolic regulation: Viral blockade of VMH BDNF induces hyperphagic obesity in mice (Unger et al. 2007). Also, deletion of estrogen receptor α (ERα) in the entire VMH results in more profound adiposity than that observed in selective ERα deletion from SF1 neurons (Xu et al. 2011; Musatov et al. 2007). Hence, VMH SF1 neurons appear to primarily control energy expenditure and glucose homeostasis, whereas non-SF1 neurons may have a more prominent role in the regulation of food intake. The specific neural pathways that lie downstream of distinct VMH neurons to control each aspect of energy homeostasis remain poorly understood, however.
Lateral Hypothalamic Area and Mesolimbic Dopaminergic System
Unlike the control of autonomic and endocrine function, foraging for and eating food require the initiation and coordination of complex behaviors. While the neural circuits that generate motor patterns represent the ultimate outputs for these behaviors, these circuits serve the brain’s motivational systems (Berthoud 2007). The central control of motivation is mediated by the mesolimbic dopamine (DA) system, at the core of which lie DA neurons of the midbrain ventral tegmental area (VTA) (Berridge 2004). The VTA DA neurons project to many places, including the nucleus accumbens, where DA release modulates motivation.
Several decades-old observations also suggested a role for the LHA in motivation. Not only does lesioning the LHA promote anhedonia and abrogate the motivation to feed in experimental animals, but also animals will self-administer activating current to the LHA, suggesting that LHA activation is rewarding/motivating (Fulton et al. 2000). Since the medial forebrain bundle, which carries axons from (among others) the VTA to the nucleus accumbens, courses through the LHA, it was not initially clear whether the perturbation of the medial forebrain bundle or rather LHA neurons mediate these effects, however.
With the discovery and functional characterization of several discrete sets of LHA neurons, it became clear that LHA neurons themselves play an important role in the control of motivation, including the mesolimbic DA system. Indeed, the LHA integrates metabolic (e.g., leptin and melanocortins) and other homeostatic signals from the hypothalamus to modulate mesolimbic DA-dependent activity, attention, and motivation (Myers et al. 2009; Berthoud 2007). Like the Arc, VMH, and DMH, the LHA contains many groups of neurons, some of which function antagonistically. Important LHA neurons include orexin (aka hypocretin)-containing cells, which project to a variety of midbrain and hindbrain sites. Orexin neurons are activated by signals of energy deficit (fasting, ghrelin, etc.) to promote arousal and food seeking; conversely, leptin inhibits orexin neurons (Myers et al. 2009; Berthoud 2007). Melanin-concentrating hormone (MCH) -expressing neurons in the LHA project widely through the forebrain, including to the nucleus accumbens, and stimulate feeding (Georgescu et al. 2005). Overexpression of MCH promotes increased feeding and weight gain, while the ablation of MCH or MCH neurons decreases feeding and promotes leanness.
While both orexin and MCH neurons are glutamatergic, the LHA also contains a substantial population of GABAergic neurons, many of which contain neuropeptides, including neurotensin and galanin. While orexin neurons contain GHSR (the receptor for orexigenic ghrelin), neither orexin nor MCH cells contain LepRb (Leinninger et al. 2009). Rather, a substantial subset of LHA GABA neurons coexpresses LepRb. Like the larger population of LHA GABA neurons, many LHA LepRb neurons also contain neurotensin and/or galanin (Laque et al. 2013).
LHA LepRb neurons contribute to the control of feeding, energy expenditure, and energy balance by leptin, since intra-LHA leptin suppresses feeding in leptin-deficient animals, and deletion of LepRb in LHA neurotensin neurons decreases activity and energy expenditure, while increasing adiposity (Leinninger et al. 2011). LHA LepRb neurons project locally onto orexin (but not MCH) neurons, in addition to innervating the VTA and other midbrain sites (Louis et al. 2010). While the action of Arc-derived melanocortins apparently drives the control of MCH neurons by leptin and energy balance, leptin action via LHA LepRb neurons inhibits the activity of orexin neurons, at least in part via galanin (Opland et al. 2010; Goforth et al. 2014). LHA leptin action also promotes the expression of orexin; this somewhat counterintuitive bidirectional regulation of orexin neurons presumably reflects the need for leptin to reduce acute foraging activity, while supporting the normal function of orexin to permit alertness and attention (Louis et al. 2010).
