Nicotinic receptor-mediated effects on appetite and food intake

Nicotinic Receptor-Mediated Effects on Appetiteand Food Intake

Young-Hwan Jo,1 David A. Talmage,2 Lorna W. Role1

1 Department of Anatomy and Cell Biology, in the Center for Neurobiology and Behavior and 2 theInstitute of Human Nutrition, Columbia University, College of Physicians and Surgeons,New York, NY 10032

Received 2 July 2002; accepted 31 July 2002

ABSTRACT: It is well known, although not wellunderstood, that smoking and eating just do not gotogether. Smoking is associated with decreased food in-take and lower body weight. Nicotine, administered ei-ther by smoking or by smokeless routes, is consideredthe major appetite-suppressing component of tobacco.Perhaps the most renowned example of nicotine’s influ-ence on appetite and feeding behavior is the significantweight gain associated with smoking cessation. This ar-ticle presents an overview of the literature at, or near,the interface of nicotinic receptors and appetite regula-

tion. We first consider some of the possible sites ofnicotine’s action along the complex network of neuraland non-neural regulators of feeding. We then presentthe hypothesis that the lateral hypothalamus is a partic-ularly important locus of the anorectic effects of nico-tine. Finally, we discuss the potential role of endogenouscholinergic systems in motivational feeding, focusingon cholinergic pathways in the lateral hypothalamus.© 2002 Wiley Periodicals, Inc. J Neurobiol 53: 618–632, 2002

Keywords: orexin; M-H; lateral hypothalamus; acetyl-choline

INTRODUCTION

Nicotine, the major addictive component of tobacco,reduces appetite and alters feeding patterns typicallyresulting in reduced body weight (Grunberg, 1986;Grunberg et al., 1986; Miyata et al., 1999). Combinedepidemiologic studies of more than a quarter of amillion subjects converge on a strong inverse relation-ship between cigarette smoking and body weight,with smokers weighing significantly less than non-smokers of the same age and sex (Albanes et al.,1987; Levin et al., 1987). Particularly striking is thehyperphagia and resultant weight gain that accompa-nies smoking cessation of 70–80% of people whoquit smoking, with women being most affected

(Grunberg et al., 1986; Klesges et al., 1989; Pomer-leau, 1999; Pomerleau et al., 2000). Withdrawal ofnicotine leads to increases in body weight of sufficientmagnitude to confound maintained abstinence, signif-icantly altering the outcomes of smoking cessationprograms as manifest in weight-gain associated re-lapse (Nordstrom et al., 1999; Pomerleau, 1999).

The effects of chronic nicotine administration onappetite suppression, decreased food intake, andleanness are not confined to human subjects (e.g.,Blaha et al., 1998; Bray, 2000; Zhang et al., 2001).Likewise, nicotine withdrawal from laboratory an-imals previously subjected to chronic drug admin-istration induces hyperphagia and weight gain thatare at least qualitatively similar to the effects elic-ited in humans by smoking cessation without nic-otine replacement therapy (Grunberg et al., 1986;Levin et al., 1987). Such findings indicate thatpostcessation weight-gain results from a fundamen-tal physiologic response, rather than just from so-cio-cultural factors, and underscore the importanceof understanding the mechanisms that underlie nic-

Correspondence to: L.W. Role ([email protected]).Contract grant sponsor: National Institutes of Health; contract

grant numbers: NS29071, NS22061, and CA79737.© 2002 Wiley Periodicals, Inc.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/neu.10147

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otine and nicotine withdrawal-induced changes inappetite and food intake.

POSSIBLE MECHANISMS FOR THEEFFECTS OF NICOTINE ON FEEDINGBEHAVIOR

Even a simplified schematic of the basic neural andnon-neural regulators of energy balance cannot hidethe mechanistic complexity of feeding behavior (seeFig. 1 and Woods et al., 1998; Kalra et al., 1999;Schwartz et al., 2000; Chiesi et al., 2001; Speigelmanand Flier, 2001, for recent reviews). Peripheral signalsof adiposity and satiety—in the form of both chemicaland mechanical indicators of sufficient metabolicstores and food intake—arise from adipose, liver,pancreas, and gastrointestinal tissues. These multiplesignals assure accurate feedback in the regulation of“start-feeding” versus “stop-feeding” behaviors.These peripheral signals are carried by both humoraland neural routes, and include sugars, peptides (e.g.,leptin, insulin, cholecystokinin, TNF�), eicosanoids,fatty acids, and other lipid-derived molecules (e.g.,prostaglandins, triglycerides, LDL). Peripheral neuro-nal reporters of satiety, originating with mechanicaland chemical signals from the gut and liver, are pri-marily conveyed via vagal afferents to the nucleus ofthe solitary tract (NTS) resulting in the activation ofboth ascending and descending circuits involved infood intake. Humoral indicators of adequate fat stor-age (such as leptin) act directly on central neurons toregulate autonomic and limbic circuits controllingmotivational aspects of feeding (see Fig. 1 and Woodset al., 1998; Kalra et al., 1999; Schwartz et al., 2000;Chiesi et al., 2001; Speigelman and Flier, 2001, forrecent reviews).

This review, and the diagram in Figure 1, empha-sizes the key integrative role of hypothalamic neuronsin the relay of feeding-linked information to and fromlimbic and autonomic structures throughout theneuraxis. Thus, the hypothalamus coordinates moti-vation and emotion-related features of feeding behav-ior (via direct interactions with medial prefrontal;mPFC and cingulate cortex, basal forebrain and me-dial septal nuclei; MS/BF) with more fundamentalaspects of appetitive and aversive responses (via in-teraction with nucleus accumbens, ACC, amygdalaAMYG, ventral tegmental area; VTA, substantianigra and raphe; e.g., Bittencourt and Elias, 1998;Broberger et al., 1998; Peyron et al., 1998; Stratfordand Kelley, 1999; Pajolla et al., 2001; Fadel andDeutch, 2002). In this manner, it is the interactions ofthe hypothalamus that convey the emotional salienceof feeding “context” from the cortex to brainstem

autonomic nuclei (e.g., the nucleus tractus solitarius,NTS, parabrachial, PBr, and ventrolateral medullarynuclei, VLM) and ultimately to the basic visceralmotor and sensory mediators of biting, chewing, andswallowing (e.g., cranial nerve nuclei 7, 9 and 10;CrN, see Fig. 1).

