Dev Disabil Res Revs - 2008 - Smith - Neurophysiology of hunger and satiety

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<p>NEUROPHYSIOLOGY OF HUNGER AND SATIETY</p><p>Pauline M. Smith and Alastair V. Ferguson*</p><p>Department of Physiology, Queen’s University, Kingston, Ontario, Canada</p><p>Hunger is defined as a strong desire or need for food while satiety</p><p>is the condition of being full or gratified. The maintenance of energy ho-</p><p>meostasis requires a balance between energy intake and energy expendi-</p><p>ture. The regulation of food intake is a complex behavior. It requires dis-</p><p>crete nuclei within the central nervous system (CNS) to detect signals</p><p>from the periphery regarding metabolic status, process and integrate this</p><p>information in a coordinated manner and to provide appropriate</p><p>responses to ensure that the individual does not enter a state of positive</p><p>or negative energy balance. This review of hunger and satiety will exam-</p><p>ine the CNS circuitries involved in the control of energy homeostasis as</p><p>well as signals from the periphery, both hormonal and neural, that</p><p>convey pertinent information regarding short-term and long-term energy</p><p>status of the individual. ' 2008 Wiley-Liss, Inc.</p><p>Dev Disabil Res Rev 2008;14:96–104.</p><p>Key Words: hypothalamus; paraventricular nucleus; area postrema; sub-</p><p>fornical organ; feeding; leptin; ghrelin; adiponectin; insulin; amylin; Pep-</p><p>tide YY; cholecystokinin; glucagon-like peptides</p><p>INTRODUCTION</p><p>Hunger is defined as a strong desire or need for food</p><p>while satiety is the condition of being full or grati-</p><p>fied. The drive for food is a powerful stimulus that</p><p>arises from a need generated by metabolic processing. Feeding</p><p>provides the energy required to maintain physiological home-</p><p>ostasis. The maintenance of energy homeostasis requires a bal-</p><p>ance between energy intake and energy expenditure, and</p><p>energy intake (feeding) must be adequate to meet the energy</p><p>needs (physical activity, basal metabolism, and adaptive ther-</p><p>mogenesis) of the organism.</p><p>Evolution has favored the development of biological</p><p>traits associated with preferences for energy-dense foods and a</p><p>thrifty metabolism and, as a consequence, the system tolerates</p><p>positive energy balance leading to an accumulation of fat and</p><p>weight gain while defending strongly against negative energy</p><p>balances that threaten to cause weight loss. These traits favor</p><p>eating behavior that will lead to a positive energy balance and</p><p>many are now considered biological risk factors associated</p><p>with obesity.</p><p>The regulation of food intake is a balance between hun-</p><p>ger, an excitatory process that arises from energy needs, and</p><p>satiety, an inhibitory process that initially arises from, in the</p><p>short-term, postingestive physiological processing. However,</p><p>the sensitivity of both the excitatory and inhibitory processes</p><p>can be modulated by signals that reflect the body’s energy</p><p>stores. The premise underlying this concept is that cumulative</p><p>energy intake is matched to energy expenditure over time via</p><p>a biological feedback control system that promotes stability of</p><p>body fat mass.</p><p>This review of hunger and satiety will examine the central</p><p>nervous system (CNS) circuitries involved in the control of</p><p>energy homeostasis as well as signals from the periphery, both</p><p>hormonal and neural, that convey pertinent information regard-</p><p>ing short-term and long-term energy status of the individual.</p><p>CENTRAL FEEDING CIRCUITS</p><p>A role for the hypothalamus in the control of feeding</p><p>was proposed as early as the 1940s, when Hetherington dem-</p><p>onstrated that hypothalamic lesions affected hunger and satiety</p><p>[Hetherington and Ranson, 1940]. These studies effectively</p><p>led to the development of a conceptual framework, in which</p><p>the lateral area of the hypothalamus was the ‘‘feeding center’’</p><p>of the brain while the ventral medial portion of the hypothala-</p><p>mus was the ‘‘satiety center.’’ Although controversy surround-</p><p>ing this model ensued in the years to follow [King, 2006], the</p><p>hypothalamus is still considered the most important central</p><p>regulator of food intake. Additional studies demonstrating that</p><p>central administration of hypothalamic neuropeptides affects</p><p>food intake and weight gain in animals, the development of</p><p>genetic models in which spontaneous genetic mutations or</p><p>targeted gene deletions impair hypothalamic neuropeptide</p><p>function causing dramatic effects on feeding behavior, and</p><p>electrophysiological and molecular biology characterization of</p><p>hypothalamic neurons has furthered our knowledge in this</p><p>field. As such, our current understanding of hunger and satiety</p><p>is that the regulation of body weight involves well-defined</p><p>hypothalamic neuronal circuits, rather than discrete hypothala-</p><p>mic feeding and satiety centers (Fig. 1). In addition, peripheral</p><p>signals that convey information regarding nutritional and met-</p><p>abolic status of the individual must be integrated by these neu-</p><p>ronal circuitries in order to regulate both food intake and</p><p>energy expenditure.</p><p>The hypothalamus contains cell bodies and/or axons of</p><p>passage that integrate information from various peripheral,</p><p>hormonal, and central sources and regulate food intake. The</p><p>hypothalamus consists of several nuclei that have been shown</p><p>Grant sponsor: Canadian Institutes for Health Research, the Heart and Stroke Foun-</p><p>dation of Ontario.