Leptin action via LHA neurotensin neurons also modulates the mesolimbic DA function, decreasing nucleus accumbens DA transport activity (hence increasing synaptic DA transmission) (Leinninger et al. 2011). Since the chemogenetic activation of LHA neurotensin neurons increases nucleus accumbens DA concentration via the release of neurotensin in the VTA, intra-VTA neurotensin release by LHA LepRb neurons presumably represents a mechanism by which LHA LepRb neurons control mesolimbic DA function (Patterson et al. 2015). While LHA LepRb neurons represent a major mechanism by which leptin and energy status control the mesolimbic DA system, some VTA cells also contain LepRb (Leshan et al. 2010; Fulton et al. 2006; Hommel et al. 2006). VTA LepRb neurons mainly project locally and to the central nucleus of the amygdala (rather than the nucleus accumbens), and the ablation of LepRb from DA neurons fails to alter energy balance or tested parameters of mesolimbic DA function. Thus, LHA LepRb neurons represent the primary link between leptin and the control of mesolimbic DA function and motivation.
Conclusions
The physiological regulation of varied components of the metabolic function relies on a coordinated action of humoral and neural signals, integrated brain circuits and orchestrated motor, and behavioral and reflex responses. With the use of molecular and genetic tools and new technology, we have a much clear picture of the role of specific neuronal populations and brain pathways associated with the control of many aspects of energy homeostasis. The “dual center” hypothesis has its heuristic value, but recent evidence using more precise tools has demonstrated the complexity of the system with the action of a series of hypothalamic and brain stem nuclei. We have also gained knowledge on the relevance of selective neurotransmitters/peptides and neural pathways in several aspects of the metabolic regulation. The next challenge will be to determine how each of these components is interconnected and integrated to generate a highly coordinated physiological system.
Cross-References
References
Acuna-Goycolea C, van den Pol A. Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal. J Neurosci. 2004;24(37):8141-8152.
Ahima RS. Adipose tissue as an endocrine organ. Obesity (Silver Spring). 2006;14(Suppl 5):242S-249S.
Ahima RS, Saper CB, Flier JS, et al. Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21(3):263-307.
Anand BK, Brobeck JR. Localization of a “feeding center” in the hypothalamus of the rat. Proc Soc Exp Biol Med Soc Exp Biol Med. 1951;77(2):323-324.
Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci. 2011;14(3):351-355.
Appleyard SM, Hayward M, Young JI, et al. A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology. 2003;144(5):1753-1760.
Aschner B. Uber die funktion der hypophyse. Pflugers Arch Physiol. 1912;146:1-146.
Atasoy D, Betley JN, Su HH, et al. Deconstruction of a neural circuit for hunger. Nature. 2012;488(7410):172-177.
Bagnol D, Lu XY, Kaelin CB, et al. Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J Neurosci. 1999;19(18):RC26.
Balland E, Dam J, Langlet F, et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 2014;19(2):293-301.
Balthasar N, Dalgaard LT, Lee CE, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123(3):493-505.
Banks WA. The blood–brain barrier: connecting the gut and the brain. Regul Pept. 2008;149(1–3):11-14.
Banks WA, Kastin AJ, Huang W, et al. Leptin enters the brain by a saturable system independent of insulin. Peptides. 1996;17(2):305-311.
Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82-93.
Baraboi ED, St-Pierre DH, Shooner J, et al. Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4. Am J Physiol Regul Integr Comp Physiol. 2011;301(4):R1011-R1024.
Berglund ED, Liu C, Sohn JW, et al. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest. 2013;123(12):5061-5070.