The first challenge, for those of us interested inunderstanding the mechanism of nicotine-dependent

Figure 1 Possible loci of nicotine effects on feeding be-havior. The brain receives a multitude of signals from theperiphery reporting on adequacy of food intake and energybalance. These include humoral signals (red ribbon arrow)such as hormones and cytokines (e.g., leptin, TNF�, insulin,cholescystokinin, norepinephrine) and metabolites (e.g.,glucose and fatty acids) as well as neural signals (greenribbon arrow). Within the hypothalamus (HYP) and thenucleus of the tractus solitarius (NTS) this information isintegrated and transmitted to multiple brain regions (darkblue arrows), and the appropriate behavior is elicited. Inaddition to these central responses, the PNS (light blue)neurons including sympathetic, parasympathetic, and en-teric, innervate the gastrointestinal tract, adipose depots, andendocrine organs. Possible sites at which nicotine mightmodify feeding behavior or energy balance are indicatedwith stars. A number of non-neural tissues express nAChRs,and could repsond directly to nicotine. In the CNS, nicotinecould act within the hypothalamus, the NTS, and in theregions throughout the neuroaxis to which these structuresproject (mPFC, medial septal, and basal forebrain nuclei;VTA, ventral tegmental area; NTS, nucleus tractus soli-tarius; PBr, parabrachial nucleus; VLM, ventrolateral med-ullary nucleus; CrN, cranial nerve nuclei; VISC. SENS andVISC MTR, visceral sensory and motor neurons; NE,norephnephrine, ENT, N’s, enteric neurons; CCK, chole-cystokinin; FAs, fatty acids).

Nicotinic Receptor-Mediated Effects on Appetite 619

hypo- versus. hyperphagia, is to find where in thiscomplex sequence of sites nicotine can act. The an-swers from the literature, as outlined below, includeseveral possible loci of the nicotinic regulation offood intake (indicated by red stars in Fig. 1). Fromthese possible sites of action, some of which we touchon below, our discussion focuses on nicotine effectson the excitability of lateral hypothalamic projectionneurons and potentially important contributions ofendogenous cholinergic systems in the control of nor-mal feeding behavior.

DOES NICOTINE AFFECT FEEDING VIAINTERACTIONS AT PERIPHERAL(NON-NEURAL) SITES OF ENERGYMETABOLISM?

Many reports implicate nicotine as the appetite sup-pressing component of smoking (Grunberg, 1986;Blaha et al., 1998; Li et al., 2000; Zhang et al., 2001).Studies of feeding behavior reveal that smoking ornicotine administration decreases meal size, measuredas the amount of food intake per meal, without sub-stantial changes in meal number (Blaha et al., 1998;Miyata et al., 2001). Although studies of nicotine-induced changes in overall metabolic rate are morevariable (Stamford et al., 1986; Sztalryd et al., 1996),nicotine administration has been shown to alter met-abolic processing in humans, intact animals and inboth hepatocytes and adipocytes, in vitro (Sztalryd etal., 1996; Ashakumary and Vijayammal, 1997; Arai etal., 2001). Nicotine decreases lipolysis by inhibitinglipoprotein lipase activity, decreasing triglyceride up-take and hence lessening net storage in adipose tissue(Sztalryd et al., 1996). Activation of nicotinic recep-tors also induces the expression of uncoupling protein1 (UCP1) in both white and brown adipose tissue(Arai et al., 2001). As UCP1 shifts the balance ofenergy metabolism from the generation of ATP to thegeneration of heat, this represents a shift in metabolicefficiency compatible with the average lower body-weight of smokers (Klesges et al., 1989). Overall, thedata on the effects of nicotine on energy metabolismin peripheral, non-neural tissue are reasonably compel-ling and certainly consistent with a significant contribu-tion of these mechanisms to nicotine’s anorectic activity.

Could the Anorectic Effects of NicotineInvolve Regulation of “Adiposity”Signaling by Leptin?

Leptin is a peptide hormone subject to regulated syn-thesis and release by adipocytes during the well-fedstate (Zhang et al., 1994; Ahima et al., 2000). Leptin–

receptor activation in the CNS and PNS decreasesappetite and increases energy expenditure, thus func-tioning as a key afferent component of the negativefeedback loops that stabilize adipose tissue mass. In-travenous leptin increases norepinephrine releasefrom the adrenal gland and increases sympatheticnerve activity to both thermogenic and non-thermo-genic tissues (e.g., brown adipose vs. adrenal gland;see Fig. 1). Administration of exogenous leptin toob/ob mice, which have a phenotype of massive over-eating and obesity due to the lack of leptin production,markedly decreased food intake and body weight(Campfield et al., 1995; Halaas et al., 1995; Pelley-mounter et al., 1995). Animals of the db/db genotypeare similarly obese, but in this case it is due to the lackof expression of leptin receptors and, as such, theirweight is unaffected by exogenous leptin administra-tion (Caro et al., 1996). Thus, regulated synthesis ofleptin and its cytokine receptor are necessary compo-nents in the maintenance of normal body weight andenergy homeostasis (see Flier and Maratos-Flier,1998; Ahima et al., 2000; Schwartz et al., 2000;Elmquist, 2001, for reviews).

