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2The Neuroendocrine Control of EnergyBalanceRobert H. LustigCONTENTSINTRODUCTIONCOMPONENTS OF THEAFFERENTSYSTEMCENTRALPROCESSINGTHEEFFERENTSYSTEMTHEHEDONICPATHWAY OFFOODREWARDTHEAMYGDALA AND THESTRESSPATHWAY OFFOODINTAKENEGATIVEFEEDBACK OFENERGYBALANCE–THERESPONSETOCALORICDEPRIVATIONLEPTINRESISTANCESUMMARYREFERENCESKey Words:Leptin, hypothalamus, vagus, reward, stress, ghrelin, insulin, endocannabinoids,sympathetic nervous system, amygdalaINTRODUCTIONWhen discussing the causes of obesity, it is easy to point fingers at the individual. “Gluttony” and“sloth” after all are two of the seven “deadly sins.” Obese adults and their children are assumed tohave “free choice” with regard to food intake and energy expenditure and are therefore “responsible”for their metabolic “fates”(1). But no child chooses to become obese; indeed the quality of life of anobese child is similar to that of children receiving cancer chemotherapy(2). Furthermore, the strikingincreases in obesity prevalence in 2- to 5-year-old children(3)suggest that there are other explanationsfor the obesity epidemic. Here I explore the biochemical determinants that control energy balanceand argue that difficulties in achieving and/or maintaining weight loss reflect the potency of centralreinforcement systems, the effects of stress, and the resilience of the body’s adaptive responses.The discovery of leptin in 1994(4)revealed a complex neuroendocrine axis regulating energy bal-ance. Much of what we know about energy balance is derived from studies of animal models, butclinical studies provide invaluable insights.From:Edited by: M. Freemark, DOI 10.1007/978-1-60327-874-4_2,C©Springer Science+Business Media, LLC 201015Contemporary Endocrinology: Pediatric Obesity: Etiology, Pathogenesis, and Treatment
16LustigFig. 1.The homeostatic pathway of energy balance. Afferent (blue), central (black), and efferent (white) pathwaysare delineated. The hormones insulin, leptin, ghrelin, and peptide YY(3–36)(PYY3–36) provide afferent informationto the ventromedial hypothalamus regarding short-term energy metabolism and energy sufficiency. From there, theventromedial hypothalamus elicits anorexigenic (α-melanocyte-stimulating hormone, cocaine–amphetamine-regulatedtranscript) and orexigenic (neuropeptide Y, agouti-related protein) signals to the melanocortin-4 receptor in the par-aventricular nucleus and lateral hypothalamic area. These lead to efferent output via the locus coeruleus and the nucleustractus solitarius, which activate the sympathetic nervous system, causing the adipocyte to undergo lipolysis; or thedorsal motor nucleus of the vagus, which activates the vagus nerve to store energy, both by increasing pancreatic insulinsecretion and (in rodents) by increasing adipose tissue sensitivity to insulin. 5-HT, serotonin (5-hydroxytryptamine);DMV, dorsal motor nucleus of the vagus; LC, locus coeruleus; LHA, lateral hypothalamic area; NE, norepinephrine;NTS, nucleus tractus solitarius; PVN, paraventricular nucleus; VMH, ventromedial hypothalamus. From Lustig(21).(Courtesy of Nature Publishing Group, with permission.)The neuroendocrine axis is composed of three arms (Fig. 1). The first is theafferent arm,whichconveys peripheral information on hunger and peripheral metabolism (in the form of hormonal andneural inputs) to the hypothalamus. The second is acentral processing unit, consisting of various areaswithin the hypothalamus. These include (a) the ventromedial hypothalamus (VMH; consisting of theventromedial (VMN) and arcuate (ARC) nuclei), which integrates afferent peripheral signals as well asother central stimuli, and (b) the paraventricular nuclei (PVN) and lateral hypothalamic area (LHA),
The Neuroendocrine Control of Energy Balance17which serve as a gated neurotransmitter system to alter neural signals for changes in feeding andenergy expenditure. Other brain areas serve as neuromodulators of this system. The third componentis anefferent armof autonomic effectors with origins in the locus coeruleus (LC) and dorsal motornucleus of the vagus (DMV), which regulate energy intake, expenditure, and storage(5,6).Anatomicdisruptions or genetic or metabolic alterations of either the afferent, central processing, or efferentarms can alter energy intake or expenditure, leading to either obesity or cachexia.There are three primary stimuli to eat:hunger, reward,andstress. While each of these internal phe-nomena infer altered behavior, each is actually mediated through a complex cascade of biochemicalsthat perturb the negative feedback pathway of energy balance and “drive” food intake in