The Function of Leptin in Nutrition, Weight, and Physiology.pdf

October 2002: (II)S1–S14

The Function of Leptin in Nutrition, Weight, and PhysiologyJeffrey M. Friedman, M.D., Ph.D.

Recent advances indicate that a robust physio-logic system acts to maintain relative constancyof weight in mammals. A key component of thissystem is leptin. Leptin is an adipocyte hormonethat functions as the afferent signal in a negativefeedback loop regulating body weight. In addi-tion, leptin functions as a key link between nutri-tion and the function of most, if not all otherphysiologic systems. When at their set point,individuals produce a given amount of leptin andin turn maintain a state of energy balance. Weightgain results in an increased plasma leptin level,which elicits a biologic response characterized inpart by a state of negative energy balance.Weight loss among both lean and obese subjectsresults in decreased plasma levels of leptin,which lead to a state of positive energy balanceand a number of other physiologic responses. Inhumans, both the intrinsic sensitivity to leptin andits rate of production vary and both appear tocontribute to differences in weight. Further stud-ies of leptin, its receptor, and the molecular com-ponents of this system are likely to have a majorimpact on our understanding of obesity and theinterplay between nutrition and physiology.Key Words: leptin, adipocyte hormone, regulat-ing body weight, energy balance, obesity© 2002 International Life Sciences Institute

Introduction

In recent years, several components of the physiologicsystem that regulate body weight and links betweennutrition and physiology have been identified. Researchin this area is at the center of several issues that are ofgeneral importance including: obesity, a pressing, someconsider the most pressing, health problem in Westernand developing countries; the ways in which alterationsof nutritional state affect physiology; the role of genesand environment in determining human characteristics;and the molecular basis of behavior.

Two essentially polar explanations characterize theviews of most individuals on the causes of human obe-sity. The first view suggests that obesity is the result of alack of discipline on the part of affected individuals.Whereas it is true that reducing weight does improve thehealth of obese and overweight individuals (and is hencedesirable), the fact is that such remedies fail in the vastmajority of cases. Thus greater than 90 percent of indi-viduals who lose weight by dieting eventually return totheir original weight.1

An alternative view suggests that body weight isphysiologically controlled and that deviations in weightin either direction elicit a potent physiologic responsethat resists that change. Implicit in this view is the notionthat biologic factors determine each individual’s weight,be they lean or obese, and that this weight is thendefended. The effectiveness of this homeostatic system isillustrated by a few simple calculations. Over a decadethe weight of an average adult individual tends to in-crease slightly. Approximately 10 million kilocaloriesare consumed over this time. To account for this modestchange in weight (assuming the excess weight is depos-ited as adipose tissue), food intake must precisely matchenergy output within 0.17% per decade.2 This extraordi-nary level of precision suggests that a robust biologicsystem balances energy intake (food consumption) andenergy expenditure.

The proposition that obesity is to a large extent theresult of biologic rather than psychologic factors is sup-ported by a plethora of genetic and physiologic data.3

Twin studies, analyses of familial aggregation and adop-tion studies all indicate that obesity is the result of majorcontributions from genetic factors.4,5 Indeed, the herita-bility of obesity is roughly equivalent to that of heightand exceeds that of many disorders that are generallyconsidered to have a genetic basis. The identity ofseveral of these genes is now known, and in general, theyencode the molecular components of the physiologicsystem that regulates body weight. Two of the keyelements of this system are leptin and its receptor.

Leptin

Leptin is an adipocyte hormone that functions as theafferent signal in a negative feedback loop regulating

Dr. Friedman is with the Rockefeller University,Box 305, 1230 York Avenue, New York, New York,10021-6399, USA.

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body weight (Figure 1). This hormone reports nutritionalinformation (i.e., the size of the organism’s energystores) to the brain and other sites. Leptin circulates as a16-kD protein in mouse and human plasma but is unde-tectable in plasma from C57BL/6J ob/ob mice.6 Ob/obmice are genetically obese as a result of mutations in theleptin gene.7,8 In the absence of leptin, these mutantanimals (as well as leptin-deficient humans) never re-ceive the signal that there are adequate fat stores and inturn become hyperphagic and obese.