Nicotine, as an appetite suppressant, may decreasefeeding by increasing leptin levels and/or by enhanc-ing step(s) along the leptin–receptor-mediated signal-ing cascade. Several laboratories have attempted totest these hypotheses; overall, it appears that nicotine-induced changes in leptin levels—measured either asleptin mRNA in adipocytes or as plasma leptin con-centration—are highly dependent on experimentalprotocol. Some studies indicate that chronic smokershave significantly higher serum leptin concentrationsthan nonsmokers, consistent with nicotine’s hypoph-agic effects (Hodge et al., 1997; Wei et al., 1997;Eliasson and Smith, 1999; Nicklas et al., 1999). Otherreports find no correlation (either positive or negative)between chronic nicotine exposure and serum leptinconcentrations (Yoshinari et al., 1998; Donahue et al.,1999). Nevertheless, the consensus remains that theanorectic affects of nicotine are somehow linked toaltered leptin signaling. Even investigators who foundthat chronic cigarette smokers had significantly re-duced plasma leptin levels propose that the low leptinlevels reflect nicotine-induced enhancement of leptin–receptor binding or increased sensitivity of down-stream transduction cascades (Hodge et al., 1997; Weiet al., 1997). Recent analyses of nicotine affects onadipocytes in vitro—i.e., under relatively controlledconditions—revealed that the changes in leptin re-lease depended on the duration of nicotine treatmentand were not necessarily correlated with the degree ofnicotine-induced decreases in food intake in vivo(Arai et al., 2001).

It remains to be tested whether nicotine can in-

620 Jo, Talmage, and Role

crease the efficacy of leptin–receptor signaling, asproposed. In principle, nicotine could enhance or aug-ment leptin–receptor signaling by several transcrip-tionally independent mechanisms—acting in concertwith reported electrophysiologic effects of leptin onspecific populations of CNS and PNS neurons (Har-vey et al., 1997; Spanswick et al., 1997; Niijima,1998; Liu et al., 1999; Sha and Szurszewski, 1999;Shiraishi et al., 2000; Spanswick et al., 2000; Cowleyet al., 2001). Alternatively, nicotine may act by en-hancing leptin receptor-mediated JAK-STAT signaltransduction or the transcriptional regulation of one ormore of the identified target genes of leptin receptorsignaling (Tartaglia, 1997; Elias et al., 1999; Ahima etal., 2000; Elias et al., 2000). Nevertheless, althoughnicotine and leptin elicit similar responses (whether atthe level of excitability or transcriptional regulation)in certain hypothalamic, vagal afferent and sympa-thetic efferent neurons, their sites of action are oftendistinct. Thus, the anorexigenic actions of nicotineparallel those of leptin and appear to involve bothcommon and distinct cellular targets.

DOES NICOTINE AFFECT APPETITEVIA INTERACTION WITH PERIPHERALAUTONOMIC, ENTERIC, OR SENSORYNEURONS?

Nicotine—like many other anorexigenic substances,including leptin, CCK, and insulin—generally exertsopposite effects on the regulation of sympathetic out-flow and appetite (Haynes et al., 1997; Yettefti et al.,1997; Niijima, 1998; Krisufek et al., 1999; Sha andSzurszewski, 1999; Bray, 2000). Thus, the net effectsof nicotine include elevated blood pressure, heart rate,and gastric motility while eliciting a sustained de-crease in food intake. Autonomic, sensory, and entericneurons each constitute potentially important loci fornicotine-mediated changes in feeding behavior. Pe-ripheral tissues involved in the regulation of foodintake receive input from sympathetic and/or para-sympathetic neurons that are themselves controlled bycholinergic transmission. All autonomic, many en-teric, and even a subset of sensory neurons are cho-linoceptive, expressing a variety of nAChR subunitsand nAChR subtypes that are potently activated bynicotine (e.g., Rust et al., 1994; Conroy and Berg,1995; De Biasi et al., 2000; Roth et al., 2000; Cooper,2001; Picciotto et al., 2001; Shoop et al., 2001). Thus,nicotine administration via smoking can evoke signif-icant activation (and sustained inactivation, via desen-sitization) of many peripheral neuron components ofvisceral-sensory and visceral-motor pathways in-volved in the regulation of feeding.

The extent (and duration) of nicotine-elicited alter-ations in peripheral neuron activity depends on mul-tiple factors, such as the concentration and duration ofnicotine exposure, the subtype(s) of nicotinic AChRexpressed and the pre- versus postsynaptic distribu-tion of the nAChRs (for recent reviews, see Gotti etal., 1997; McGehee, 1999; De Biasi et al., 2000;Temburni et al., 2000; Cooper, 2001; Dani, 2001;Leonard and Bertrand, 2001; Picciotto et al., 2001,and articles in this volume). In addition to alteringneuronal excitability directly by the activation of syn-aptic and “extra-synaptic” nAChRs, nicotine is anestablished modulator of transmitter release in theperiphery. Nicotine enhances the release of both AChand norepinephrine (NE) from pre- and postgangli-onic neurons by interaction with presynaptic nAChRs(e.g., McGehee et al., 1995; Krisufek et al., 1999; DeBiasi et al., 2000; Leonard and Bertrand, 2001; Pic-ciotto et al., 2001). Peripheral administration of nic-otine results in decreased food intake and increasedsympathetic activity to liver, adipose and gut, remi-niscent of its effects on cardiovascular parameters(Bray, 2000). Although consistent with direct, nico-tine-induced enhancement of norepinephrine releasefrom peripheral nerve terminals, such changes arealso due to more indirect routes of controlling foodintake and sympathetic outflow (Fig. 1). Systemicadministration of nicotine stimulates visceral afferentsand activates brain stem autonomic control centers,such as the solitary tract, ventrolateral medullary, andparabrachial nuclei (noted in Fig. 1 as NTS, VLM,and PBr, respectively; Yettefti et al., 1997; Bray,2000; Cooper, 2001; Tribollet et al., 2001). Nicotine-evoked responses are elicited in less than 25% of theNTS neurons when tested by direct ionotophoreticapplication, implicating both central and peripheralneuronal circuits in nicotine’s effects on feeding (Yet-tefti et al., 1997). Other studies underscore the con-tribution of nAChRs on cranial nerve and spinal cordvisceral motor neurons in the regulation of sympa-thetic and parasympathetic outflow (e.g., McGehee etal., 1995; Tribollet et al., 2001). In sum, nicotine’sanorexigenic activity is likely due—at least inpart—to alterations in the excitability of visceral sen-sory and motor neurons as well as to modulation oftransmitter release at brain stem, spinal cord (pregan-glionic), and/or peripheral synapses.