stereotypicalpatterns.COMPONENTS OF THE AFFERENT SYSTEMAlimentary Afferents That Promote HungerThe afferent vagus:The vagus nerve is the primary neural connection between the brain and the gut.The afferent vagus nerve conveys information regarding mechanical stretch of the stomach and duo-denum and feelings of gastric fullness to the nucleus tractus solitarius (NTS)(7). Of note, the effectsof alimentary neuropeptides (below) on hunger and satiety are obviated by concomitant vagotomy,implicating the afferent vagus as the primary mediator of alimentary energy balance signals(8–10).Ghrelin:Ghrelin, an octanoylated 28-amino acid peptide, was discovered serendipitously during asearch for the endogenous ligand of the growth hormone secretagogue receptor (GHS-R)(11). Ghrelininduces GH release through stimulation of the pituitary GHS-R. The endogenous secretion of ghrelinfrom the stomach is high during fasting and decreased by nutrient administration; volumetric stretchingof the stomach wall has no effect. In addition to interacting with pituitary GHS receptors, ghrelinbinds to the GHS-R in the VMH and thereby increases hunger, food intake, and fat deposition(12,13).Ghrelin also increases the respiratory quotient (RQ) in rats, suggesting a reduction of fat oxidation.Ghrelin appears to link the lipolytic effect of GH with hunger signals and is probably important in theacute response to fasting. In humans, ghrelin levels rise with increasing subjective hunger and peakat the time of voluntary food consumption(14), suggesting that ghrelin acts on the VMH to triggermeal initiation. Ghrelin infusion increases food intake in humans(15). However, plasma ghrelin levelsare low in most obese individuals and increase with fasting(16), suggesting that ghrelin is a responseto, rather than a cause of, obesity. The Prader–Willi syndrome, an obesity disorder associated withhyperghrelinemia, may be a unique exception (see Chapter 4 by Haqq, this volume).Alimentary Afferents That Promote SatietyPeptide YY3–36(PYY3–36):PYY3–36is a gastrointestinal signal to control meal volume(17).Thispeptide fragment is secreted by intestinal L-cells following exposure to nutrients; PYY crosses theblood–brain barrier and binds to the Y2receptor in the VMH. Activation of this receptor reducesneuropeptide Y (NPY) mRNA in neurons of the orexigenic arm of the central processing unit (below).In non-obese humans, infusion of PYY3–36during a 12-h period decreased the total volume of foodingested from 2,200 to 1,500 k/cal but had no effect on food ingested during the next 12-h interval(17).Although the pharmacology of this peptide is being elucidated, and agonists are being developed, itsspecific role in obesity is not yet known.Glucagon-like peptide-1 (GLP-1):Those same intestinal L-cells produce GLP-1 through post-translational processing of the preproglucagon molecule. Two equipotent forms of GLP-1 aregenerated: a glycine-extended form GLP-17–37and the amidated peptide GLP-17–36amide(18).GLP-1 acts on the stomach to inhibit gastric emptying; this increases the time available for absorp-tion of a meal. GLP-1 also activates its receptor onβ-cells to stimulate cAMP production, protein
18LustigFig. 2.Central regulation of leptin signaling, autonomic innervation of the adipocyte andβ-cell, and the starvationresponse. (a) The arcuate nucleus transduces the peripheral leptin signal as one of sufficiency or deficiency. In leptinsufficiency, efferents from the hypothalamus synapse in the locus coeruleus, which stimulates the sympathetic ner-vous system. In leptin deficiency or resistance, efferents from the hypothalamus stimulate the dorsal motor nucleus ofthe vagus. (b) Autonomic innervation and hormonal stimulation of white adipose tissue. In leptin sufficiency, nore-pinephrine binds to theβ3-adrenergic receptor, which stimulates hormone-sensitive lipase, promoting lipolysis ofstored triglyceride into free fatty acids. In leptin deficiency or resistance, vagal acetylcholine increases adipose tissueinsulin sensitivity (documented only in rats to date), promotes uptake of glucose and free fatty acids for lipogenesis,and promotes triglyceride uptake through activation of lipoprotein lipase. (c) Autonomic innervation and hormonalstimulation of theβ-cell. Glucose entering the cell is converted to glucose-6-phosphate by the enzyme glucokinase,generating ATP, which closes an ATP-dependent potassium channel, resulting in cell depolarization. A voltage-gatedcalcium channel opens, allowing for intracellular calcium influx, which activates neurosecretory mechanisms leadingto insulin vesicular exocytosis. In leptin sufficiency, norepinephrine binds toα2-adrenoceptors on theβ-cell membraneto stimulate inhibitory G proteins, decrease adenyl cyclase and its product cAMP, and thereby reduce protein kinaseA levels and insulin release. In leptin deficiency or resistance, the vagus stimulates insulin secretion(105). Octreotidebinds to a somatostatin receptor on theβ-cell, which is coupled to the voltage-gated calcium channel, limiting cal-cium influx and the amount of insulin released in response to glucose (reprinted with kind permission of SpringerScience and Business media).α2-AR,α2-adrenergic receptor;β3-AR,β3-adrenergic receptor; AC, adenyl cyclase;