Bernardis LL, Bellinger LL. The lateral hypothalamic area revisited: ingestive behavior. Neurosci Biobehav Rev. 1996;20(2):189-287.
Bernardis LL, Frohman LA. Effects of hypothalamic lesions at different loci on development of hyperinsulinemia and obesity in the weanling rat. J Comp Neurol. 1971;141(1):107-115.
Berridge KC. Motivation concepts in behavioral neuroscience. Physiol Behav. 2004;81(2):179-209.
Berthoud HR. Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev. 2002;26(4):393-428.
Berthoud HR. Interactions between the “cognitive” and “metabolic” brain in the control of food intake. Physiol Behav. 2007;91(5):486-498.
Berthoud HR, Sutton GM, Townsend RL, et al. Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size. Physiol Behav. 2006;89(4):517-524.
Betley JN, Cao ZF, Ritola KD, et al. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell. 2013;155(6):1337-1350.
Betley JN, Xu S, Cao ZF, et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature. 2015;521(7551):180-185.
Biag J, Huang Y, Gou L, et al. Cyto- and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6 J male mouse: a study of immunostaining and multiple fluorescent tract tracing. J Comp Neurol. 2012;520(1):6-33.
Biddinger SB, Kahn CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol. 2006;68(1):123-158.
Bingham NC, Anderson KK, Reuter AL, et al. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology. 2008;149(5):2138-2148.
Blevins JE, Schwartz MW, Baskin DG. Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol. 2004;287(1):R87-R96.
Blevins JE, Morton GJ, Williams DL, et al. Forebrain melanocortin signaling enhances the hindbrain satiety response to CCK-8. Am J Physiol Regul Integr Comp Physiol. 2009;296(3):R476-R484.
Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science. 2004;304(5667):108-110.
Broadwell RD, Brightman MW. Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. J Comp Neurol. 1976;166(3):257-283.
Bruning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122-2125.
Bumaschny VF, Yamashita M, Casas-Cordero R, et al. Obesity-programmed mice are rescued by early genetic intervention. J Clin Invest. 2012;122(11):4203-4212.
Butler AA, Kesterson RA, Khong K, et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology. 2000;141(9):3518-3521.
Canteras NS, Simerly RB, Swanson LW. Organization of projections from the ventromedial nucleus of the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J Comp Neurol. 1994;348(1):41-79.
Casanueva FF, Dieguez C. Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol. 1999;20(4):317-363.
Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet. 2005;366(9479):74-85.
Chaudhri OB, Salem V, Murphy KG, et al. Gastrointestinal satiety signals. Annu Rev Physiol. 2008;70:239-255.
Chen AS, Metzger JM, Trumbauer ME, et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res. 2000;9(2):145-154.
Chen Y, Lin YC, Kuo TW, et al. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell. 2015;160(5):829-841.
Choi S, Horsley C, Aguila S, et al. The hypothalamic ventromedial nuclei couple activity in the hypothalamo-pituitary-adrenal axis to the morning fed or fasted state. J Neurosci. 1996;16(24):8170-8180.
Chua SC Jr, Chung WK, Wu-Peng XS, et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor [see comments]. Science. 1996;271(5251):994-996.
Chung O, Andrea H. Vagal control of satiety and hormonal regulation of appetite. J Neurogastroenterol Motil. 2011;17(4):338-348.
Cone RD. Anatomy and regulation of the central melanocortin system. Nat Neurosci. 2005;8(5):571-578.
Cowley MA, Smart JL, Rubinstein M, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480-484.
Cox JE, Powley TL. Prior vagotomy blocks VMH obesity in pair-fed rats. Am J Physiol. 1981;240(5):E573-E583.
Crowe SJ, Cushing H, Homans J. Experimental hypophysectomy. Bull Johns Hopkins Hosp. 1910;21(230):127-169.