Leptin is not modified post-translationally becausethe molecular mass of the native protein is identical tothat predicted by the primary sequence (without thesignal sequence).9 The plasma level of leptin is highlycorrelated with adipose tissue mass and decreases in both

humans and mice after weight loss.10 The levels ofprotein are increased in several genetic and environmen-tally induced forms of rodent obesity and in obesehumans. Administration of recombinant leptin either byinjection or as a constant subcutaneous infusion to wild-type mice results in a dose-dependent decrease in bodyweight at increments of plasma leptin levels within thephysiologic range.6,11

In aggregate, these data establish leptin’s role ashormonal signal in a feedback loop modulating the sizeof adipose tissue mass and indicate that body weight to asignificant extent is under endocrine control. However,leptin is not the only afferent signal that regulates foodintake and body weight. The systems that control feedingbehavior and energy balance appear to be comprised of ashort-term and a long-term system. The short-term sys-tem regulates meal pattern and feeding throughout theday. Previous work indicates that changes in plasmaglucose concentration, body temperature, plasma aminoacids, cholecystokinin, and other hormones can all mod-ulate meal patterns.12 The long-term system balancesfood intake and energy expenditure and thus plays adominant role in ultimately regulating the size of thebody’s energy stores.

Leptin appears to function largely within the long-term system and influences the quantity of food con-sumed relative to the amount of energy that is expended.Leptin level does not increase significantly after a mealand does not, by itself, lead to the termination of ameal.10 These results suggest that leptin is not a classicsatiety factor. However, leptin and the other componentsof the long-term system interact extensively with thecomponents of the short-term system by modulating theamount of food that is consumed during a meal and/orthe likelihood that an organism will miss a meal.

A Broader Role for Leptin

Quantitative changes in plasma leptin concentrationelicit a potent biologic response. Decreases in plasmaleptin level activate what can be termed a “response tostarvation,” whereas increasing leptin levels elicit a “re-sponse to obesity” (Figure 2). The presence of lowplasma levels of leptin indicates that there are inadequateamounts of fat (stored energy) and that an adaptiveresponse that would lead to the replenishment of thosestores needs to be effected. Several clues concerning thenature of this “response to starvation” have been pro-vided by detailed analyses of the phenotype of ob mice.Leptin-deficient (ob/ob) mice manifest myriad endocrineand metabolic abnormalities.8 Many of these derange-ments, which include decreased body temperature, hy-perphagia, decreased energy expenditure (including ac-tivity), immune defects, and infertility, are also observedin starved animals.8 This has suggested that in the ab-

Figure 1. Leptin and the regulation of adipose tissue mass. Thecloning of the ob gene and the characterization of leptin hassuggested that body fat content is under homeostatic control.The available data suggests that leptin is the afferent signal ina negative feedback loop regulating adipose tissue mass. Thelevel of leptin is positively correlated with differences in bodyfat. Increasing leptin levels result in negative energy balance(energy expenditure � food intake), whereas decreasing levelslead to positive energy balance (food intake � energy expen-diture). These effects maintain constancy of fat cell mass. Theavailable data also suggest that the hypothalamus is an impor-tant site of leptin action. VMH � ventromedial hypothalamus.

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sence of leptin, ob/ob mice exist in a state of perceivedstarvation and thus exhibit a constellation of signs thatare characteristic of the starved state. Indeed, in circum-stances where food is readily available, this biologicresponse would be expected to lead to the massiveobesity evident in ob/ob mice. As predicted, replacementof leptin corrects all of the aforementioned abnormalitiesof mutant ob/ob mice.6

The possibility that falling plasma leptin levels sig-nal nutrient deprivation is further suggested by the ob-servation that exogenous leptin attenuates the neuroen-docrine responses to food restriction.13 Fasted wild-typemice receiving leptin continue to ovulate, whereas fastedcontrols given PBS experience an ovulatory delay ofseveral days. Leptin treatment blunts the changes incirculating thyroid hormone and corticosterone levelsthat are normally associated with food deprivation.13

Starvation is also associated with decreased immune

function and leptin corrects these abnormalities aswell.14 In treated ob/ob mice, leptin stimulates prolifer-ation of CD4� T cells and increases production ofcytokines by T-helper-1 cells.14 These results indicatethat leptin may also be a key link between nutritionalstate and the immune system.