</p><p>*Correspondence to: Alastair V. Ferguson, Department of Physiology, Queen’s</p><p>University, Kingston, Ontario, Canada K7L 3N6. E-mail: avf@queensu.ca</p><p>Received 24 January 2008; Accepted 24 January 2008</p><p>Published online in Wiley InterScience (www.interscience.wiley.com).</p><p>DOI: 10.1002/ddrr.13</p><p>DEVELOPMENTAL DISABILITIES</p><p>RESEARCH REVIEWS 14: 96 – 104 (2008)</p><p>' 2008Wiley -Liss, Inc.</p><p>to be important in food intake. These</p><p>nuclei include the arcuate nucleus</p><p>(ARC), the paraventricular nucleus</p><p>(PVN), the ventromedial nucleus (VMH),</p><p>the dorsomedial nucleus (DMH), and</p><p>the lateral hypothalamic area (LHA).</p><p>These nuclei communicate with each</p><p>other and project to areas in the brain-</p><p>stem involved in the modulation of</p><p>neural signals from the gut reflecting</p><p>meal size and meal composition as well</p><p>as detecting circulating signals relaying</p><p>information regarding nutritional status</p><p>of the ingested meal and metabolic</p><p>status of the animal, and forebrain lim-</p><p>bic areas involved in motivation and</p><p>reward.</p><p>THE ARCUATE NUCLEUS (ARC)</p><p>The ARC, located in the basal</p><p>hypothalamus, plays an essential role in</p><p>modulating food intake. Two distinct</p><p>populations of neurons within the ARC</p><p>have been shown to be critical for con-</p><p>trolling energy homeostasis. One popu-</p><p>lation of neurons coexpress mRNA for</p><p>the orexigenic neuropeptides, agouti-</p><p>gene-related-peptide (AgRP), and neu-</p><p>ropeptide Y (NPY). Intracerebroven-</p><p>tricular (ICV) injections of either AgRP</p><p>or NPY have demonstrated potent</p><p>dose-dependent increases in food intake</p><p>[Clark et al., 1984; Levine and Morley,</p><p>1984; Rossi et al., 1998]. A second</p><p>population of neurons within the ARC</p><p>express mRNA for anorexigenic pepti-</p><p>des neuropeptides, a melanocyte-stimu-</p><p>lating hormone (MSH) derived from</p><p>pro-opiomelanocortin (POMC) precur-</p><p>sor and cocaine-and amphetamine-</p><p>related transcript (CART). These pepti-</p><p>des have been shown to decrease food</p><p>intake when administered ICV [Tsujii</p><p>and Bray, 1989; Edwards et al., 2000].</p><p>Melanocortins exert their effects at one</p><p>(or more) of five G protein coupled</p><p>melanocortin receptors, which show a</p><p>discrete distribution to a number of dif-</p><p>ferent CNS nuclei that have been</p><p>implicated in the control of metabolism.</p><p>The endogenous antagonists, agouti,</p><p>and agouti-related peptide (AgRP) also</p><p>Fig. 1. Hypothalamic circuitry involved in hunger and satiety. These schematic sections illustrate the anatomical projections highlighted in the cur-</p><p>rent review. The upper sagital section (0.4-mm midline) shows the relative location of CNS structures emphasized in this review. Bottom left: This</p><p>expanded sagital view of the hypothalamus outlines the major anatomical projections of the hypothalamic circuitry involved in the control of feeding</p><p>behavior. Projections from the ARC (arcuate nucleus) to the VMH (ventromedial hypothalamus), DMH (dorsomedial hypothalamus), LHA (lateral</p><p>hypothalamic area), and PVN (paraventricular</p><p>nucleus) are shown as well as projections from the PVN to the SFO (subfornical organ), a forebrain cir-</p><p>cumventricular organ that lies at dorsal aspect of the third ventricle, and the NTS (nucleus tractus solitarius) in the brainstem. The coronal sections</p><p>to the right show the relative anatomical locations of these hypothalamic nuclei 20.7 mm Bregma (upper) and 22.6 mm Bregma (lower). [Color fig-</p><p>ure can be viewed in the online issue, which is available at www.interscience.wiley.com.]</p><p>Dev Disabil Res Rev � NEUROPHYSIOLOGY OF HUNGER AND SATIETY � SMITH & FERGUSON 97</p><p>19405529, 2008, 2, D</p><p>ow</p><p>nloaded from</p><p>https://onlinelibrary.w</p><p>iley.com</p><p>/doi/10.1002/ddrr.13 by U</p><p>FPI - U</p><p>niversidade Federal do Piaui, W</p><p>iley O</p><p>nline L</p><p>ibrary on [06/10/2024]. See the T</p><p>erm</p><p>s and C</p><p>onditions (https://onlinelibrary.w</p><p>iley.com</p><p>/term</p><p>s-and-conditions) on W</p><p>iley O</p><p>nline L</p><p>ibrary for rules of use; O</p><p>A</p><p>articles are governed by the applicable C</p><p>reative C</p><p>om</p><p>m</p><p>ons L</p><p>icense</p><p>act at the melanocortin receptors. Dis-</p><p>ruption of this system at multiple levels</p><p>can lead to obesity in humans and ani-</p><p>mals. A number of excellent reviews on</p><p>this topic have recently been published</p><p>[Ellacott and Cone, 2004, 2006; Adan</p><p>and van, 2006; Lee and Wardlaw, 2007].</p><p>Individual neurons within the</p><p>ARC have been shown to be sensitive</p><p>to a number of peptides known to be</p><p>involved in the control of feeding</p><p>behavior including leptin [van den Top</p><p>et al., 2004] and insulin [van den Top</p><p>et al., 2004; Wang et al., 2004]. In</p><p>short, signals that activate AgRP/NPY</p><p>neurons have been shown to increase</p><p>feeding behavior as do signals that</p><p>inhibit a MSH/CART, while those</p><p>that inhibit AgRP/NPY neurons or</p><p>activate a MSH/CART neurons inhibit</p><p>feeding behavior. Again, excellent re-</p><p>views describing the interaction be-</p><p>tween AgRP/NPY neurons and a</p><p>MSH/CART in regulating feeding be-</p><p>havior are available and as such, this will</p><p>not be discussed further in this review</p><p>[Jobst et al., 2004; Lee and Wardlaw,</p><p>2007; Millington, 2007].</p><p>Orexigenic (AgRP and NPY) and</p><p>anorexigenic (a MSH and CART)</p><p>ARC neurons project to second-order</p><p>neurons in the PVN, VMH, DMH,</p><p>and the LHA that process information</p><p>regarding energy and metabolic status.