Dalvi PS, Nazarians-Armavil A, Purser MJ, et al. Glucagon-like peptide-1 receptor agonist, exendin-4, regulates feeding-associated neuropeptides in hypothalamic neurons in vivo and in vitro. Endocrinology. 2012;153(5):2208-2222.
Dezaki K, Sone H, Koizumi M, et al. Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. Diabetes. 2006;55(12):3486-3493.
Dhillon H, Zigman JM, Ye C, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 2006;49(2):191-203.
Dimicco JA, Zaretsky DV. The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R47-R63.
Dodd GT, Worth AA, Nunn N, et al. The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus. Cell Metab. 2014;20(4):639-649.
Dong H-W, Swanson LW. Organization of axonal projections from the anterolateral area of the bed nuclei of the stria terminalis. J Comp Neurol. 2004;468(2):277-298.
Ellacott KL, Cone RD. The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. Recent Prog Horm Res. 2004;59:395-408.
Elmquist JK, Ahima RS, Maratos-Flier E, et al. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology. 1997;138(2):839-842.
Elmquist JK, Bjorbaek C, Ahima RS, et al. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol. 1998a;395(4):535-547.
Elmquist JK, Ahima RS, Elias CF, et al. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci U S A. 1998b;95(2):741-746.
Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron. 1999;22(2):221-232.
Farooqi IS, O’Rahilly S. Genetics of obesity in humans. Endocr Rev. 2006;27(7):710-718.
Farooqi IS, Keogh JM, Yeo GS, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085-1095.
Fei H, Okano HJ, Li C, et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci U S A. 1997;94(13):7001-7005.
Ferguson AV, Latchford KJ, Samson WK. The paraventricular nucleus of the hypothalamus – a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets. 2008;12(6):717-727.
Flak JN, Patterson CM, Garfield AS, et al. Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat Neurosci. 2014;17(12):1744-1750.
Flier JS. Clinical review 94: what’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab. 1998;83(5):1407-1413.
Fontes MA, Xavier CH, de Menezes RC, et al. The dorsomedial hypothalamus and the central pathways involved in the cardiovascular response to emotional stress. Neuroscience. 2011;184:64-74.
Fox EA, Phillips RJ, Baronowsky EA, et al. Neurotrophin-4 deficient mice have a loss of vagal intraganglionic mechanoreceptors from the small intestine and a disruption of short-term satiety. J Neurosci. 2001;21(21):8602-8615.
Fröhlich A. Ein fall von tumor der hypophysis cerebri ohne akromegalie. Wien Klin Rundsch. 1901;15:883-886.
Fulton S, Woodside B, Shizgal P. Modulation of brain reward circuitry by leptin. Science. 2000;287(5450):125-128.
Fulton S, Pissios P, Manchon RP, et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron. 2006;51(6):811-822.
Ganong WF. Circumventricular organs: definition and role in the regulation of endocrine and autonomic function. Clin Exp Pharmacol Physiol. 2000;27(5–6):422-427.
Garfield AS, Patterson C, Skora S, et al. Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract. Endocrinology. 2012;153(10):4600-4607.
Garfield AS, Shah Bhavik P, Madara Joseph C, et al. A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab. 2014;20(6):1030-1037.
Garfield AS, Li C, Madara JC, et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci. 2015;18(6):863-871.
Georgescu D, Sears RM, Hommel JD, et al. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci. 2005;25(11):2933-2940. doi:10.1523/JNEUROSCI.1714-04.2005.
Goforth PB, Leinninger GM, Patterson CM, et al. Leptin acts via lateral hypothalamic area neurotensin neurons to inhibit orexin neurons by multiple GABA-independent mechanisms. J Neurosci. 2014;34(34):11405-11415.
Gold RM. Hypothalamic obesity: the myth of the ventromedial nucleus. Science. 1973;182(4111):488-490.
Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012;16(3):296-309.
Hahn TM, Breininger JF, Baskin DG, et al. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci. 1998;1(4):271-272.