The Neuroendocrine Control of Energy Balance19kinase A activation, and insulin secretion (Fig. 2) and thereby improves glucose tolerance in patientswith type 2 diabetes. GLP-1 also stimulatesβ-cell replication and increasesβ-cell mass(19). Lastly,GLP-1 reduces food intake by reducing gastric emptying and corticotropin-releasing hormone (CRH)signaling in the PVN and increasing leptin signaling in the VMH(20).Cholecystokinin (CCK):CCK is an 8-amino acid gut peptide released in response to a caloric load.It circulates and binds to CCKAreceptors in the pylorus, vagus nerve, NTS, and area postrema(7)topromote satiety.Metabolic Afferents Controlling Energy BalanceLeptin:The balance of energy intake and expenditure is normally regulated very tightly (within0.15% per year) by the hormone leptin. Leptin is a 167-amino acid hormone produced by whiteadipocytes. Leptin’s primary neuroendocrine role is to mediate information about the size of periph-eral adipocyte energy stores to the VMH(4,21). As such, it is a prerequisite signal to the VMH for theinitiation of high-energy processes such as puberty and pregnancy(22,23). Leptin reduces food intakeand increases the activity of the sympathetic nervous system (SNS)(24). Conversely, low leptin levelsinfer diminished energy stores, which impact on the VMH to increase food intake and reduce energyexpenditure. Serum leptin concentrations drop precipitously (and to a greater degree than fat mass)during short-term fasting(25,26), and it seems likely that leptin functions more as a peripheral signalto the hypothalamus of inadequate caloric intake than as a hunger or satiety signal per se(27).In the fed state, circulating levels of leptin correlate with percent body fat(28,29). Leptin produc-tion by adipocytes is stimulated by insulin and glucocorticoids(30,31)and inhibited byβ-adrenergicstimulation(27). Programming of relative leptin concentrations by early caloric intake may be onemechanism that links early overnutrition with later obesity(32).Leptin binds to its receptor (a member of the Class 1 cytokine receptor superfamily) on target VMHneurons. There are four receptor isoforms formed by differential splicing: ObRa, an isoform witha shortened intracellular domain, which may function as a transporter; ObRb, the intact full-lengthreceptor; ObRc, also with a short intracellular domain; and ObRe, which lacks an intracellular domainand functions as a soluble receptor(33).As leptin binds to its VMH receptor, three neuronal signals are transduced. The first is openingof an ATP-sensitive potassium channel, which hyperpolarizes the neuron and decreases its firing rate(34). The second is the activation of a cytoplasmic Janus kinase 2 (JAK2), which phosphorylates atyrosine moiety on proteins of a family called signal transduction and transcription (STAT-3)(35).Thephosphorylated STAT-3 translocates to the nucleus, where it promotes leptin-dependent gene tran-scription(36). Third, leptin activates the insulin receptor substrate 2/phosphatidylinositol-3-kinase(IRS2/PI3K) second messenger system in ARC neurons, which increases neurotransmission of thecentral anorexigenic signaling pathway(37).Fig. 2.(continued) ACh, acetylcholine; DAG, diacylglycerol; DMV, dorsal motor nucleus of the vagus; FFA, freefatty acids; Gi, inhibitory G protein; GK, glucokinase; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor;Glu-6-PO4, glucose-6-phosphate; Glut4, glucose transporter-4; HSL, hormone-sensitive lipase; IML, intermediolat-eral cell column; IP3, inositol triphosphate; LC, locus coeruleus; LHA, lateral hypothalamic area; LPL, lipoproteinlipase; MARCKS, myristoylated alanine-rich protein kinase C substrate; NE, norepinephrine; PIP2, phosphatidyli-nositol pyrophosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PVN, paraventricularnucleus; SSTR5, somatostatin-5 receptor; TG, triglyceride; VCa, voltage-gated calcium channel; VMH, ventromedialhypothalamus; SUR, sufonylurea receptor. From Lustig(21). (Courtesy of Nature Publishing Group, with permission.)