</p><p>In turn, these hypothalamic neurons</p><p>project to the dorsal vagal complex</p><p>(DVC) which includes the nucleus trac-</p><p>tus solitarius (NTS) and the dorsal</p><p>motor nucleus of the vagus (DMV),</p><p>and provide a route through which</p><p>meal-related satiety signals and thus, the</p><p>long-term regulation of energy homeo-</p><p>stasis, may be controlled.</p><p>ACCESS OF SYSTEMIC</p><p>SIGNALS TO THE CNS</p><p>In order for the CNS to modu-</p><p>late feeding, peripheral signals reflecting</p><p>both the immediate and long-term</p><p>energy status of the animal must gain</p><p>access to the CNS. The brain is pro-</p><p>tected by a blood brain barrier (BBB)</p><p>which prevents transport and passive</p><p>diffusion of lipophobic blood borne</p><p>constituents from the bloodstream to</p><p>CNS tissue. The presence of the BBB</p><p>raises the question as to how the brain</p><p>can detect peripheral satiety signals that</p><p>indicate energy status. The ARC has</p><p>been suggested to play critical roles in</p><p>such sensory processing, although it</p><p>should be emphasized that there is no</p><p>direct anatomical evidence indicating</p><p>lack of a normal BBB in arcuate capilla-</p><p>ries, although systemic administration of</p><p>HRP has been shown to penetrate this</p><p>region [Krisch et al., 1978; Armstrong</p><p>and Hatton, 1980]. Although peptide</p><p>transporter systems [Banks et al., 1996]</p><p>and transendothelial signaling [Paton</p><p>et al., 2007] represent alternative mech-</p><p>anisms through which such signals may</p><p>reach ARC neurons behind the BBB, a</p><p>further alternative explanation may</p><p>deserve some consideration.</p><p>The sensory circumventricular</p><p>organs (CVOs) are a group of CNS</p><p>structures that lack the normal BBB.</p><p>These specialized regions have been</p><p>shown to contain a dense vasculature,</p><p>fenestrated epithelium, and the presence</p><p>of a large variety of peptidergic recep-</p><p>tors. Thus, the CVOs are uniquely</p><p>suited to detect the presence (or ab-</p><p>sence) of circulating signals and relay</p><p>this information via well-documented</p><p>efferent pathways to hypothalamic auto-</p><p>nomic nuclei [see Fry et al., 2007 for</p><p>review] without the need to cross the</p><p>In order for the CNS to</p><p>modulate feeding,</p><p>peripheral signals</p><p>reflecting both the</p><p>immediate and long-term</p><p>energy status of the</p><p>animal must gain access</p><p>to the CNS.</p><p>BBB. Although the ARC is not consid-</p><p>ered a CVO, many have suggested that,</p><p>through the close proximity of the ARC</p><p>to the underlying median eminence, a</p><p>CVO possessing a modified blood brain</p><p>area, neurons within the ARC are also</p><p>in the position to directly detect levels</p><p>of peripheral blood borne signals indi-</p><p>cating nutritional status and metabolic</p><p>state. Alternatively, the sensory CVOs</p><p>(in particular the area postrema (AP)</p><p>in the brainstem and the subfornical</p><p>organ (SFO) in the forebrain) may</p><p>transduce blood borne satiety signals</p><p>and relay this information to hypo-</p><p>thalamic areas through well-docu-</p><p>mented anatomical connections.</p><p>THE PARAVENTRICULAR</p><p>NUCLEUS (PVN)</p><p>The PVN lies adjacent to the</p><p>dorsal aspect of the third ventricle and</p><p>has been implicated in numerous auto-</p><p>nomic functions including energy bal-</p><p>ance. Studies demonstrating that lesions</p><p>of the PVN result in obesity [Sims and</p><p>Lorden, 1986] and that microinjection</p><p>of orexigenic peptides such as NPY</p><p>[Stanley and Leibowitz, 1985] and ghre-</p><p>lin [Szentirmai et al., 2007] directly into</p><p>the PVN exert a potent stimulatory</p><p>action on feeding, while microinjection</p><p>of other peptides or their agonists known</p><p>to have anorexigenic effects such as a</p><p>MSH [Wirth et al., 2001] and CART</p><p>[Wang et al., 2000a] decrease NPY-</p><p>induced feeding, suggest this nucleus to</p><p>be an important region contributing to</p><p>the control of feeding behavior.</p><p>In accordance with this perspec-</p><p>tive electrophysiological studies from</p><p>our laboratory and others have demon-</p><p>strated that neurons within the PVN</p><p>are influenced by a variety of central</p><p>and peripheral peptides involved in the</p><p>regulation of food intake, including lep-</p><p>tin [Powis et al., 1997], orexin [Follwell</p><p>and Ferguson, 2002], cholecystokinin</p><p>(CCK) [Ueta et al., 1993], and GLP-1</p><p>[Acuna-Goycolea and van den Pol,</p><p>2004]. The role of PVN neurons in the</p><p>integration of these multiple signals will</p><p>likely prove a fruitful area for future</p><p>study.</p><p>Neuroanatomical studies have</p><p>demonstrated that the PVN receives</p><p>input from NPY and a MSH neurons</p><p>from the ARC as well as orexinergic</p><p>input from the LHA [Nambu et al.,</p><p>1999]. In addition, the PVN contains</p><p>neurons expressing corticotrophin-</p><p>releasing hormone and thyrotropin-</p><p>releasing hormone. As such, the PVN</p><p>plays a major role in the modulation of</p><p>nutritional signals with the hypothala-</p><p>mic pituitary axis [see Richard and Bar-</p><p>aboi, 2004] and the thyroid.