Hentges ST, Otero-Corchon V, Pennock RL, et al. Proopiomelanocortin expression in both GABA and glutamate neurons. J Neurosci. 2009;29(43):13684-13690.
Hetherington AW, Ranson SW. Hypothalamic lesions and adiposity in the rat. Anat Rec. 1940;78:149-172.
Hommel JD, Trinko R, Sears RM, et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron. 2006;51(6):801-810.
Huo L, Gamber KM, Grill HJ, et al. Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats. Endocrinology. 2008;149(2):492-497.
Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131-141.
Ibrahim N, Bosch MA, Smart JL, et al. Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology. 2003;144(4):1331-1340.
Ikeda Y, Luo X, Abbud R, et al. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol. 1995;9(4):478-486.
Jarvie BC, Hentges ST. Expression of GABAergic and glutamatergic phenotypic markers in hypothalamic proopiomelanocortin neurons. J Comp Neurol. 2012;520(17):3863-3876.
Johnson A, Gross P. Sensory circumventricular organs and brain homeostatic pathways. FASEB J. 1993;7(8):678-686.
Kang L, Routh VH, Kuzhikandathil EV, et al. Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes. 2004;53(3):549-559.
Kim KW, Sohn J-W, Kohno D, et al. SF-1 in the ventral medial hypothalamic nucleus: a key regulator of homeostasis. Mol Cell Endocrinol. 2011a;336(1–2):219-223.
Kim KW, Zhao L, Donato J Jr, et al. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proc Natl Acad Sci U S A. 2011b;108(26):10673-10678.
King BM. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol Behav. 2006;87(2):221-244.
Kishi T, Aschkenasi CJ, Lee CE, et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol. 2003;457(3):213-235.
Kiss J, Csaba Z, Csaki A, et al. Glutamatergic innervation of neuropeptide Y and pro-opiomelanocortin-containing neurons in the hypothalamic arcuate nucleus of the rat. Eur J Neurosci. 2005;21(8):2111-2119.
Kleinridders A, Ferris HA, Cai W, et al. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014;63(7):2232-2243.
Klockener T, Hess S, Belgardt BF, et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci. 2011;14(7):911-918.
Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660.
Kokoeva MV, Yin H, Flier JS. Evidence for constitutive neural cell proliferation in the adult murine hypothalamus. J Comp Neurol. 2007;505(2):209-220.
Krashes MJ, Koda S, Ye C, et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest. 2011;121(4):1424-1428.
Krashes MJ, Shah BP, Koda S, et al. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 2013;18(4):588-595.
Krashes MJ, Shah BP, Madara JC, et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. 2014;507(7491):238-242.
Krieger DT. Ventromedial hypothalamic lesions abolish food-shifted circadian adrenal and temperature rhythmicity. Endocrinology. 1980;106(3):649-654.
Lam DD, de Souza FS, Nasif S, et al. Partially redundant enhancers cooperatively maintain Mammalian pomc expression above a critical functional threshold. PLoS Genet. 2015;11(2):e1004935.
Langlet F. Tanycytes: a gateway to the metabolic hypothalamus. J Neuroendocrinol. 2014;26(11):753-760.
Laque A, Zhang Y, Gettys S, et al. Leptin receptor neurons in the mouse hypothalamus are colocalized with the neuropeptide galanin and mediate anorexigenic leptin action. Am J Physiol Endocrinol Metab. 2013;304(9):E999-E1011.
Lee HM, Udupi V, Englander EW, et al. Stimulatory actions of insulin-like growth factor-I and transforming growth factor-alpha on intestinal neurotensin and peptide YY. Endocrinology. 1999;140(9):4065-4069.
Lee DA, Bedont JL, Pak T, et al. Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci. 2012;15(5):700-702.
Leinninger GM, Jo YH, Leshan RL, et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 2009;10(2):89-98.
Leinninger GM, Opland DM, Jo YH, et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 2011;14(3):313-323.