20LustigInsulin:Insulin plays a critical role in energy balance(38). In peripheral tissues it promotesglycogenesis, muscle protein synthesis, and fat storage and regulates the production and action ofneuroendocrine modulators of nutrient uptake and metabolism. But insulin is also transported acrossthe blood–brain barrier and binds to receptors in a subpopulation of VMH neurons(39,40), suggestingthat it acts centrally to regulate food intake. Indeed in animals, acute and chronic intracerebroven-tricular insulin infusions decrease feeding behavior and induce satiety(41–43). The data on acuteand chronic peripheral insulin infusions are less clear. Studies of overinsulinized diabetic rats demon-strate increased caloric intake (in order to prevent subacute hypoglycemia) and the development ofperipheral insulin resistance(44,45). Chronic peripheral insulin infusions in experimental animalsdecrease hepatic and skeletal muscle glucose uptake by reducing Glut4 expression but do not alteradipose tissue glucose uptake(46,47). One human study injecting short-term insulin peripherally dur-ing meals did not demonstrate an effect on satiety(48). Insulin acutely activates the insulin receptorsubstrate 2/phosphatidylinositol-3-kinase (IRS2/PI3K) second messenger system in arcuate nucleus(ARC) neurons(49), which increases neurotransmission of the central anorexigenic signaling path-way (see below). The importance of CNS insulin action was underscored by the phenotype of a brain(neuron)-specific insulin receptor knockout (NIRKO) mouse, which cannot transduce a CNS insulinsignal(50). NIRKO mice become hyperphagic, obese, and infertile with age and have high peripheralinsulin levels. These findings suggest that peripheral insulin mediates a satiety signal in the VMHto help control energy balance(51). Various knockouts of the insulin signal transduction pathway thatreduce insulin signaling lead to an obese phenotype(52,53), while those that increase insulin signalinglead to a lean phenotype(54,55).CENTRAL PROCESSINGPeripheral afferent (neural and hormonal) signals reaching VMH neurons are integrated by agated neural circuit designed to control both energy intake and expenditure (Fig. 2). This circuitconsists of two arms: the anorexigenic arm, which contains neurons expressing the co-localized pep-tides proopiomelanocortin (POMC) and cocaine/amphetamine-regulated transcript (CART), and theorexigenic arm, which contains neurons with the co-localized peptides neuropeptide Y (NPY) andagouti-related protein (AgRP). Ghrelin receptor immunoreactivity co-localizes with NPY and AgRPneurons, while insulin and leptin receptors are located on both POMC/CART and NPY/AgRP neuronsin the VMH(56), suggesting divergent regulation of each arm. These two arms compete for occupancyof melanocortin receptors (MCRs; either MC3RorMC4R) in the PVN and LHA.Anorexigenesis, POMC/α-MSH, and CARTPOMC is differentially cleaved in different tissues and neurons. The ligandα-melanocyte-stimulating hormone (α-MSH) is the primary product involved in anorexigenesis. Both overfeedingand peripheral leptin infusion induce the synthesis of POMC andα-MSH within the ARC(57).α-MSH induces anorexia by binding to melanocortin receptors within the PVN or LHA. CART isa hypothalamic neuropeptide induced by leptin and reduced by fasting. Intrahypothalamic infusionblocks appetite, while antagonism of endogenous CART increases caloric intake(58).Orexigenesis, NPY, and AgRPNPY and AgRP co-localize to a different set of neurons within the ARC, immediately adjacent tothose expressing POMC/CART(59). NPY has numerous functions within the hypothalamus, includinginitiation of feeding, puberty, and regulation of gonadotropin secretion and adrenal responsiveness(60,61). NPY is the primary orexigenic peptide. ICV infusion of NPY in rats causes hyperphagia,
The Neuroendocrine Control of Energy Balance21energy storage, and obesity(62,63). These actions are mediated through Y1and Y5receptors. Fastingand weight loss increase NPY expression in the ARC, accounting for increased hunger, while PYY3–36(through Y2receptors) and leptin decrease NPY mRNA(17,64).AgRP is the human homolog of the protein agouti, which is present in abundance in the yellow(Ay-a) mouse(65). This protein is an endogenous competitive antagonist of all melanocortin receptors(MCR), accounting for the yellow color in these mice. In the presence of large amounts of AgRP atthe synaptic cleft in the PVN,α-MSH cannot bind to the MC4R to induce satiety(66).Other Neuroendocrine Modulators of Energy BalanceNorepinephrine (NE):NE neurons in the locus coeruleus synapse on VMH neurons to regulate foodintake(67). The actions of NE on food intake seem paradoxical, as intrahypothalamic NE infusionsstimulate