</p><p>The PVN shares reciprocal con-</p><p>nections with areas in the brainstem</p><p>such as the NTS. The NTS contains</p><p>NPY neurons that have been shown to</p><p>project to the PVN. In addition, the</p><p>NTS receives vagal afferent fibers from</p><p>the gastrointestinal (GI) tract [Chern-</p><p>icky et al., 1984]. The NTS is immedi-</p><p>ately adjacent to and shares extensive</p><p>reciprocal connections with the AP a</p><p>circumventricular structure that lacks</p><p>the BBB. The AP is uniquely posi-</p><p>tioned to monitor the constituents of</p><p>peripheral circulation, thereby sensing</p><p>circulating satiety signals [Fry et al.,</p><p>2007]. The AP has been shown to con-</p><p>tain a number of peptidergic receptors,</p><p>and electrophysiological studies have</p><p>demonstrated individual neurons within</p><p>the AP to be responsive to these mole-</p><p>cules. Thus, the NTS is able to relay</p><p>information it receives regarding meta-</p><p>98 Dev Disabil Res Rev � NEUROPHYSIOLOGY OF HUNGER AND SATIETY � SMITH & FERGUSON</p><p>19405529, 2008, 2, D</p><p>ow</p><p>nloaded from</p><p>https://onlinelibrary.w</p><p>iley.com</p><p>/doi/10.1002/ddrr.13 by U</p><p>FPI - U</p><p>niversidade Federal do Piaui, W</p><p>iley O</p><p>nline L</p><p>ibrary on [06/10/2024]. See the T</p><p>erm</p><p>s and C</p><p>onditions (https://onlinelibrary.w</p><p>iley.com</p><p>/term</p><p>s-and-conditions) on W</p><p>iley O</p><p>nline L</p><p>ibrary for rules of use; O</p><p>A</p><p>articles are governed by the applicable C</p><p>reative</p><p>C</p><p>om</p><p>m</p><p>ons L</p><p>icense</p><p>bolic status from the periphery via the</p><p>AP to the PVN.</p><p>THE VENTROMEDIAL</p><p>NUCLEUS (VMH)</p><p>Evidence for a role for the VMH</p><p>in the control of feeding behavior is</p><p>derived from both lesion studies show-</p><p>ing that destruction of the VMH</p><p>increases food intake, leading to obesity</p><p>and electrical stimulation experiments</p><p>showing that activation of VMH neu-</p><p>rons stops hungry animals from eating</p><p>[see King, 2006 for review]. At the</p><p>level of the individual VMH neuron,</p><p>electrophysiological studies have shown</p><p>that the firing rate of VHM neurons is</p><p>affected by stomach distention [Sun</p><p>et al., 2006], an effect mediated by the</p><p>vagus nerve. Glucose-sensing neurons in</p><p>the VMH are involved in the regulation</p><p>of glucose homeostasis and alter their</p><p>action potential frequency in response</p><p>to physiological changes in extracellular</p><p>glucose, insulin, and leptin. Intense</p><p>immunoreactivity for the leptin receptor</p><p>has been detected in the VMH [Funa-</p><p>hashi et al., 1999] and it has been sug-</p><p>gested that the VMH is a key target for</p><p>the biological actions of leptin [Jacob</p><p>et al., 1997].</p><p>THE DORSOMEDIAL</p><p>NUCLEUS (DMN)</p><p>The DMH has extensive connec-</p><p>tions with other hypothalamic pathways</p><p>important for regulation of feeding,</p><p>body weight, and energy consumption</p><p>[Bellinger and Bernardis, 2002] as well</p><p>as direct and indirect inputs from the</p><p>suprachiasmatic nucleus, suggesting that</p><p>the DMH may influence a wide range</p><p>of behavioral circadian rhythms [Chou</p><p>et al., 2003] including feeding. Recent</p><p>studies have suggested that DMH neu-</p><p>rons play an important role in the</p><p>expression of food entrainable rhythms</p><p>[Gooley et al., 2006; Mieda et al.,</p><p>2006].</p><p>In situ hybridization histochemis-</p><p>try reveals that NPY-expressing neurons</p><p>are localized in the DMH [Gehlert</p><p>et al., 1987] and that chronic food</p><p>restriction results in significant increases</p><p>in NPY mRNA levels in the DMH,</p><p>independent of leptin changes [Bi et al.,</p><p>2003]. NPY gene expression is also</p><p>affected by CCK. In the absence of an</p><p>inhibitory action of CCK, NPY gene</p><p>expression is elevated, causing increases</p><p>in food intake and body weight [Bi</p><p>et al., 2001].</p><p>THE LATERAL</p><p>HYPOTHALAMIC AREA (LHA)</p><p>The LHA is the most lateral of</p><p>the hypothalamic nuclei mentioned so</p><p>far. Bilateral lesions located in the LHA</p><p>can produce aphagia, while electrical</p><p>stimulation of this region induces eat-</p><p>ing, even in satiated animals. The LHA</p><p>contains specific neuronal populations</p><p>that affect feeding in different ways,</p><p>both in the long-term and short-term.</p><p>The LHA contains glucose sensitive</p><p>neurons [Burdakov et al., 2005] and it</p><p>has been demonstrated that a decrease</p><p>in glucose activates glucose-sensitive</p><p>neurons in the LHA [Silver and Erecin-</p><p>ska, 1998]. Interestingly, glucose-sensi-</p><p>tive neurons in the LHA are inhibited</p><p>by leptin [Shiraishi et al., 2000],</p><p>whereas orexin preferentially excites</p><p>glucose-sensitive neurons in this area</p><p>[Liu et al., 2001]. The LHA is also the</p><p>principle hypothalamic site where orex-</p><p>ins are found and orexigenic fibers are</p><p>widely distributed throughout the brain</p><p>to areas involved in the control of feed-</p><p>ing behavior, attention and arousal, and</p><p>autonomic regulation [Nambu et al.,</p><p>1999]. Neurons expressing the appetite-</p><p>stimulating peptide, orexin A, are</p><p>stimulated by starvation (but not food</p><p>restriction) and by hypoglycemia if food</p><p>is withheld [Cai et al., 1999]. Orexin</p><p>neurons are also activated by low glu-</p><p>cose but are inhibited by visceral feed-</p><p>ing signals, the latter effects probably</p><p>being mediated through vagal sensory</p><p>pathways that first synapse in the NTS</p><p>[Cai et al., 2001]. Thus the LHA is</p><p>implicated in the short-term control of</p><p>feeding behavior by initiating feeding.</p><p>Other LHA neurons express melanin-</p><p>concentrating hormone (MCH), which</p><p>transiently increases food intake when</p><p>injected centrally. MCH neurons in the</p><p>LHA may be regulated by leptin, insulin,</p><p>and glucose.