Leptin is also important in regulating the onset ofpuberty. Extremely thin women often stop ovulating andabnormally thin adolescent women enter puberty laterthan their heavier counterparts. These observations havesuggested that reproductive potential in women is sup-pressed in the absence of adequate nutritional stores.These findings have further suggested that fat tissue mayproduce a signal that regulates reproduction.15 This fac-tor appears to be leptin. Treatment of mice with leptinaccelerates the maturation of the female reproductivetract and leads to an earlier onset of the estrous cycle andreproductive capacity.16 In humans, a surge in plasma

Figure 2. Biologic response to high versus low leptin levels. Leptin allows the body to maintain constant stores of fat. A loss of bodyfat (starvation) leads to a decrease in leptin, which in turn leads to a state of positive energy balance wherein food intake exceedsenergy expenditure. This biologic response also includes a pleiotype set of effects on the hypothalamic pituitary axis. Other effectsinclude decreased temperture and an increase of parasympathetic tone. Conversley an increase in adiposity leads to an increase inlevels of leptin. This response also includes a set of novel effects on fat and glucose metabolism and activation of the sympatheticnervous system. CRH � corticotrophin-releasing hormone, GnRH � gonadotrophin-releasing hormone, GH � growth hormone,SRIF � somatotrophin release–inhibiting factor, GHRH � growth hormone–releasing factor.


leptin concentration is seen in prepubertal males.17 Theevidence suggests that sufficient levels of leptin arenecessary but not sufficient for the onset of puberty.These studies suggest that leptin modulates reproductivefunction and provides a direct link between reproductionand the nutritional status of an organism.

Leptin’s physiologic role in preventing weight gainhas also been confirmed in a number of studies. Leanmice given chronic infusions of leptin lose adipose massin a dose-dependent fashion at leptin levels within thephysiologic range.11 These data indicate that increasingleptin levels elicits a “response to obesity” and thatdynamic changes in plasma leptin concentration act toresist weight change in either direction. The precisenature of this response to obesity is less well understoodbut is under intense investigation.

The Leptin Receptor and Leptin’s Sites ofAction

The leptin receptor is a member of the cytokine family ofreceptors. These receptors have a single transmembranedomain and are generally expressed as monomers ordimers on the cell surface. Ligand binding inducesdimerization and/or activation of the receptor and acti-vates signal transduction. Ob-R is predicted to have twoseparate leptin-binding regions and binds leptin withnanomolar affinity.18 Five splice forms of the leptinreceptor that differ at the carboxyl terminus have beenidentified.19 Four of these receptor forms are membranebound, whereas Ob-Re encodes a secreted form of thereceptor that circulates in plasma.20

Mutations that disrupt the leptin receptor have beenidentified in each of the available strains of diabetic(db/db) mice. Db/db mice are also genetically obese andmanifest a phenotype that is identical to that evident inleptin-deficient ob/ob mice. DNA sequence analyses ofthe available db strains have implicated the Ob-Rb formof the receptor as mediating many, if not all of leptin’sweight-reducing effects. The Ob-Rb form is widely ex-pressed but is enriched in the hypothalamus.18,19 Thesedata have suggested that the brain is an important targetof leptin action. This possibility is supported by the highpotency of leptin when delivered directly into the centralnervous system (CNS).11 In addition, leptin modulatesthe electrical activity of neurons in culture and in slicepreparations.21,22

Leptin also acts on some peripheral cell types andhas direct mitogenic effects on CD4� human T cells(Figure 3).14 It affects endothelial cells directly andincreases angiogenesis, although high doses are re-quired.23 Leptin modulates pancreatic cell function invivo and has direct effects on other cell types in vitroincluding liver, bone, and platelets.24 The leptin receptoris widely expressed, though the Ob-Ra (short) form of

the receptor predominates in many of these tis-sues.19,25,26 Although the potency of i.c.v. leptin indi-cates that direct peripheral effects are not required forweight loss, the full spectrum of leptin’s sites of action isnot known and could include sites that have not beenmentioned.

The function of the short forms of the leptin receptor(Ob-Ra, c, d) is unclear, although it has been suggestedthat they play a role in mediating the uptake of leptin intothe CNS as well as regulating its turnover.