Last, but not least, the activation of nicotinic re-ceptors on peripheral neurons has also been linked toaltered phospholipid and fatty-acid metabolism (e.g.,Vijayaraghavan et al., 1995; Marin et al., 1997; Stellaand Piomelli, 2001; Tieman et al., 2001, and refer-ences therein). As several of these metabolites affectappetite and/or modulate nAChRs, the reciprocal in-teraction of nicotinic and lipid-signaling pathways


may constitute an important “feedback” (pun in-tended) mechanism for regulating peripheral signalsand circuits controlling food intake (e.g., Vija-yaraghavan et al., 1995; Marin et al., 1997; Bray,2000; Du and Role, 2001; Tieman et al., 2001).

ARE THE ANORECTIC EFFECTS OFNICOTINE DUE TO MODULATION OFCENTRAL AUTONOMIC NEURONS

The Hypothalamus

The hypothalamus is a region of the brain critical forregulation of homeostatic processes such as feeding,thermoregulation, and reproduction (Elmquist et al.,1999). To accomplish these ends, the hypothalamusreceives neural, endocrine, and metabolic signals, in-tegrates these inputs, and engages distinct effectorpathways, resulting in behavioral, autonomic, and en-docrine responses. The essential role of the hypothal-amus in appetite regulation was initially suggested bystudies utilizing “localized” lesion and stimulation ofthe hypothalamus. Disruption of the ventromedial hy-pothalamus produced hyperphagia and obesity, whilelesions of the lateral hypothalamus resulted in hypo-phagia and dramatic weight loss. Although early pro-posals for a ventromedial “satiety” center and a lateralhypothalamic “appetite” controller were oversimpli-fied (and somewhat confounded by varying disruptionof medial forebrain bundle projections), they correctlyestablished the hypothalamus as a key contributor tomotivational aspects of feeding (see Flier and Mara-tos-Flier, 1998; Woods et al., 1998; Elmquist et al.,1999; Kalra et al., 1999; Schwartz et al., 2000; Chiesiet al., 2001; Speigelman and Flier, 2001). The under-standing of the chemical signals and neuronal cir-cuitry involved in the regulation of appetite has grownsubstantially during the past decade. As such, it isparticularly surprising that we know so little about therole of nicotinic receptors in the hypothalamic controlof food intake in smokers, ex-smokers and nonsmok-ers. In Figure 2, and in the discussion below, weconsider the key relays to, from and within the hypo-thalamus that may be involved in the anorexigenicactions of nicotine.

First and foremost, nicotinic receptors with thepharmacology of both �7-containing (�7*) and �/�-like pharmacology are detected throughout the hypo-thalamus (Harfstrand et al., 1988; Pabreza et al., 1991;Britto et al., 1992; Okuda et al., 1993; Shioda et al.,1997; O’Hara et al., 1998; Davila-Garcia et al., 1999;Hatton and Yang, 2002). Application of nicotine to invitro preparations of hypothalamus elicits the usualpanoply of neurophysiologic responses, including di-

rect depolarization as well as alterations in GABA,glutamate, norepinephrine, and serotonin release(Pabreza et al., 1991; Meguid et al., 2000; Hatton andYang, 2002). These findings are consistent with lo-calization of nAChRs at both pre- and postsynapticsites (Schwartz et al., 1984; Li and Pan, 2001). In situhybridization with nAChR-subunit probes revealsmoderate to high levels of expression of �4, �7, and�2-mRNAs in hypothalamus, with particularly prom-inent expression in the supraoptic and suprachias-matic nuclei. Examination of the nAChR distributionwithin the subnuclei involved in the regulation ofingestive behavior further guided our search for can-didate sites of nicotine’s anorectic activity to focus onthe lateral hypothalamus (Jo and Role, 2002, andunpublished observations).

Numerous studies have emphasized the contribu-tions of the arcuate, ventromedial, dorsomedial, para-ventricular, and/or lateral hypothalamic nuclei in ap-petite regulation. In view of the stated emphasis ofthis volume we will confine our discussion to the firstand last of these regions as of particular interest to thenicotinologist.

The Arcuate Nucleus. The arcuate nucleus is locatedat the base of the hypothalamus on either side of thethird cerebral ventricle (Arc; Fig 2), extending rostro-caudally from the posterior borders of the optic chi-asm to the mamillary bodies. Two relatively recentobservations have placed the arcuate nucleus in aposition of prominence among the sites that are asso-ciated with the detection and integration of orexigenicversus anorexigenic signals [indicated by the open-mouthed vs. closed-mouth faces, respectively, in Fig.2(C)]. First, the arcuate nucleus contains a high den-sity of neurons that produce the orexigenic peptides,neuropeptide Y (NPY; Erickson et al., 1996), opioids,dynorphin (Neal and Newman, 1989), �-endorphin(Lantos et al., 1995), and galanin (Merchenthaler etal., 1993). The agouti-related peptide, a selective an-tagonist of �MSH receptors (see below), is coex-pressed with NPY mRNA in the arcuate nucleus(Broberger et al., 1998). These two peptides alsocoexist in nerve terminals surrounding and in closeapposition to perikarya and processes of both orexin(ORX) and melanin-concentrating hormone (MCH)-immunoreactive cells in the LH [Fig 2(C); Brobergeret al., 1998; Horvath et al., 1999]. Thus, ORX andMCH expressing neurons within the lateral hypothal-amus are considered likely downstream targets ofNPY-positive projections from the arcuate nucleusand, as such, are important mediators of NPY-inducedfeeding signals.