</p><p>BRAINSTEM</p><p>As mentioned in the previous sec-</p><p>tions, the caudal brainstem contains</p><p>extensive reciprocal connections with</p><p>areas in the hypothalamus, including the</p><p>ARC, PVN, and LHA, and therefore is</p><p>well positioned to play a pivotal role in</p><p>energy homeostasis (Fig. 2).</p><p>GI and gustatory feedback are the</p><p>primary controls of ingestive behavior</p><p>in the short-term and the caudal brain-</p><p>stem has been shown to be an impor-</p><p>tant center for this feedback. The NTS</p><p>receives vagal afferent fibers and is thus</p><p>privy to satiety information from the</p><p>periphery. As well, the NTS is the ini-</p><p>tial gustatory relay in the hindbrain and</p><p>conditioned taste aversions have been</p><p>shown to modify neural responses in</p><p>the NTS reinforcing the involvement of</p><p>the hindbrain in hedonistics and sophis-</p><p>ticated taste-related processes [Chang</p><p>and Scott, 1984]. There is also evidence</p><p>to suggest that the NTS contains a mel-</p><p>anocortin system, distinct from that in</p><p>the ARC. POMC neurons in the NTS</p><p>are activated by CCK [Appleyard et al.,</p><p>2005] and POMC overexpression in</p><p>this nucleus produces a sustained hypo-</p><p>phagia and decrease in body weight [Li</p><p>et al., 2007].</p><p>The NTS is immediately adjacent</p><p>to and has reciprocal connections with</p><p>the AP a CVO that lacks the normal</p><p>BBB, contains a variety of peptidergic</p><p>receptors, and has a dense vascular sup-</p><p>ply [see Ferguson and Bains, 1996; Cot-</p><p>trell and Ferguson, 2004 for review].</p><p>The AP is thus uniquely positioned to</p><p>monitor the constituents of peripheral</p><p>circulation, thereby sensing circulating</p><p>satiety signals.</p><p>The AP has been shown to con-</p><p>tain receptors for peripheral peptides</p><p>signaling energy status and electrophysi-</p><p>ological studies have demonstrated indi-</p><p>vidual neurons within the AP to be</p><p>responsive to these molecules. We have</p><p>demonstrated populations of neurons</p><p>within the AP to be responsive to adi-</p><p>ponectin (ADP), a circulating adipokine</p><p>[Fry et al., 2006], CCK [Sun et al.,</p><p>1995], and orexin A [Yang and Fergu-</p><p>son, 2002]. It has also been suggested</p><p>that the orexigenic effect of peripheral</p><p>ghrelin is mediated by the AP [Gilg and</p><p>Lutz, 2006]. In addition, cFos activity is</p><p>increased in the AP and NTS by the</p><p>anorexigenic peptides GLP-1 and amy-</p><p>lin [Rowland et al., 1997], while exog-</p><p>enous administration of CCK increases</p><p>cFos expression in areas where vagal</p><p>afferent fibers terminate [Fraser and</p><p>Davison, 1992]. Receptors for CCK</p><p>and Peptide YY (PYY) have been local-</p><p>ized in the AP [Leslie et al., 1988;</p><p>Niehoff, 1989; Dumont et al., 1996]</p><p>and NTS [Harfstrand et al., 1986;</p><p>Niehoff, 1989]. It has been suggested</p><p>that the anorexic actions of PYY are</p><p>not dependent on vagal afferents but</p><p>rather PYY activates neurons in the AP</p><p>and NTS to cause conditioned taste</p><p>aversions [Halatchev and Cone, 2005].</p><p>The presence of orexin immunoreactive</p><p>neurons in the AP and NTS [Nambu</p><p>et al., 1999] and electrophysiological</p><p>studies from our laboratory demonstrat-</p><p>ing neurons in the AP [Yang and</p><p>Ferguson, 2002] and NTS [Yang and</p><p>Dev Disabil Res Rev � NEUROPHYSIOLOGY OF HUNGER AND SATIETY � SMITH & FERGUSON 99</p><p>19405529, 2008, 2, D</p><p>ow</p><p>nloaded from</p><p>https://onlinelibrary.w</p><p>iley.com</p><p>/doi/10.1002/ddrr.13 by U</p><p>FPI - U</p><p>niversidade Federal do Piaui, W</p><p>iley O</p><p>nline L</p><p>ibrary on [06/10/2024]. See the T</p><p>erm</p><p>s and C</p><p>onditions (https://onlinelibrary.w</p><p>iley.com</p><p>/term</p><p>s-and-conditions) on W</p><p>iley O</p><p>nline L</p><p>ibrary for rules of use; O</p><p>A</p><p>articles are governed by the applicable C</p><p>reative C</p><p>om</p><p>m</p><p>ons L</p><p>icense</p><p>Ferguson, 2003] to be sensitive to</p><p>orexin, suggest that these areas may be</p><p>a central site of action for orexin.</p><p>Thus, the caudal brainstem repre-</p><p>sents a site that plays important roles in</p><p>both short-term and long-term energy</p><p>homeostasis, as a consequence of the</p><p>ability of neurons in this region which</p><p>project to hypothalamic control cen-</p><p>ters, to receive and integrate conver-</p><p>gent vagal, gustatory, and circulating</p><p>signals.</p><p>SHORT-TERM VERSUS</p><p>LONG-TERM REGULATION OF</p><p>FOOD INTAKE AND ENERGY</p><p>HOMEOSTASIS: SIGNALS</p><p>FROM THE PERIPHERY</p><p>Short-term regulation of energy</p><p>homeostasis is mediated primarily by</p><p>peripheral signals from the liver and GI</p><p>tract. In the immediate postprandial</p><p>period, the presence and energy density</p><p>of food is detected</p><p>by stretch receptors</p><p>and chemoreceptors in the gut, releas-</p><p>ing a variety of gut peptides which, in</p><p>turn, signal the brain via neural and en-</p><p>docrine mechanisms (via gut peptides)</p><p>to regulate short-term appetite and sati-</p><p>ety. Regulation of short-term appetite</p><p>and satiety involves signals that initiate</p><p>meal termination, modulate the intake</p><p>of subsequent meals, and/or orexigenic</p><p>modulation. These signals may be inte-</p><p>grated in the brainstem (i.e., vagus</p><p>nerve afferents signal the NTS) or</p><p>through neurons in the hypothalamus</p><p>(i.e., glucose-sensitive neurons in the</p><p>hypothalamus have the ability to</p><p>respond to increases or decreases in cir-</p><p>culating glucose concentrations to ter-</p><p>minate or initiate a meal, respectively.)