The Neural Circuit Regulating Weight

The available data suggest that the concentration ofleptin as well as glucose and other afferent signals aresensed by groups of neurons in the hypothalamus andother brain regions. During starvation leptin levels fall,thus activating a behavioral, hormonal, and metabolicresponse that is adaptive when energy stores are reduced.Weight gain increases plasma leptin concentration andelicits a different response leading to a state of negativeenergy balance. It appears likely that different neuronsrespond to increasing and/or decreasing leptin levels. Inaddition, the spectrum of leptin’s effects is likely to becomplex, as recent studies have indicated that differentthresholds exist for several of leptin’s effects.27

A number of hypothalamic nuclei have been previ-ously implicated in the control of food intake. Thuslesions of the arcuate nucleus, the ventromedial hypo-thalamus (VMH), DMH, and LH perturb body weightand each plays a role in the regulation of food intake orbody weight.28 Leptin receptors have been localized toeach of these hypothalamic nuclei.26,29 The LH andVMH project both within and outside the hypothalamusand modulate activity of the parasympathetic and sym-pathetic nervous system, respectively.30 The DMH alsohas inputs to the parasympathetic nervous system andhas been implicated in integrating information among theVMH, LH, and PVN. The PVN controls secretion ofpeptides from both the posterior and anterior pituitaryand projects to nuclei with sympathetic or parasympa-thetic afferents.30 The PVN also projects to numeroussites outside of the hypothalamus including higher cen-ters known to modulate motivational behaviors.

These hypothalamic nuclei express one or morebrain neuropeptides and neurotransmitters that regulatefood intake and/or body weight.12 Several lines of evi-dence have implicated these neuropeptides as playing arole in the response to leptin and other nutritional signals.The data are consistent with the possibility that neu-ropeptide Y (NPY) and Agouti-related transcript (ART,also known as AgRP) play a role in the response toabsent (and possibly low) leptin levels, whereas centrallyexpressed �-melanocyte-stimulating hormone (�MSH)and its MC-4 receptor play a role in the response to an


increased plasma leptin concentration (Figure 4).31 Whatfollows is a review of these and other neuropeptides andneurotransmitters.

When administered intrathecally, NPY is the mostpotent orexigenic agent that is known. NPY RNA isincreased in ob/ob mice and its levels decrease afterleptin treatment.32 An NPY knockout attenuates theobesity and other features of ob/ob mice indicating that itplays a role in the response to absent leptin.33 Data fromother knockout mice indicate that both the Y2 andpossible Y5 receptors play a role in mediating some ofNPY’s effects on food intake and body weight.34–36

�MSH and MSH agonists decrease food intake. Re-duced signaling of �MSH in genetically obese Ay orMC-4R knockout mice results in obesity and leptin resis-tance.11,33,37 Leptin modulates the expression of pro-opi-omelanocortin (POMC), the precursor of �MSH.38 A sub-set of neurons express both Ob-R and POMC and �MSH

antagonists blunts the response to exogenous leptin.39 Fi-nally, leptin depolarizes GFP-labeled POMC neurons in aslice preparation.40

AgRP, an endogenous antagonist of melancortinsignaling, is also implicated in the regulation of weightbecause transgenic mice that overexpress AgRP aremarkedly obese.41 In addition, mRNA for this hypotha-lamic peptide is increased eightfold in ob/ob mice.42 Intotal, these results suggest that NPY and AGRP may playa role in mediating the response to absent leptin, whereasincreased leptin levels stimulate melanocortin-signalingpathways. It is important to note, however, that thesemolecules are likely to respond to other signals and thatthese complex neural circuits are likely to interact withone another.

Melanin-concentrating hormone (MCH), a neu-ropeptide expressed in the lateral hypothalamus, is in-creased in ob/ob mice and injections of it increase food

Figure 3. Adipocyte leptin and the regulation of adipose tissue mass. Leptin is the afferent signal in a negative feedback loop thatmaintains constaancy of adipose tissue mass. Leptin is secreted from adipocytes (bottom left) either as a 16-KDa protein or boundto a soluble form of its receptor (Ob-R). The level of leptin is positively correlated with differences in body fat. Increased leptin resultsin negative energy balance (energy expenditure � food intake), whereas decreased levels lead to positive energy balance (foodintake � energy expenditure). Leptin acts mainly on the hypothalamus (top). Extensive connections exist between the hypothalamusand other brain regions. Leptin acts centrally to decrease food intake and modulate glucose and fat metabolism (right). Peripheraleffects on t-cells, pancreatic islets, and other tissues have also been demonstrated. CVO � circumventricular organ.


intake in mice.43 Mice with mutations of MCH arehypophagic and lean thus confirming a role for thispeptide in the maintenance of body weight.44 MCH-expressing neurons receive inputs from NPY neurons inthe arcuate nucleus and appear to relay NPY’s orexigenicsignal to a number of sites throughout the brain. Theseneurons project to many of the same brain regions as�MSH and these molecules have opposite effects onfood intake. Both act via distinct receptors and MSHincreases, whereas MCH decreases cAMP signaling.Thus the plasma leptin concentration influences the rel-ative activity of these anorexigenic and orexigenic cir-cuits at multiples levels.