Melanocortins such as �-melanocyte-stimulatinghormone (�MSH) are peptides that are cleaved from


the pro-opiomelanocortin (POMC) precursor mole-cule and exert their effects by binding to members ofthe family of melanocortin receptors (Lawrence et al.,1999). A synthetic agonist of these receptors sup-

presses food intake, whereas a synthetic antagonisthas the opposite effect (Fan et al., 1997). The reportthat mice lacking the MC4-type of �MSH receptor arehyperphagic and very obese indicates that under nor-

Figure 2 CNS sites of glucose, leptin, and (possibly) nicotine effects—up close and personal. (A)Glucose (Gluc), leptin, and nicotine signaling converge on the arcuate nucleus within the hypo-thalamus. The triangle shows the region from which the coronal sections in (B) and (C) are taken.(B) Higher magnification, coronal section showing the spatial relationship of the lateral hypothal-amus (LH), the dorsal medial, and ventromedial hypothalamus (DM, VM) and the arcuate nuclus(Arc). ZI—zona inserta. (C) Glucose and leptin responsive neurons in the arcuate project to the LH.The first group of neurons, which are inhibited by the anorexigenic leptin signal (face with closedmouth), express the orexigenic peptides NPY and AgRP (face with open mouth). Leptin also excitesa second group of neurons that contain the anorexigenic peptides, �MSH and CART. Both classesof Arc neurons project to the LH interacting with neurons and interneurons that express GABA(yellow), orexin (green), or MCH (red). Orexin and MCH neurons are orexigenic and project toother brain regions such as the mPFC, BF, VTA, etc. Key relays implicated in the regulation offeeding within the hypothalamic nuclei. The yellow stars represent possible loci of nicotine effects.(D) Nicotine treatment of LH neurons in vitro enhances neurotransmitter (GABA) release. Thenicotine target is believed to be preynaptic nAChRs on GABAergic interneurons. The figure wasmodified from Jo and Role, 2002b, in press. (NPY, neuropeptide Y; AgRP, agouti-related peptide;�MSH, �-melanocyte-stiimulating hormone; CART, cocaine- and amphetamine-regulated tran-script; ORX, orexin, MCH, melanin-concentrating hormone; f, fornix).


mal conditions tonic signaling by MC4 receptors lim-its food intake and body fat mass (Huszar et al., 1997).

The cocaine- and amphetamine-regulated tran-script (CART) was originally identified as an mRNAinvolved in CNS responses to drugs of abuse. Intra-cerebroventricular (i.c.v.) administration of CARTencoded peptides inhibits normal, starvation-, andNPY-induced feeding in rats (Kristensen et al., 1998;Lambert et al., 1998), whereas i.c.v. administration ofneutralizing anti-CART sera increases night-timefeeding (Kristensen et al., 1998). These results sup-port a role for CART peptides as endogenous inhibi-tors of feeding. Interestingly, POMC and CART arecolocalized in a subset of Arc neurons distinct fromthe NPY/AgRP coexpressing neurons (Elias et al.,1998). Taken together, these studies of the expressionpatterns and the distinct downstream effects of NPY/AgRP vs. �MSH/CART on feeding indicate that cir-cuits originating in the Arc have highly specializedroles in energy homeostasis.

In addition, due to the absence of a blood–brainbarrier, the arcuate nucleus is strategically positionedto be in direct communication with peripheral signalssuch as leptin and insulin (reviewed in Kalra et al.,1999). A majority of both NPY/AgRP and POMC/CART neurons express leptin receptors (Cowley etal., 2001). Of particular importance in this regard arestudies demonstrating that leptin differentially regu-lates the NPY/AgRP versus POMC/CART neuronsprojecting from the arcuate to the LH nuclei [indi-cated by � vs. � in Fig. 2(C); Elias et al., 1999;Cowley et al., 2001]. In addition, the presence ofdirect glucose-sensing neurons within the arcuate (aswell as within the VMN) underscores their likelycontribution to direct monitoring and transduction ofprimary metabolic signals to control food intake (e.g.,Spanswick et al., 2000). The arcuate nucleus is thusconsidered to play a key integrative role between theinitial afferent signals from the periphery (e.g., leptinsand glucose) and CNS responses in the regulation ofappetite.

The Lateral Hypothalamus. The lateral hypothala-mus is comprised of a band of cells contiguous withthe dorsomedial, and lateral to the ventromedial, nu-clei of the hypothalamus [Fig. 2(B) and (C)], extend-ing rostrally from the mesencephalic tegmentum tothe lateral preoptic area. It is the site of passage for themedial forebrain bundle, a major conduit of projec-tions connecting forebrain and midbrain structureswith each other and with several hypothalamic sites.Lesions in the LH produced temporary aphagia, ad-ipsia, and loss in body weight consistent with animportant contribution of LH to appetite regulation.The demonstration that lateral hypothalamic neurons

are essentially unique in their expression of the orexi-genic neuropeptides, melanin-concentrating hormone(MCH) (Qu et al., 1996), and orexin (ORX) (Sakuraiet al., 1998) (also called hypocretin; de Lecea et al.,1998) reaffirmed the essential role of the LH in mo-tivational aspects of feeding. Starvation sharply in-creases the levels of mRNA encoding both of theseorexigenic signals (Qu et al., 1996; Sakurai et al.,1998), when leptin levels rapidly fall (Ahima et al.,1996).

Cells expressing MCH and ORX comprise distinctpopulations of neurons within the LH. ORX cells arelocated primarily in the perifornical LH, whereasMCH cells are more broadly distributed within theLH, with the most anterior MCH neurons lining theborders of the LH, by the zona incerta and substantiainnominata. More posterior MCH neurons are in theventral lateral portion of the perifornical area andsurround the ORX population (Broberger et al., 1998;Fadel and Deutch, 2002). Interestingly, CART-posi-tive cell bodies in the LH coexpress MCH and glu-tamic acid decarboxylase mRNA (Elias et al., 2001).ORX-immunoreactive terminals originating from theLH make direct synaptic contact with neurons of thearcuate nucleus that express NPY and contain leptinreceptors (Horvath et al., 1999). ORX-containing neu-rons also express leptin receptor immunoreactivity(Horvath et al., 1999). The excitatory actions of ORXcould increase NPY release, resulting in enhancedfeeding behavior, whereas leptin, released from adi-pose tissue as an indicator of fat stores, would havethe opposite effect on the same neurons, leading to adecrease in NPY and NPY-mediated hypothalamicfunctions.