</p><p>The long-term control of food</p><p>intake also involves signals from the pe-</p><p>riphery and some of the gut peptides</p><p>act to influence both the long-term</p><p>control and short-term control of food</p><p>intake. In addition, there are blood-</p><p>borne substances that indicate utilizable</p><p>or stored fuels that are essential for the</p><p>long-term control of food intake. Many</p><p>of these long-term signals indicating</p><p>metabolic status are derived from adi-</p><p>pose tissue. In the past, adipose tissue</p><p>was largely considered a storage site for</p><p>energy. More recently, however, adipose</p><p>tissue has been found to be an impor-</p><p>tant endocrine tissue capable of secret-</p><p>ing a variety of metabolically active pro-</p><p>teins called adipokines which control</p><p>feeding, thermogenesis, immune and</p><p>neuroendocrine function, and glucose</p><p>and lipid metabolism.</p><p>GUT PEPTIDES MEDIATING</p><p>FEEDING BEHAVIOR</p><p>CCK has been shown to influ-</p><p>ence the short-term regulation of food</p><p>intake by influencing the termination of</p><p>an individual meal and decreasing both</p><p>meal size and duration [Gibbs et al.,</p><p>1973; Kissileff et al., 1981], thereby in-</p><p>hibiting food intake. CCK is rapidly</p><p>released from the small intestine and</p><p>activates gastric and duodenal vagal</p><p>afferent neurons sensitive to volume</p><p>and/or food composition. [Schwartz</p><p>et al., 1993]. The short duration of bio-</p><p>activity (half life of CCK is 1–2 min)</p><p>attributes to the short duration of CCK</p><p>actions [Gibbs et al., 1973]. A synergis-</p><p>tic interaction between leptin and CCK</p><p>to reduce food intake in lean mice has</p><p>also been reported [Barrachina et al.,</p><p>1997]. Although CCK-like immuno-</p><p>reactivity has been observed in the SFO</p><p>and the VMH [Ciofi and Tramu, 1990]</p><p>and cFOS activity is increased in the</p><p>PVN and amygdala [Billig et al., 2001],</p><p>controversy exists over the involvement</p><p>of CCK in the long-term regulation of</p><p>energy balance.</p><p>Short-term regulation of</p><p>energy homeostasis is</p><p>mediated primarily by</p><p>peripheral signals from</p><p>the liver and GI tract.</p><p>Ghrelin, a 28 amino acid peptide</p><p>produced primarily in endocrine cells</p><p>in the gastric mucosa, is expressed in</p><p>the hypothalamus and exerts its effects</p><p>through activation of the growth hor-</p><p>mone secretagogue receptor [Sun et al.,</p><p>2004].</p><p>Ghrelin is the only peripheral</p><p>orexigenic signal known to date. Ghre-</p><p>lin secretion is downregulated under</p><p>conditions of positive energy balance</p><p>such as obesity [Tschop et al., 2000]</p><p>and upregulated under conditions of</p><p>negative energy balance such as star-</p><p>vation and anorexia nervosa [Ariyasu</p><p>et al., 2001]. This preprandial</p><p>increase in ghrelin may signal meal</p><p>initiation [Cummings et al., 2001].</p><p>It has been demonstrated that</p><p>ghrelin reduces the activity of vagal affer-</p><p>ents, while vagotomy blocks ghrelin-</p><p>induced feeding and growth hormone</p><p>secretion [Date et al., 2002; Peeters</p><p>2003], indicating that gastric vagal affer-</p><p>ents comprise a major pathway convey-</p><p>ing ghrelin’s signals for starvation and</p><p>growth hormone secretion to the brain.</p><p>ICV and peripheral injections of ghrelin</p><p>in rodents causes a dose-dependent</p><p>increase in food intake and body weight</p><p>[Tschop et al., 2000; Wren et al., 2001].</p><p>Ghrelin has been shown to influ-</p><p>ence the activity of neurons in the SFO</p><p>[Pulman et al., 2006], providing a route</p><p>through which circulating ghrelin can</p><p>access the CNS. Ghrelin has been shown</p><p>to directly activate NPY/AgRP neurons</p><p>[Cowley et al., 2003; van den Top et al.,</p><p>2004] and inhibit POMC neurons in the</p><p>ARC, the latter effect being abolished in</p><p>the presence of Y1 and GABAA antago-</p><p>nists [Cowley et al., 2003].</p><p>It has been postulated that ghrelin</p><p>may be regarded as a ‘‘thrifty gene</p><p>product,’’ which has evolved to help</p><p>animals consume and store fat effec-</p><p>tively, increasing their chances of sur-</p><p>vival during times of famine [Cum-</p><p>mings et al., 2005].</p><p>Amylin is a 36 amino acid ano-</p><p>rectic peptide, which is coreleased with</p><p>insulin from pancreatic b cells in</p><p>response to food intake. Amylin levels</p><p>rise rapidly following a meal and remain</p><p>elevated during the meal and postpran-</p><p>dially. Amylin decreases food intake</p><p>when administered i.p., ICV, or intra-</p><p>hypothalamically [Chance et al., 1991;</p><p>Morley and Flood, 1991] and delays</p><p>gastric emptying. In contrast to ghrelin,</p><p>the satiety actions of amylin are not</p><p>vagally mediated [Lutz et al., 1995].</p><p>Chronic amylin administration</p><p>reduces food intake and body weight</p><p>(by preferentially decreasing body fat),</p><p>while increasing energy expenditure in</p><p>DIO rats, a rodent model of obesity</p><p>[Roth et al., 2006].</p><p>A role for the sensory CVOs in</p><p>mediating the effect of amylin has been</p><p>suggested. The AP has been shown to</p><p>be involved in the anorectic effect of</p><p>amylin via direct activation of AP neu-</p><p>rons by circulating amylin, as AP lesions</p><p>block the anorectic effects of amylin</p><p>[Lutz et al., 2001]. In addition, the</p><p>SFO has also been suggested to mediate</p><p>amylin effects as studies from our own</p><p>laboratory have demonstrated that</p><p>amylin directly influences a population</p><p>of neurons in the SFO. Interestingly,</p><p>neurons in the SFO that are activated</p><p>by amylin are inhibited or unaffected by</p><p>ghrelin, a peripheral orexigenic peptide,</p><p>and vice versa [Pulman et al., 2006].