Many other neurotransmitters and neuropeptides arelikely to function in this homeostatic system.39 It is likelythat leptin, glucose levels, and other signals potentiatethe action of some of these anorexogenic agents andantagonize the orexigenic (i.e., stimulate food intake)and activity of others. These are briefly reviewed here.Cholecystokinin (CCK) was the first neuropeptide sug-gested to play a role in regulating food intake.45 Injec-

tions of CCK increase satiety in food-deprived rats viaafferent vagal nerves.46 Recently, CCK was reported topotentiate the anorectic effect of leptin.47

Cocaine-amphetamine-regulated transcript (CART),a hypothalamic peptide, is implicated in the response toleptin.48 CART decreases food intake, CART antibodiesincrease food intake, and CART mRNA is increased inob/ob mice. In addition, CART is co-localized with�MSH and Ob-R in some hypothalamic neurons.

Bombesin also reduces food intake and inducedmutations of the bombesin 3-receptor result in mildobesity.49 A growing body of evidence indicates thatinsulin acts on the hypothalamus to decrease food in-take.50 Two recently identified neuropeptides, orexin-aand orexin-b, that regulate the state of an animal’sarousal may also modulate food intake.51,52

Corticotropin-releasing factor (CRF) is another fac-tor that is likely to mediate some of leptin’s effects. CRFis expressed at high levels in the PVN and in theamygdala, which projects to the LH.53,54 Additionally,the DMH has CRF-containing neurons.55 CRF regulates

Figure 4. The neural circuit activated by leptin. In the arcuate nucleus of the hypothalamus the leptin receptor is expressed in at leasttwo different classes of neurons. One class expresses NYP and AGRP, two neuropeptides that increase food intake. Another classexpresses POMC, the precursor of �MSH and CART. Both CART and �MSH decrease food intake. The evidence suggests that leptinsuppresses the activity of NPY/AGRP neurons and stimulates the activity of POMC/CART neurons. Thus in the absence of leptinthe NPY/AGRP neurons are maximally active and food intake is stimulated. In the presence of increased leptin levels thePOMC/CART neurons are maximally active and food intake is reduced. When an individual is at their stable weight the activity ofthese pathways is balanced. The neural mechanisms by which these neurons change food intake is not known. Figure credit: Lex vonder Plueg, Merck Pharmaceuticals. NPY � neuropeptide Y, 5HT � serotonin, MCH � melanin-concentrating hormone, DMH �dorsomedial hypothalamic nucleus, VMH � ventromedial hypothalamus, CART � cocaine-amphetamine–regulated transcript,POMC � pro-opiomelanocortin, AGRP � Agouti-related peptide, LHA � lateral hypothalamic area, PVN � paraventricularnucleus, ARC � arcuate nucleas, CRH � corticotrophin-releasing hormone, FI � food intake, ORXN � Orexin.


pituitary ACTH release and adrenal glucocorticoid se-cretion. Delivery of CRF to the PVN also results inreduced food intake and increased energy expenditure inlean and obese rodents.56,57 Leptin has been shown toincrease CRH mRNA in the PVN and to stimulaterelease of CRF from perfusion slices of both amygdalaand the PVN.58,59 Leptin may also inhibit the increase inCRH evident during a stress response.60

Glucocorticoids have long been known to play a rolein regulating body weight. Increased fat deposition is afeature of Cushings syndrome and increased glucorticoidsresult in obesity in mice.61 High levels of glucocorticoidsare also observed in most strains of genetically obese mice.Moreover, adrenalectomy and glucocorticoid antagonistsblunt the obesity evident in ob/ob, db/db, and other obesemice.62,63 Low-dose glucocorticoid replacement restoresthe obese phenotype of adrenalectomized ob/ob mice indi-cating that they play a permissive role in its development.63

It is unclear if the requirement for glucocorticoids in thedevelopment of the full ob/ob phenotype depends on thesuppression of CRH, a known effect of glucocorticoids, orif another mechanism is operative.