Why is the LH an important candidate locus ofnicotine-elicited appetite suppression? First, nicotineadministration into the LH significantly decreasesfood intake (Miyata et al., 1999; Yang et al., 1999;Miyata et al., 2001). Second, nicotine treatment elicitsboth short- and long-term changes in the release of avariety of transmitters in LH (Miyata et al., 1999;Meguid et al., 2000; Li and Pan, 2001; Zhang et al.,2001). Third, nicotine alters the expression of feed-ing-related neuropeptides and their receptors withinthe LH (Frankish et al., 1995; Kane et al., 2000; Li etal., 2000a, Li et al., 2000b; Kane et al., 2001). Inparticular, nicotine regulates dopamine and serotoninrelease from extrinsic projections to the LH (Miyata etal., 1999; Meguid et al., 2000) and it modulatesGABA and glutamate transmission within the LH[Fig. 2(D) and Y. Jo and L. Role, unpublished obser-vations]. Likewise, nicotine regulates the levels ofexpression of NPY, orexin and an orexin receptor.The complexity arises in assessing which of the manychanges that are elicited by nicotine in the lateral


hypothalamus underlie the nicotine-induced hypopha-gia and, perhaps even more importantly, the persistenthyperphagia accompanying nicotine cessation (Grun-berg et al., 1986; Levin et al., 1987; Nordstrom et al.,1999; Pomerleau et al., 2000).

Does Nicotine Affect Appetite viaRegulation of Release fromDopaminergic or SerotoninergicProjections to the LateralHypothalamus?First let’s consider the effects of nicotine on therelease of dopamine and serotonin, two critical foodintake-related neurotransmitters. The absence of do-pamine production (in mice that cannot express ty-rosine hydroxylase (Szczypka et al., 2000) results inan inability to initiate feeding, although the basicmotor ability to eat is unaffected. In the hypothala-mus, dopamine release is associated with the durationof meal consumption, an important determinant offeeding pattern. As dopamine is required to initiatemeals, decreased dopamine is associated with reducedmeal number and meal duration (reviewed in Meguidet al., 2000). In contrast, serotonin is implicated in theinhibition of food intake (see Meguid et al., 2000).Serotonin release in the hypothalamus is enhancedduring feeding (D.H. Schwartz et al., 1989) and isthought to promote satiety. Mice lacking serotinergicreceptors display food intake and body weight-relatedabnormalities (Nonogaki et al., 1998).

Studies of nicotine infusion and amine release inhypothalamus support the idea that activation ofnAChRs on serotinergic projections to LH may con-tribute to the anorectic effects of nicotine. The role ofdopamine release in nAChR-induced appetite sup-pression—as opposed to meal initiation—is less clear(Miyata et al., 1999; Yang et al., 1999; Meguid et al.,2000). Continuous nicotine administration into theLH induces long-lasting increases in 5-HT release thatparallel the sustained suppression of food intake in thesame animals. If enhanced serotinergic transmissionin hypothalamus signals satiety as proposed(Schwartz et al., 1989; Nonogaki et al., 1998), nico-tine may act as a false indicator of the well-fed state,resulting in early meal termination (i.e., decreasingmeal size and duration, as previously reported; Miyataet al., 2001) due to nAChR-mediated presynaptic fa-cilitation of serotonin release.

Does Nicotine Affect Appetite viaRegulation of NPY Neurons that Projectto the Lateral Hypothalamus?NPY, a 36-amino acid neuropeptide, is abundant inthe brain of rats, and is highly concentrated in the

hypothalamus. NPY administration is potently orexi-genic and expression of NPY mRNA in the arcuatenucleus is increased in response to fasting or chronic,but moderate food restriction (see Woods et al., 1998;Kalra et al., 1999; Lawrence et al., 1999; M.W.Schwartz et al., 2000, for reviews). A simple predic-tion is that if NPY signaling is a target for nicotine’sanorectic action, then nicotine treatment might sup-press the expression of NPY or NPY receptors. In theshort term, this appears to be true. Frankish and col-laborators found that acute (24-h) nicotine adminis-tration, reduced food intake by 30%, and loweredNPY and NPY mRNA levels in the Arc nucleus by35% (Frankish et al., 1995). The situation followingchronic nicotine administration is murky; however, as2 weeks of nicotine treatment, lowers food intake butsignificantly increases levels of NPY mRNA. Li andcolleagues (Li et al., 2000) found that after 14 daysnicotine suppressed food intake and elicited a dose-dependent increase in hypothalamic NPY mRNA lev-els (by 20–50% depending on the dose of nicotine)and increased NPY immunoreactivity by 24–69%(the magnitude of the increase varied in differentregions of the hypothalamus). In a valiant attempt toresolve the conflict between nicotine-induced hypo-phagia and the observed induction of a renownedorexigenic peptide, the authors propose that nicotinesomehow modifies the sensitivity of NPY and/or nico-tinic acetylcholine receptors; consequently, modulatingNPY synthesis and food intake. A long-term increase inNPY levels might desensitize the NPY receptor systems.We provide an alternative explanation, based on initialstudies of nicotine effects on LH circuits, below.

Does Nicotine Affect Appetite viaRegulation of Orexin Neurons in theLateral Hypothalamus?

Orexin A and B (also called hypocretins) are twopeptides derived from a single 131-residue precursorpeptide (prepro-orexin), that are produced exclusivelyin the LH (Sakurai, 1999; Shiraishi et al., 2000; Willieet al., 2001; Kotz et al., 2002). In view of the orexi-genic activity of these peptides, the simplest predictedlink between nicotine-induced hypophagia and orex-ins would be that nicotine depresses orexin signaling.No such luck.