food intake through effects on centralα2-andβ-adrenergic receptors(68), whereas centralinfusion ofα1-agonists markedly reduces food intake(69).Serotonin (5-HT):Five lines of evidence impicate a role for 5-HT in the perception of satiety: (1)Injection of 5-HT into the hypothalamus increases satiety, particularly with respect to carbohydrate(70); (2) central administration of 5-HT2creceptor agonists increases satiety, while antagonists inducefeeding(71); (3) administration of selective 5-HT reuptake inhibitors induces early satiety(72);(4)leptin increases 5-HT turnover(73); and (5) the 5-HT2cR-KO mouse exhibits increased food intake andbody weight(74). The role of 5-HT in the transduction of the satiety signal may have both central andperipheral components, as intestinal 5-HT secreted into the bloodstream during a meal may impact GIneuronal function and muscle tone while binding to 5-HT receptors in the NTS (see earlier) to promotesatiety(75).Melanin-concentrating hormone (MCH):MCH is a 17-amino acid peptide expressed in the zonaincerta and LHA. MCH neurons synapse on neurons in the forebrain and the locus coeruleus.MCH appears to be important in behavioral responses to food such as anxiety and aggression(76).Expression of the peptide is upregulated inob/obmice. MCH knockout mice are hypophagic and lean(77), while transgenic MCH-overexpressing mice develop obesity and insulin resistance(78).ICVadministration of MCH stimulates food intake, similar to that seen with NPY administration(79).Orexins A and B:These 33- and 28-amino acid peptides, respectively, have been implicated inboth energy balance and autonomic function in mice(80). Orexin knockout mice develop narcolepsy,hypophagia, and obesity(81), suggesting that orexins bridge the gap between the afferent and efferentenergy balance systems(82). Orexins in the LHA stimulate neuropeptide Y (NPY) release, which mayaccount for their induction of food intake; they also increase corticotropin-releasing factor (CRF) andsympathetic nervous system (SNS) output to promote wakefulness, energy expenditure, learning andmemory, and the hedonic reward system (see later)(83). Conversely, orexin neurons in the perifornicaland dorsomedial hypothalamus regulate arousal and the response to stress.Endocannabinoids (ECs):It has long been known that marijuana and its major constituent tetrahy-drocannabinol stimulate food intake. Recently, endogenous ECs and the CB1receptor have been linkedto energy balance and the metabolic syndrome(84).TheCB1receptor is expressed in corticotropin-releasing factor (CRH) neurons in the PVN, in CART neurons in the VMN, and in MCH- andorexin-positive neurons in the LHA and perifornical region. Fasting and feeding are associated withhigh and low levels of ECs in the hypothalamus, respectively. CB1receptor knockout mice haveincreased CRH and reduced CART expression. Hypothalamic EC levels are increased in leptin-deficientob/obmice; intravenous leptin reduces EC levels, indicating that a direct negative controlis exerted by leptin on the EC system. Glucocorticoids increase food intake in part by stimulating ECsynthesis and secretion, while leptin blocks this effect(85). Finally, the presence of CB1receptors on
22Lustigafferent vagal neurons suggests that endocannabinoids may be involved in mediating satiety signalsoriginating in the gut.Melanocortin Receptors (MCR) and Central Neural IntegrationThe human MC4R localizes to chromosome 2 and is a 7-transmembrane G-coupled receptor,encoded by an intronless 1 kB gene. The binding of hypothalamicα-MSH to the MC4R in the PVNand LHA results in a state of satiety, whereas ICV administration of MC4R antagonists stimulatesfeeding. These observations suggest that the MC4R transduces satiety information on caloric suffi-ciency. The role of the MC4R in human obesity is well known; in some studies, 2.5–5% of morbidlyobese adults had heterozygous mutations in the MC4R(86).IntheMC3R knockout mouse, a differentphenotype is seen. These animals are obese but hypophagic and have increased body fat relative tolean body mass. They gain weight on either low- or high-fat chow and do not change caloric oxidationin response to changes in dietary fat content. These findings suggest a defect in energy expenditure(87). The role of the MC3R in human obesity is less clear. Functional variants of the MC3R have beennoted in certain populations(88,89). One hypothesis is that the MC4R modulates energy intake, whilethe MC3R modulates energy expenditure(90).THE EFFERENT SYSTEMThe MCRs in the PVN and LHA transduce signals emanating from the VMH in order to modulateactivity of the sympathetic nervous system (SNS), which promotes energy expenditure, and the efferentvagus, which promotes energy