</p><p>Although a direct role for amylin on</p><p>the neural circuits controlling the inhi-</p><p>bition of feeding has not been estab-</p><p>lished, it is also possible that the ano-</p><p>100 Dev Disabil Res Rev � NEUROPHYSIOLOGY OF HUNGER AND SATIETY � SMITH & FERGUSON</p><p>19405529, 2008, 2, D</p><p>ow</p><p>nloaded from</p><p>https://onlinelibrary.w</p><p>iley.com</p><p>/doi/10.1002/ddrr.13 by U</p><p>FPI - U</p><p>niversidade Federal do Piaui, W</p><p>iley O</p><p>nline L</p><p>ibrary on [06/10/2024]. See the T</p><p>erm</p><p>s and C</p><p>onditions (https://onlinelibrary.w</p><p>iley.com</p><p>/term</p><p>s-and-conditions) on W</p><p>iley O</p><p>nline L</p><p>ibrary for rules of use; O</p><p>A</p><p>articles are governed by the applicable C</p><p>reative C</p><p>om</p><p>m</p><p>ons L</p><p>icense</p><p>rectic effect of amylin is due to the</p><p>reduced expression of orexigenic neuro-</p><p>peptides in LHA [Barth et al., 2003] or</p><p>increased expression of POMC mRNA</p><p>in the ARC [Roth et al., 2006].</p><p>PYY, a 36 amino acid peptide</p><p>produced by the intestinal L-cells, and</p><p>PYY3–36, the active anorectic form of</p><p>the peptide, circulates in levels propor-</p><p>tional to the energy content of the meal</p><p>[Lin and Chey, 2003] with the peak</p><p>levels occurring 1–2 hr postprandially</p><p>[Adrian et al., 1985]. PYY3–36 shows</p><p>high affinity for the Y2 receptors, but</p><p>also demonstrates lower affinity for the</p><p>Y1 and Y5 receptor [Larhammar, 1996].</p><p>Peripheral administration of PYY3–36</p><p>has been shown to decrease food intake</p><p>and weight gain [Batterham et al.,</p><p>2002; Challis et al., 2003].</p><p>PYY may play a role in the short-</p><p>term regulation of energy balance, as</p><p>PYY administration causes a delay in</p><p>gastric emptying, secretions from the</p><p>stomach and pancreas, while increasing</p><p>the absorption of fluids and electrolytes</p><p>from the intestine [Allen et al., 1984;</p><p>Chen and Rogers, 1995].</p><p>A role for the long-term effects</p><p>on energy regulation is supported by</p><p>electrophysiological studies demonstrat-</p><p>ing that PYY3–36 depolarizes and</p><p>increases action potential frequency in</p><p>POMC neurons in the ARC [Bat-</p><p>terham et al., 2002]. In addition,</p><p>PYY3–36 has been shown to act presy-</p><p>naptically at Y2 receptors to decrease</p><p>glutamatergic transmission between the</p><p>NTS and GI projecting neurons in the</p><p>DMV [Browning and Travagli, 2003].</p><p>Glucagon-like peptides (GLP-</p><p>1 and GLP-2) GLP-1 and GLP-2 are</p><p>produced by the post-translational proc-</p><p>essing</p><p>of preproglucagon gene in the L-</p><p>cells in the distal intestinal tract (like</p><p>PYY) and released into circulation fol-</p><p>lowing a meal [Hoyt et al., 1996]. In</p><p>the periphery, GLP-1 has been shown</p><p>to stimulate glucose-dependent insulin</p><p>secretion and inhibit gastric emptying</p><p>[Nauck et al., 1997]. Acute GLP-1</p><p>administration has no effect on food</p><p>intake or body weight due to a very</p><p>short half life [Deacon et al., 1995].</p><p>Chronic central administration of</p><p>GLP-1 decreases food intake [Turton</p><p>et al., 1996] and body weight and indu-</p><p>ces c-Fos expression in the PVN and</p><p>amygdala [Turton et al., 1996], while</p><p>the ARC, NTS, and AP showed only</p><p>Fig. 2. Brainstem circuitry involved in hunger and satiety. The upper sagital section (0.4-mm midline) shows the relative location of CNS structures</p><p>highlighted in this review. Bottom right: This expanded sagital view of the caudal brainstem outlines the major anatomical projections of brainstem</p><p>nuclei involved in the control of feeding behavior. The NTS (nucleus tractus solitarius) shares extensive reciprocal connections with the AP (area post-</p><p>rema), a circumventricular organ at the level of the fourth ventricle and the PVN (paraventricular nucleus) in the hypothalamus. In addition, the NTS</p><p>receives afferent information from the DVC and the vagus. The coronal section to the left shows the relative anatomical locations of these brainstem</p><p>nuclei. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]</p><p>Dev Disabil Res Rev � NEUROPHYSIOLOGY OF HUNGER AND SATIETY � SMITH & FERGUSON 101</p><p>19405529, 2008, 2, D</p><p>ow</p><p>nloaded from</p><p>https://onlinelibrary.w</p><p>iley.com</p><p>/doi/10.1002/ddrr.13 by U</p><p>FPI - U</p><p>niversidade Federal do Piaui, W</p><p>iley O</p><p>nline L</p><p>ibrary on [06/10/2024]. See the T</p><p>erm</p><p>s and C</p><p>onditions (https://onlinelibrary.w</p><p>iley.com</p><p>/term</p><p>s-and-conditions) on W</p><p>iley O</p><p>nline L</p><p>ibrary for rules of use; O</p><p>A</p><p>articles are governed by the applicable C</p><p>reative C</p><p>om</p><p>m</p><p>ons L</p><p>icense</p><p>modest expression [Larsen et al., 1997].</p><p>It has been suggested that GLP-1 may</p><p>decrease body weight by decreasing</p><p>food intake and increasing thermogene-</p><p>sis [O’Shea et al., 1996].</p><p>High-affinity binding sites for</p><p>GLP-1 have been identified in hypo-</p><p>thalamus and brainstem [Merchenthaler</p><p>et al., 1999], and peripheral and central</p><p>GLP administration influences neurons</p><p>in the ARC, PVN, AP, and NTS</p><p>[Larsen et al., 1997].</p><p>Microinjection of GLP-1 into the</p><p>PVN decreases food intake, supporting</p><p>a role for the PVN in mediating the</p><p>central effects of GLP-1 [McMahon</p><p>and Wellman, 1997]. GLP-1 has been</p><p>shown to decrease NPY-induced feed-</p><p>ing [Turton et al., 1996; Furuse et al.,</p><p>1997] and it has been suggested that</p><p>GLP-1 may act at the level of the PVN</p><p>to alter NPY signaling, causing a</p><p>decrease NPY release thereby inhibiting</p><p>feeding.