Kane and colleagues (Kane et al., 2000) showedthat chronic nicotine treatment (14 days) elicited adose-dependent increase in the expression of prepro-orexin mRNA expression in hypothalamus. This in-crease in prepro-orexin mRNA in nicotine-treated an-imals is expected to yield increased levels of orexinprotein in the LH and/or at sites of projection oforexin-producing neurons. This increase might lead to


downregulation of orexin and/or NPY receptor ex-pression. Indeed, the same authors demonstrated thathypothalamic orexin-A binding sites were downregu-lated by chronic nicotine treatment (Kane et al.,2001). It should be kept in mind that orexin mayregulate sleep/wakefulness states, rather than feedingbehavior (Hungs and Mignot, 2001; Sutcliffe and DeLecea, 2002). Mice lacking orexin show a phenotypesimilar to human narcolepsy, including behavioralarrests and premature entry into rapid eye movement(REM) sleep (Chemelli et al., 1999). Hara and col-leagues (Hara et al., 2001) observed similar results inmice lacking orexin neurons. Thus, effects of nicotineon orexin signaling might be manifested as alterationsin sleep/wake states rather than feeding behavior.

Does Nicotine Affect Appetite viaRegulation of MCH Neurons inHypothalamus?

MCH, another peptide uniquely expressed in lateralhypothalamic neurons, is also orexigenic (see discus-sion above and Fig. 2). Fasting animals upregulatehypothalamic MCH mRNA levels and MCH receptorantagonists block NPY, �-endorphin, and fasting-in-duced increases in food intake. Mice lacking MCHhave lower body weights and enhanced leanness, as-sociated with marked hypophagia, compared withcontrol animals (Shimada et al., 1998). Recent studies

showing that MCH receptor-deficient mice, like thoselacking MCH expression, are hypophagic, furthersupporting the importance of MCH in appetite regu-lation (Marsh et al., 2002).

The activity of MCH-expressing neurons is elabo-rately regulated by interneurons within the LH, inputsfrom other hypothalamic nuclei and by projectionsfrom other brain regions (e.g., Qu et al., 1996; Bayeret al., 1999; Fig. 2; see below, and Fig. 3). Orexigenic,NPY-positive inputs from the Arc strongly enhancethe activity of MCH neurons (Flier and Maratos-Flier,1998). AgRP neurons have the same net effect ascostored NPY on the activity of MCH neurons but themechanisms are distinct. AgRP is an antagonist ofreceptors for the anorexigenic peptide, �MSH, andthereby inhibits the inhibition (!) normally mediatedby �MSH–MC4 receptor interactions. Decreased ac-tivation of MCH neurons results from enhanced in-hibitory GABAergic input and by inhibitory influ-ences of CART/�MSH projections (Fan et al., 1997).Finally, MCH projections may mediate a positivefeedback control by inhibition of GABAergic inputs(Gao and van den Pol, 2001).

Recent work investigates the possibility that nico-tinic receptor activation regulates the excitability ofMCH neurons in LH [Fig. 2(D); Y. Jo and L. Role,unpublished observations]. In principle, nicotinecould suppress appetite either by decreasing any ofthe multiple inputs that normally activate MCH neu-

Figure 3 Acetylcholine containing neurons are found throughout the lateral hypothalamus. (A)ACh-positive neurons (yellow/green circles) and ACh-positive projections (green, yellow/greenshading; green represents highest density) are distributed throughout the LH. Some ACh-positiveneurons are also found in the Arc. (B) ACh-positive neurons identified by VAChT (vesicular AChtransport) immunoreactivity and MCH-positive neurons (red—MCH immunoreactivity) are inter-spersed. (C) VAChT-positive bouton-like structures (red/brown immunostaining) are present in theperifornical region of the LH.


rons or by increasing the overall inhibition of MCHneurons. We propose that both mechanisms are in-volved in nicotine’s actions [Fig. 2(C) and (D)].

GABA is the primary inhibitory transmitter in thehypothalamus (Elias et al., 2001) and a prominentcomponent of synaptic input in in vitro preparationsof rat, chick, and mouse lateral hypothalamus (Gaoand van den Pol, 2001; Jo and Role, 2002a; Jo andRole, unpublished). Activation of nicotinic receptorsby treatment with nicotine [Fig. 2(D)] or by increas-ing ACh release (not shown) strongly facilitatesGABAergic transmission to LH neurons (Jo and Role,2002b; Jo and Role, unpublished data). Initial effortsin mouse brain slices to identify the post synaptic LHneurons under study are consistent with our proposalthat MCH-positive neurons receive GABAergic inputand that GABA release is potently enhanced by presyn-aptic nAChRs. In this scenario, activation of presynapticnAChRs on GABAergic interneurons would offset thepro-appetite, orexigenic signaling of NYP/AgRP inputs,favoring a net inhibition of MCH-positive neurons. Thissort of synaptic tuning of LH neurons could explain, atleast in part, nicotine’s anorexigenic activity.

The model can also resolve the apparent conflictbetween elevated NPY expression and the sustainedhypophagia that characterizes chronic nicotine expo-sure. Under these conditions, we would predict thatthe nAChR-mediated enhancement of GABA releaseis maintained and results in an elevated set point forsteady-state inhibition of orexigenic outflow via MCHprojections. Increased expression of NPY peptide(due to diminished negative regulation by leptin, asleptin levels fall with chronic nicotine exposure) can-not elicit sufficient activation of MCH neurons tooverride the elevated GABAergic inhibition. Obvi-ously, this model can (and must) be tested. Whethercorrect in detail or not, such studies would provide asystematic foray into the effects of nicotine and nic-otine withdrawal in appetite regulation.

How Might Endogenous CholinergicCircuits Be Involved in the NormalRegulation of Appetite?

The effects of neuronal nAChR activation on hypo-thalamic activity, food intake, and body weight regu-lation beg the question of how central cholinergicsystems might participate in normal appetite control.The role of cholinergic and/or cholinoceptive neuronsin the hypothalamus has received relatively little at-tention. Several recent studies, however, implicateacetylcholine effects within the hypothalamus in thecontrol of both neuroendocrine and behavioral func-tions, including food intake and arousal (Hara et al.,2001; Saper et al., 2001).