Leshan RL, Opland DM, Louis GW, et al. Ventral tegmental area leptin receptor neurons specifically project to and regulate cocaine- and amphetamine-regulated transcript neurons of the extended central amygdala. J Neurosci. 2010;30(16):5713-5723.
Leshan RL, Greenwald-Yarnell M, Patterson CM, et al. Leptin action through hypothalamic nitric oxide synthase-1-expressing neurons controls energy balance. Nat Med. 2012;18(5):820-823.
Louis GW, Leinninger GM, Rhodes CJ, et al. Direct innervation and modulation of orexin neurons by lateral hypothalamic LepRb neurons. J Neurosci. 2010;30(34):11278-11287.
Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994;77(4):481-490.
Luo S, Luo J, Cincotta AH. Chronic ventromedial hypothalamic infusion of norepinephrine and serotonin promotes insulin resistance and glucose intolerance. Neuroendocrinology. 1999;70(6):460-465.
Luquet S, Perez FA, Hnasko TS, et al. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005;310(5748):683-685.
Majdic G, Young M, Gomez-Sanchez E, et al. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology. 2002;143(2):607-614.
Majeed NH, Przewlocka B, Wedzony K, et al. Stimulation of food intake following opioid microinjection into the nucleus accumbens septi in rats. Peptides. 1986;7(5):711-716.
McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol. 2004;490(1–3):13-24.
McNay DE, Briancon N, Kokoeva MV, et al. Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J Clin Invest. 2012;122(1):142-152.
Mercer JG, Hoggard N, Williams LM, et al. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 1996;387(2–3):113-116.
Merkle FT, Maroof A, Wataya T, et al. Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells. Development. 2015;142(4):633-643.
Moore RY. Organization and function of a central nervous system circadian oscillator: the suprachiasmatic hypothalamic nucleus. Fed Proc. 1983;42(11):2783-2789.
Morton GJ, Blevins JE, Williams DL, et al. Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest. 2005;115(3):703-710.
Mountjoy KG. Distribution and function of melanocortin receptors within the brain. Adv Exp Med Biol. 2010;681:29-48.
Mullier A, Bouret SG, Prevot V, et al. Differential distribution of tight junction proteins suggests a role for tanycytes in blood-hypothalamus barrier regulation in the adult mouse brain. J Comp Neurol. 2010;518(7):943-962.
Musatov S, Chen W, Pfaff DW, et al. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci U S A. 2007;104(7):2501-2506.
Myers MG Jr, Olson DP. SnapShot: neural pathways that control feeding. Cell Metab. 2014;19(4):732-732. e731.
Myers MG, Leibel RL. Lessons from rodent models of obesity. In: De Groot LJ, Beck-Peccoz P, Chrousos G, et al., eds. Endotext-Free online Endocrinology Textbook. South Dartmouth, MA: MDText.com; 2015.
Myers MG Jr, Münzberg H, Leinninger GM, et al. The geometry of leptin action in the brain: more complicated than a simple ARC. Cell Metab. 2009;9(2):117-123.
Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194-198.
Nasif S, de Souza FS, Gonzalez LE, et al. Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood. Proc Natl Acad Sci U S A. 2015;112(15):E1861-E1870.
Niijima A, Rohner-Jeanrenaud F, Jeanrenaud B. Role of ventromedial hypothalamus on sympathetic efferents of brown adipose tissue. Am J Physiol. 1984;247(4 Pt 2):R650-R654.
Nogueiras R, Tschop MH, Zigman JM. Central nervous system regulation of energy metabolism: ghrelin versus leptin. Ann N Y Acad Sci. 2008;1126:14-19.
Ollmann MM, Wilson BD, Yang YK, et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278(5335):135-138.
Opland DM, Leinninger GM, Myers MG Jr. Modulation of the mesolimbic dopamine system by leptin. Brain Res. 2010;1350:65-70.
Padilla SL, Carmody JS, Zeltser LM. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat Med. 2010;16(4):403-405.
Parton LE, Ye CP, Coppari R, et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 2007;449(7159):228-232.