</p><p>Experiments demonstrating that</p><p>administration of a GLP-1 antagonist</p><p>(exendin) blocks the effects of leptin on</p><p>food intake [Goldstone et al., 1997]</p><p>and that peripheral leptin administra-</p><p>tion increases hypothalamic GLP-1</p><p>peptide in food-restricted mice [Gold-</p><p>stone et al., 2000] suggest that leptin</p><p>may signal through the central GLP-1</p><p>pathway.</p><p>Insulin has been suggested to</p><p>function as an adiposity signal involved</p><p>in the modulation of energy balance.</p><p>Insulin is a hormone produced by the</p><p>pancreas and insulin levels are positively</p><p>correlated with adiposity [Bagdade</p><p>et al., 1967]. Thus, visceral fat is impor-</p><p>tant in both insulin sensitivity and cir-</p><p>culating insulin levels. Insulin levels</p><p>increase rapidly following a meal.</p><p>Administration of insulin into the brain</p><p>reduces food intake and body weight</p><p>[Foster et al., 1991], and mice with a</p><p>genetic deletion of neuronal insulin</p><p>receptors are hyperphagic and obese</p><p>[Masaki et al., 2004]. ICV administra-</p><p>tion of an insulin mimetic causes a</p><p>dose-dependent reduction of food</p><p>intake and body weight in normal rats</p><p>and increased the expression of POMC</p><p>mRNA [Air et al., 2002]. Insulin recep-</p><p>tors have been demonstrated in the</p><p>ARC, VMN, and PVN in the hypo-</p><p>thalamus [Pardini et al., 2006a]. Within</p><p>the ARC, insulin receptors were colo-</p><p>calized with a-MSH and NPY, suggest-</p><p>ing that the NPY and melanocortin sys-</p><p>tems are important for the effects of in-</p><p>sulin on food intake and body weight.</p><p>ICV insulin administration during fast-</p><p>ing has been shown to prevent fasting</p><p>induced increase in NPY in the PVN</p><p>and NPY mRNA in the ARC</p><p>[Schwartz et al., 1992].</p><p>In addition to these hypothalamic</p><p>nuclei, areas in the brainstem including</p><p>the AP, NTS, and the DMV also con-</p><p>tain insulin receptors [Pardini et al.,</p><p>2006].</p><p>ADIPOKINES: LONG-TERM</p><p>CONTROL OF ENERGY</p><p>HOMEOSTASIS</p><p>Leptin is a 16 kDa adipokine that</p><p>circulates at levels in proportion to adi-</p><p>pose tissue mass. Leptin has been shown</p><p>to be an important sensor of energy</p><p>balance. During periods of weight gain</p><p>(when food intake exceeds energy ex-</p><p>penditure) circulating leptin levels rise,</p><p>causing decreased energy intake and</p><p>increased energy expenditure. Chronic</p><p>leptin infusion to obese and wild-type</p><p>animals reduces food intake and</p><p>decreases body weight by preferentially</p><p>decreasing fat mass [Halaas et al., 1995].</p><p>Leptin has been shown to act synergisti-</p><p>cally with CCK to decrease food intake</p><p>and body weight in lean and obese rats</p><p>[Wang et al., 2000b], and modulates</p><p>behavioral and neural responses to CCK</p><p>[Emond et al., 1999]. The signaling</p><p>form of the leptin receptor is found in</p><p>the ARC, PVN, DMH, and LHA of</p><p>the hypothalamus and leptin has been</p><p>shown to cause the downregulation of</p><p>the orexigenic neuropeptides, NPY,</p><p>MCH, ORXs, and AgRP while caus-</p><p>ing upregulation of the anorexigenic</p><p>peptides, a MSH, CART, and CRH</p><p>[see Jequier, 2002 for review].</p><p>ADP is a 246 amino acid protein</p><p>produced exclusively by mature adipo-</p><p>cytes. ADP has been shown to modulate</p><p>a number of metabolic processes includ-</p><p>ing glucose regulation, fatty acid catabo-</p><p>lism, insulin sensitivity, and weight loss.</p><p>Two receptors (AdipoR1 and AdipoR2)</p><p>have been identified for ADP and are</p><p>widely distributed throughout the pe-</p><p>riphery and in the brain. Central actions</p><p>for ADP have been demonstrated by</p><p>studies, showing that ICV ADP adminis-</p><p>tration causes decreases in serum glucose,</p><p>increased insulin sensitivity, and de-</p><p>creased body weight [see Ahima, 2006</p><p>for review]. Studies from our own labo-</p><p>ratory have demonstrated the presence of</p><p>AdipoR1 and R2 mRNA in the AP</p><p>[Fry et al., 2006], and electrophysiologi-</p><p>cal studies have demonstrated neurons</p><p>within the AP to be sensitive to ADP</p><p>[Fry et al., 2006].</p><p>CONCLUSION</p><p>Clearly the past 15 years have led</p><p>to a tremendous explosion in our</p><p>knowledge of the complex brain cir-</p><p>cuitry involved in controlling energy</p><p>balance (Fig. 2). New areas of the brain</p><p>that contribute to this integrated control</p><p>system have been identified, and the</p><p>important roles they play in controlling</p><p>feeding and/or satiety have been slowly</p><p>unraveled. At the same time, important</p><p>new signaling molecules have been dis-</p><p>covered (leptin, PYY, ADP, ghrelin) and</p><p>the contributions of each of them to</p><p>the integrated control of energy balance</p><p>have been slowly elucidated. Perhaps</p><p>what this explosion of knowledge</p><p>emphasizes more than anything is that</p><p>we should not anticipate a simplistic</p><p>dominant peptide or all important nu-</p><p>cleus models to explain the complex</p><p>CNS regulation of energy homeostasis.</p><p>The emerging literature suggests a sys-</p><p>tem of interconnected CNS nuclei</p><p>gathering ‘‘energy status’’ information</p><p>from all available sources, information</p><p>which when integrated allows modifica-</p><p>tion in intake, storage, and excretion</p><p>that are directed toward maintenance of</p><p>a balanced energy state. n</p><p>REFERENCES</p><p>Acuna-Goycolea C, van den Pol A. 2004. 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