storage (Fig. 2).The Sympathetic Nervous System (SNS) and Energy ExpenditureAnorexigenic pressure increases energy expenditure through activation of the SNS(91).Forinstance, leptin administration toob/obmice increases brown adipose tissue thermogenesis, renovas-cular activity, and spontaneous motor activity; all are associated with increased energy expenditure andfacilitate weight loss(92). Similarly, insulin administration acutely increases SNS activity in normalrats and in humans(93,94).The SNS increases energy expenditure by activating lipolysis in white and brown adipose tissueand promoting energy utilization in skeletal and cardiac muscle. Binding of catecholamines to muscleβ2-adrenergic receptors(95)stimulates glycogenolysis, myocardial energy expenditure, and increasesin glucose and fatty acid oxidation and increases protein synthesis(96,97). Binding toβ3-adrenergicreceptors in white and brown adipose tissue increases cAMP, which activates protein kinase A (PKA)(98). In white adipose PKA activates hormone-sensitive lipase, which generates ATP from hydrolysisof triglyceride. In brown fat PKA phosphorylates CREB, which induces expression of PGC-1α.PGC-1αin turn binds to the uncoupling protein-1 (UCP-1) promoter and increases its expression(99,100).UCP1 is an inner membrane mitochondrial protein that uncouples proton entry from ATP syn-thesis(101); therefore, UCP1 expression dissipates energy as heat and thereby reduces the energyefficiency of brown fat. UCP1 is induced by FFAs derived from triglyceride breakdown; FFAs releasedfrom adipocytes are transported to the liver, where they are utilized for energy through ketogenesis.Lipolysis reduces leptin expression; thus a negative feedback loop is achieved between leptin and theSNS (Fig. 2).The Efferent Vagus and Energy StorageIn response to declining levels of leptin and/or persistent orexigenic pressure, the LHA and PVNsend efferent projections residing in the medial longitudinal fasciculus to the dorsal motor nucleus of
The Neuroendocrine Control of Energy Balance23the vagus nerve (DMV), activating the efferent vagus(102). The efferent vagus opposes the SNS bypromoting energy storage in four ways: (a) it reduces myocardial oxygen consumption by reducingheart rate; (b) it increases nutrient absorption by promoting GI peristalsis and pyloric opening; (c) itincreases insulin sensitivity by potentiating the uptake of glucose and FFA into adipose tissue; and (d)it increases postprandial insulin secretion, which increases fat deposition(103–106).Retrograde tracing of white adipose tissue reveals a wealth of efferents originating at the DMV(106). These efferents synapse on M1muscarinic receptors, which increase insulin sensitivity.Denervation of white adipose tissue reduces glucose and FFA uptake and increases HSL expression.Thus, vagal modulation of the adipocyte augments storage of both glucose and FFAs by improvingadipose insulin sensitivity and reducing triglyceride breakdown(107)(Fig. 2).The DMV also sends efferent projections to theβ-cells of the pancreas(108). This pathway isresponsible for the “cephalic” or preabsorptive phase of insulin secretion, which is glucose inde-pendent and can be blocked by atropine(109). Overactive vagal neurotransmission increases insulinsecretion fromβ-cells in response to an oral glucose load through three distinct but overlapping mech-anisms (Fig. 2; see the Chapter 26 on Hypothalamic Obesity for full discussion): (1) the muscarinicactivation of a sodium channel, resulting in increasedβ-cell depolarization; (2) the muscarinic acti-vation ofβ-cell phospholipases which hydrolyze intracellular phosphatidylinositol to diacylglycerol(DAG) and inositol triphosphate (IP3), inducing insulin vesicular exocytosis; and (3) the stimulationof GLP-1 from intestinal L-cells, which activates protein kinase A and increases insulin exocytosis.Vagal induction of insulin secretion promotes lipogenesis through increased expression of Glut 4,acetyl-CoA carboxylase, fatty acid synthase, and lipoprotein lipase(110,111).THE HEDONIC PATHWAY OF FOOD REWARDHypothalamic feedback systems are modulated by a “hedonic pathway” that mediates the pleasur-able and motivational responses to food. The hedonic pathway comprises the ventral tegmental area(VTA) and the nucleus accumbens (NA), with inputs from various components of the limbic systemincluding the striatum, amygdala, hypothalamus, and hippocampus. Food intake is a readout of thehedonic pathway; administration of morphine to the NA increases food intake in a dose-dependentfashion(112). Functional suppression of the hedonic pathway curtails food intake when energy storesare replete; dysfunction or continuous activation of the hedonic pathway can increase