Patterson CM, Leshan RL, Jones JC, et al. Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. Brain Res. 2011;1378:18-28.
Patterson CM, Wong JM, Leinninger GM, et al. Ventral tegmental area neurotensin signaling links the lateral hypothalamus to locomotor activity and striatal dopamine efflux in male mice. Endocrinology. 2015;156(5):1692-1700.
Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex – linking immunity and metabolism. Nat Rev Endocrinol. 2012;8(12):743-754.
Pennock RL, Hentges ST. Differential expression and sensitivity of presynaptic and postsynaptic opioid receptors regulating hypothalamic proopiomelanocortin neurons. J Neurosci. 2011;31(1):281-288.
Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116(7):1761-1766.
Qian S, Chen H, Weingarth D, et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol. 2002;22(14):5027-5035.
Qiu J, Fang Y, Ronnekleiv OK, et al. Leptin excites proopiomelanocortin neurons via activation of TRPC channels. J Neurosci. 2010;30(4):1560-1565.
Qiu J, Zhang C, Borgquist A, et al. Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab. 2014;19(4):682-693.
Rezai-Zadeh K, Yu S, Jiang Y, et al. Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol Metab. 2014;3(7):681-693.
Routh VH. Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) and hypoglycemia-associated autonomic failure (HAAF). Diabetes Metab Res Rev. 2003;19(5):348-356.
Sadovsky Y, Crawford PA, Woodson KG, et al. Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A. 1995;92(24):10939-10943.
Sakkou M, Wiedmer P, Anlag K, et al. A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior. Cell Metab. 2007;5(6):450-463.
Salter-Venzon D, Watts AG. The role of hypothalamic ingestive behavior controllers in generating dehydration anorexia: a Fos mapping study. Am J Physiol Regul Integr Comp Physiol. 2008;295(4):R1009-R1019.
Sanz E, Quintana A, Deem JD, et al. Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. J Neurosci. 2015;35(14):5549-5556.
Sawchenko PE, Swanson LW. Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol. 1982;205(3):260-272.
Sawchenko PE, Swanson LW. The organization of forebrain afferents to the paraventricular and supraoptic nuclei of the rat. J Comp Neurol. 1983;218(2):121-144.
Scott MM, Lachey JL, Sternson SM, et al. Leptin targets in the mouse brain. J Comp Neurol. 2009;514(5):518-532.
Segal JP, Stallings NR, Lee CE, et al. Use of laser-capture microdissection for the identification of marker genes for the ventromedial hypothalamic nucleus. J Neurosci. 2005;25(16):4181-4188.
Shah BP, Vong L, Olson DP, et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A. 2014;111(36):13193-13198.
Shinoda K, Lei H, Yoshii H, et al. Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn. 1995;204(1):22-29.
Simonds SE, Pryor JT, Ravussin E, et al. Leptin mediates the increase in blood pressure associated with obesity. Cell. 2014;159(6):1404-1416.
Song Z, Levin BE, McArdle JJ, et al. Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes. 2001;50(12):2673-2681.
Stellar E. The physiology of motivation. Psychol Rev. 1954;61(1):5-22.
Sternson SM, Shepherd GM, Friedman JM. Topographic mapping of VMH → arcuate nucleus microcircuits and their reorganization by fasting. Nat Neurosci. 2005;8(10):1356-1363.
Stricker EM, Verbalis JG. Control of appetite and satiety: insights from biologic and behavioral studies. Nutr Rev. 1990;48(2):49-56. discussion 114–131.
Sun Y, Asnicar M, Saha PK, et al. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 2006;3(5):379-386.
Sutton AK, Pei H, Burnett KH, et al. Control of food intake and energy expenditure by nos1 neurons of the paraventricular hypothalamus. J Neurosci. 2014;34(46):15306-15318.
Swanson LW, Sawchenko PE, Wiegand SJ, et al. Separate neurons in the paraventricular nucleus project to the median eminence and to the medulla or spinal cord. Brain Res. 1980;198(1):190-195.
Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83(7):1263-1271.
Tong Q, Ye CP, Jones JE, et al. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. 2008;11(9):998-1000.
Tung YC, Ma M, Piper S, et al. Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J Neurosci. 2008;28(47):12419-12426.
Unger TJ, Calderon GA, Bradley LC, et al. Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci. 2007;27(52):14265-14274.
van den Pol AN, Cassidy JR. The hypothalamic arcuate nucleus of rat – a quantitative Golgi analysis. J Comp Neurol. 1982;204(1):65-98.
Vong L, Ye C, Yang Z, et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron. 2011;71(1):142-154.
Wan S, Browning KN, Coleman FH, et al. Presynaptic melanocortin-4 receptors on vagal afferent fibers modulate the excitability of rat nucleus tractus solitarius neurons. J Neurosci. 2008;28(19):4957-4966.
Wang L, Meece K, Williams DJ, et al. Differentiation of hypothalamic-like neurons from human pluripotent stem cells. J Clin Invest. 2015a;125(2):796-808.
Wang D, He X, Zhao Z, et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat. 2015b;9:40.
Wardlaw SL. Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol. 2011;660(1):213-219.
Watts AG, Swanson LW, Sanchez-Watts G. Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J Comp Neurol. 1987;258(2):204-229.
Weyer C, Bogardus C, Mott DM, et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787-794.
Will MJ, Franzblau EB, Kelley AE. Nucleus accumbens mu-opioids regulate intake of a high-fat diet via activation of a distributed brain network. J Neurosci. 2003;23(7):2882-2888.
Wu Q, Palmiter RD. GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur J Pharmacol. 2011;660(1):21-27.
Wu Q, Boyle MP, Palmiter RD. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell. 2009;137(7):1225-1234.
Wu Q, Clark MS, Palmiter RD. Deciphering a neuronal circuit that mediates appetite. Nature. 2012;483(7391):594-597.
Wu Q, Howell MP, Cowley MA, et al. Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc Natl Acad Sci U S A. 2008;105(7):2687-2692.
Xi D, Gandhi N, Lai M, et al. Ablation of Sim1 neurons causes obesity through hyperphagia and reduced energy expenditure. PLoS One. 2012;7(4):e36453.
Xu Y, Hill JW, Fukuda M, et al. PI3K signaling in the ventromedial hypothalamic nucleus is required for normal energy homeostasis. Cell Metab. 2010;12(1):88-95.
Xu Y, Nedungadi TP, Zhu L, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 2011;14(4):453-465.
Yaswen L, Diehl N, Brennan MB, et al. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med. 1999;5(9):1066-1070.
Zhan C, Zhou J, Feng Q, et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J Neurosci. 2013;33(8):3624-3632.
Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue [published erratum appears in Nature 1995 Mar 30;374(6521):479] [see comments]. Nature. 1994;372(6505):425-432.
Zheng H, Patterson LM, Phifer CB, et al. Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections. Am J Physiol Regul Integr Comp Physiol. 2005;289(1):R247-R258.
Zigman JM, Jones JE, Lee CE, et al. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol. 2006;494(3):528-548.
Acknowledgments
The authors are supported by the National Institutes of Health grants (DK056731, DK078056, DK098853 to MGM; DK104999-01, DK078056 to DPO; DK066604 and DK068400 to MJL; HD61539, HD69702 to CFE), the American Diabetes Association to MGM, the Marilyn H. Vincent Foundation to MGM, and the Whitehall Foundation to DPO.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this entry
Cite this entry
Myers, M.G., Olson, D.P., Low, M.J., Elias, C.F. (2016). Brain Regulation of Feeding and Energy Homeostasis. In: Ahima, R.S. (eds) Metabolic Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-319-11251-0_22
Download citation
DOI: https://doi.org/10.1007/978-3-319-11251-0_22
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-11250-3
Online ISBN: 978-3-319-11251-0
eBook Packages: MedicineReference Module Medicine