Cholinergic projections to neurons within the hy-pothalamus arise from both extrinsic and intrinsicsources; approximate areas of cholinergic input areindicated in Figure 3 by green (high level) and yellow(lower level) shading (Tago et al., 1987; Risold et al.,1989; Woolf, 1991; Schafer et al., 1998; Bayer et al.,1999). Cholinergic neurons intrinsic to the hypothal-amus, identified by their positive immunoreactivityfor choline acetyltransferase (ChAT), or the vesiculartransporter for ACh (VAChT) are present in the ar-cuate nucleus and scattered through the paraventricu-lar, periventricular, and posterior nuclei (Fig. 3;adapted from Tago et al., 1987; Risold et al., 1989;Woolf, 1991; Schafer et al., 1998; Bayer et al., 1999).Higher densities of both large and small ChAT-stained somata are found in the lateral hypothalamicarea and in the adjacent substantia innominata (Tagoet al., 1987). Extrinsic cholinergic projections to thehypothalamus arise primarily from the ponto-mesen-cephalic cell groups (i.e., the pedunculopontine andlaterodorsal tegmental nucleus; Woolf, 1991).

The density of cholinergic fibers (whether intrinsicor extrinsic in origin) within the LH ranges frommoderate to strong (see especially Tago et al., 1987;Bayer et al., 1999). LH areas with substantial numbersof ACh-positive projections include the perifornicalarea, the dorsal border of the LH (adjacent to the zonaincerta) and, at a more anterior level than illustratedhere, along the lateral border of the LH and substantiainnominata. The overlap between MCH and cholin-ergic neurons and fibers is particularly striking, espe-cially with respect to proposed mechanisms of nico-tine effects in LH. In the zona incerta and perifornicalregions of the rat LH, many choline acetyltransferase(ChAT) fibers are detected in the immediate vicinityof MCH-positive perikarya and their proximal den-drites [Bayer et al., 1999; and Fig. 3(B) and (C)].

Of course, new levels of complexity are added bychanging the question from “how does nicotine affectappetite?” to an analysis of how central cholinergiccircuits might participate in feeding regulation. Anobvious, and substantial wrinkle, is that ACh (asopposed to nicotine) interacts with multiple subtypesof muscarinic as well as nicotinic AChRs. Severalsubtypes of both nicotinic and muscarinic AChRs(mAChRs) are expressed within the LH including �4,�7, and �2 type nAChRs, and m1 and m2 typemAChRs (Ehlert and Tran, 1990; Britto et al., 1992;Okuda et al., 1993; J. Wei et al., 1994).

So, what happens when cholinergic neurons orcholinergic projections in the lateral hypothalamus areactivated? Little is known. Initial attempts, usingchanges in GABAergic transmission as an assay ofelevated ACh release in LH slice, appear to confirm invitro results demonstrating corelease of GABA and


ATP, but differential modulation of GABAergic andpurinergic transmission by nicotinic versus musca-rinic receptors (Jo and Role 2002a, 2002b, and Y. Joand L. Role, unpublished). The net effect of nicotinicreceptor activation in hypothalamus—even with ATPand glutamate transmission added to the analysis— isincreased inhibition. Muscarinic receptors mediateexactly the opposite effects: GABAergic transmissionis depressed and purinergic transmission is enhanced.

Similar pharmacologic approaches to assessing therole of cholinergic signaling in LH examine the ef-fects of carbachol treatment on expression of MCHmRNA in hypothalamic slices in vitro. Carbacholinduces a rapid increase in MCH mRNA, which isabolished both by atropine, a muscarinic antagonist,and hexamethonium, a nicotinic antagonist (Bayer etal., 1999). This finding is consistent with studies ex-amining the regulation of MCH mRNA in animalslacking specific muscarinic signaling pathways. MCHmRNA is increased in WT, fasted animals, therebyinducing a compensatory increase in food intake.However, MCH mRNA levels are significantly re-duced, even with fasting, in certain types of musca-rinic receptor knock-out mice (Yamada et al., 2001).

Taken together, the data are consistent with endog-enous cholinergic control of hypothalamic circuitsinvolved in food intake. Basal levels of cholinergicactivity in the LH appear to elicit a low level of tonicinhibition that involves nicotinic receptor-mediatedenhancement of GABAergic transmission distinctfrom its effects in other hypothalamic nuclei (see D.P.Li and Pan, 2001; D.P. Li et al., 2001). Increased AChlevels appear to activate M3 receptor-mediated stim-ulation of MCH mediated-orexigenic pathways (Shi-mada et al., 1998; Yamada et al., 2001; Marsh et al.,2002). The muscarinic induction of MCH signalingmust occur along the LH circuit past the point ofleptin activation of the �MSH/CART system, butbefore the MCH neuron. In view of in vitro findingsand prior proposals (Flier and Maratos-Flier, 1998;Elmquist et al., 1999; Jo and Role, 2002b; Y Jo and L.Role, unpublished), it is tempting to speculate thatcholinoceptive GABAergic neurons are the missinglink between the arcuate projections to the LH and theMCH neurons that coordinate cortical and brainstemregions involved in motivational feeding (Fadel andDeutch, 2002; Qu et al., 1996; Bittencourt and Elias,1998; Elias et al., 2001; Marsh et al., 2002).

SUMMARY, CONCLUSIONS, ANDFUTURE STUDIES

The literature is clear with respect to the effects ofnicotine and nicotinic receptors in the regulation of

appetite. Smokers are leaner and smoking cessation inthe absence of nicotine replacement therapy typicallyresults in significant and sustained hyperphagia andweight gain.

Identifying the cellular substrates of nicotine ac-tion is no small task. Despite numerous reports on theseriousness of nicotine-cessation related weight gain,considerable progress in our understanding ofnAChRs (to wit this volume) and staggering discov-eries in the identification of the molecular scaffolds offeeding behavior, the interface between the fields ofsmoking and eating remains sketchy, at best. We arestill lacking systematic studies aimed at identifyingthe major regulatory nodes of where nicotine effectsand appetite control converge. Our knowledge of therole of central cholinergic circuits in appetite is em-bryonic, despite impressive efforts in the neuroanat-omy and immunocytochemistry of cholinergic neu-rons and their diffuse terminal fields. In sum, it appearsthat the physiologists—from systems to synaptic-ana-lysts—have not (ahem) towed their weight in addressingthese fundamental issues in the neural regulation offeeding behavior. There’s lots of work to do.

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Nicotinic receptor-mediated effects on appetite and food intake