food intake andpromote excessive weight gain.The VTA appears to mediate feeding on the basis of palatability rather than energy need. Thedopaminergic projection from the VTA to the NA mediates the motivating, rewarding, and reinforc-ing properties of various stimuli, such as food and addictive drugs. Leptin and insulin receptors areexpressed in the VTA, and both hormones have been implicated in modulating rewarding responses tofood and other pleasurable stimuli(113). For instance, fasting and food restriction (when insulin andleptin levels are low) increase the addictive properties of drugs of abuse, while central leptin admin-istration can reverse these effects(114). Food deprivation in rodents increases addictive behavior andthe pleasurable responses to a food reward, as measured by dopamine release and dopamine recep-tor signaling(115). Conversely, insulin increases expression and activity of the dopamine transporter,which clears and removes dopamine from the synapse; thus acute insulin exposure blunts the rewardof food(116). Furthermore, insulin appears to inhibit the ability of VTA agonists (e.g., opioids) toincrease intake of sucrose(117). Finally, insulin blocks the ability of rats to form a conditioned placepreference association to a palatable food(118).The role of the hedonic pathway in human obesity is not yet elucidated, but can be surmised.Dopamine D2receptor abundance is inversely related to BMI; the depression of dopaminergic activity
24Lustigin obese subjects might trigger a “reward-seeking” increase in food intake that promotes further weightgain. This may explain in part the higher risk of obesity in patients taking drugs that block D2recep-tors (e.g., antipsychotics(119)). Alternatively, the down-regulation of dopaminergic activity in obesesubjects may be an adaptive response to prior weight gain. Under normal circumstances, leptin andinsulin signal adipose and nutrient sufficiency to the VTA, suppressing dopamine neurotransmissionand the reward of food(113). However, these negative feedback loops are blocked in states of insulinand leptin resistance that characterize obesity(120).Positron emission tomography suggests that hunger and satiety neuronal circuits in the VMH con-nect with other regions of the limbic system(121)that control primal emotions, reproductive activity,and survival instinct; a primal “reward” or pleasure response might explain ingestive behavior in theabsence of hunger, a common finding in obese children and adults. It has been argued that much ofthe impasse in efforts to both treat and prevent obesity stems from the intrinsic difficulty of overridinginstinct with reason(122).THE AMYGDALA AND THE STRESS PATHWAY OF FOOD INTAKEThe VMH and VTA-NA mediate satiety when energy stores are replete, but appear to be overriddenby amygdala activation and the concomitant stress response associated with insulin resistance(123).Stress hormones such as the glucocorticoids are essential for the full expression of obesity in rodentsand humans and may explain the disruptive role that stress plays in weight regulation(124).Stress and glucocorticoids are integral in promoting the constellation of features characteristic ofthe metabolic syndrome. Studies of adrenalectomized (ADX) rats supplemented with corticosteronedemonstrate that exogenous fat intake is directly proportional to circulating corticosterone concen-trations(125,126). In intact rats, corticosterone stimulates intake of high-fat food; likewise, cortisoladministration increases food intake in humans(127). Human research shows increased caloric intakeof “comfort foods” (i.e., those with high energy density) after acute stress(128). Moreover, sev-eral studies in children have observed relationships between stress and unhealthy dietary practices,including increased snacking and an elevated risk of weight gain during adolescence and adulthood(129,130).NPY and catecholamines co-localize in sympathetic neurons in the peripheral nervous system aswell as the central nervous system. In response to chronic stress, peripheral neurons express moreNPY, which stimulates endothelial cell (angiogenesis) and preadipocyte proliferation, differentia-tion, and adipogenesis by activating Y2 receptors in visceral adipose tissue. This causes abdominalobesity, inflammation, hyperlipidemia, hyperinsulinemia, glucose intolerance, hepatic steatosis, andhypertension, reproducing the features of the human metabolic syndrome. Conversely, local intra-fatY2R antagonists or adenoviral Y2R knock-down reverses or prevents fat accumulation and metaboliccomplications(131). This suggests that acute stress causes lipolysis and weight loss, but chronicstress “hijacks” the SNS, increasing NPY expression to cause visceral fat accumulation and metabolicdysfunction.NEGATIVE FEEDBACK OF ENERGY BALANCE – THE RESPONSE TO CALORICDEPRIVATIONThe response to caloric deprivation serves as a model for understanding the regulation of energybalance and the adaptation to weight loss. Everyone appears to have a “personal leptin threshold,”probably genetically determined, above which the brain interprets a state of energy sufficiency(132).The leptin-replete fed state is characterized by increased physical activity, decreased appetite, andfeelings of well-being. In response to caloric restriction, leptin levels decline even before weight
The Neuroendocrine Control of Energy Balance25loss is manifest(25,26). This is interpreted by the VMH as starvation. Gastric secretion of ghrelinincreases; this stimulates pituitary GH release, which promotes lipolysis to provide energy substrate forcatabolism. Ghrelin also stimulates the expression of NPY/AgRP, which antagonizesα-MSH/CARTand reduces MC4R occupancy. The resultant lack of anorexigenic pressure on the MC4R increasesfeeding behavior, reduces fat oxidation, and promotes fat deposition. Fat storage is facilitated byincreases in insulin sensitivity.Total and resting energy expenditure decline in an attempt to conserve energy(133); the fall in leptinreduces plasma T3 levels, and UCP1 levels in adipose tissue decline(134)as a result of decreased SNSactivity(135). Yet, in spite of decreased SNS tone at the adipocyte, there is an obligate lipolysis due toinsulin suppression and upregulation of hormone-sensitive lipase. Lipolysis is necessary to maintainenergy delivery to the musculature and brain in the form of liver-derived ketone bodies.Under conditions of fasting or caloric deprivation, vagal tone is increased. Together with the fallin T3 levels, this slows the heart rate and reduces myocardial oxygen consumption. Heightenedvagal tone also increasesβ-cell insulin secretion and adipose insulin sensitivity; in sum, these effectspromote increased energy fat storage(135). The effects of fasting revert once caloric sufficiency isre-established and leptin levels rise.Thus the adaptive/compensatory response to fasting or caloric deprivation is designed to re-establishhomeostasis and recover lost weight by inducing food intake and reducing energy expenditure; thisexplains the great difficulty that most obese people have in achieving or maintaining long-term weightloss.LEPTIN RESISTANCEMost obese children have high leptin levels but do not have receptor mutations, manifesting whatis commonly referred to as “leptin resistance.” Leptin resistance prevents exogenous leptin adminis-tration from promoting weight loss(136). The response to most weight loss regimens plateaus rapidlydue to the rapid fall of peripheral leptin levels below a personal “leptin threshold”(137),whichis likely genetically determined. Leptin decline causes the VMH to sense a reduction in peripheralenergy stores. This fosters a decrease in REE to conserve energy, analogous to the starvation responsedescribed earlier(133)but occurring at elevated leptin levels.The cause of leptin resistance in obesity is likely multifactorial. First, leptin crosses the blood–brain barrier via a saturable transporter, which limits the amount of leptin reaching its receptor inthe VMH(138,139). Second, activation of the leptin receptor induces intraneuronal expression ofsuppressor of cytokine signaling-3 (SOCS-3), which limits leptin signal transduction(54). Finally,hypertriglyceridemia limits access of peripheral leptin to the VMH(140)and interferes with leptinsignal transduction upstream of STAT-3, its primary second messenger(141). Thus, factors that inducehypertriglyceridemia, such as dietary fructose and insulin resistance, tend to promote leptin resistance(21).Two clinical paradigms have been shown to improve leptin sensitivity. After weight loss throughcaloric restriction, exogenous administration of leptin can then increase REE back to baseline andpermit further weight loss(142,143). This suggests that weight loss itself improves leptin sensitivity.Second, suppression of insulin correlates with improvement in leptin sensitivity and promotes weightloss(144), suggesting that hyperinsulinemia promotes leptin resistance by interfering with leptin signaltransduction in the VMH and VTA(145). Indeed, insulin reduction strategies may be effective inpromoting weight loss in obese children by improving leptin sensitivity(146).Thishasledtothehypothesis that chronic hyperinsulinemia functions to block leptin signal transduction at the VMH andVTA, which turns a negative feedback cycle into a vicious feedforward cycle (Fig. 3)(147).However,this hypothesis remains to be proven.
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