More recent data have implicated endocannabinoidsand the muscarinic 3 receptor in the response to leptinand/or feeding in general. Endocannabinoids play a rolein the response to decreased leptin levels, whereas anMC3 knockout leads to hypophagia and decreasedweight.64,65 Ghrelin, a peptide that is synthesized instomach and brain, increases food intake by interactingwith a hypothalamic G protein–coupled receptor.66

A more full understanding of the system thatcontrols weight will also require the identification ofthe upstream and downstream components of thesekey hypothalamic neurons. Recently a novel systemthat employs an engineered pseudorabies virus to traceneural circuits was developed.67 This vector was suc-cessfully used to identify inputs to leptin-responsiveneurons in the hypothalamus. Results using this sys-tem have shown that a number of brain regions includ-ing pyriform cortex (which receives olfactory infor-mation), the amygdala (known to regulate emotionalbehavior), and cortical regions (known to controlhigher brain functions) can modulate leptin signalingin hypothalamus. Studies aimed at understanding theways in which these multiple relevant inputs are inte-grated may illuminate the interplay between consciousand unconscious (and other) factors in regulating foodintake and body weight. These studies may also havegeneral implications for our understanding of the reg-ulation of a complex behavior.

Efferent Pathways Regulating Metabolism

The evidence indicating that leptin can act centrally tomodulate body weight raises the following question:

How does the CNS regulate peripheral metabolism inresponse to differences in leptin and other signals? Theeffects of leptin on metabolism are distinct from thosethat are seen after food restriction. Whereas increasingleptin levels lead to fatty acid oxidation and a reductionin adipose tissue mass, leptin deficiency, evident in ob/obmice or mice receiving a leptin antagonist, is associatedwith an increase in fat deposition.8,68 In ob/ob mice therate of lipogenesis is markedly increased as is the abun-dance of the RNAs encoding the enzymes that are ratelimiting in fatty acid synthesis.8,69 It as yet unclearwhether the metabolic derangements of ob/ob mice aresolely the result of increased food intake or if otherfactors are also important.

The mechanism by which centrally administeredleptin leads to lipolysis and the loss of adipose tissuemass is similarly unclear. It is important to note thatincreased fatty acid oxidation is not restricted to adiposetissue and that leptin treatment also results in the loss ofintracellular lipid in other cell types.70 In this and otherrespects, the available data show that the metabolicresponse to leptin is markedly different from the re-sponse to reduced food intake. Whereas food restriction(i.e., dieting) leads to the loss of both lean body mass andadipose tissue mass, leptin-induced weight loss is spe-cific for the adipose tissue mass.6,11,71 Leptin also pre-vents the reduced energy expenditure normally associ-ated with a decreased food intake.11 Hyperleptinemicanimals undergoing a rapid period of weight loss fail toshow any rise in serum free fatty acids or ketones.70 Thiscontrasts with food-restricted (pair-fed) animals, whichshow a marked rise in serum free fatty acids. Indeed,despite the fact that the respiratory quotient falls afterleptin treatment (indicative of fatty acid oxidation), themetabolic fate of stored triglycerides in adipose tissue isunknown.11 Finally, data using DNA microarrays haveshown that leptin has novel (indirect) effects on geneexpression in adipose tissue.72

Leptin also has novel effects on glucose metabolism.The possibility that leptin modulates glucose metabolismwas first suggested in studies of ob/ob mice treated withleptin. Ob/ob mice are diabetic and the severity of thediabetes is dependent on the background strain carryingthe mutation.8 In one study, leptin normalized the hyper-glycemia and hyperinsulinemia evident in C57BL/6Job/ob mice at doses that did not decrease weight.73

Anti-diabetic effects have also been observed in insulin-deficient rats.74

Leptin also improves the insulin resistance and hy-perglycemia evident in a diabetic lipodystrophic trans-genic mouse line.75 The anti-diabetic effects of leptin inthese animals appear to come from leptin’s ability tostimulate lipolysis and fatty acid oxidation in liver,skeletal muscle, and other peripheral tissues. Previous


studies have indicated that insulin signaling is adverselyaffected by excess intracellular lipid.76–78 For example, aselective increase of lipid uptake by liver or muscle leadsto decreased insulin action only in that organ.79 Thusleptin appears to improve insulin signaling by reducingintracellular lipid levels. The precise mechanism bywhich intracellular lipid decreases insulin signaling isnot precisely known but may be the result of effects onPKC theta and IRS1 (personal communication).78 Theseresults could in part explain the frequent association ofobesity with insulin resistance because obesity is associ-ated with increased fat deposition in all cell types, notjust adipose tissue.

Pathogenesis of Obesity

In principle, alterations in body weight could be theresult of abnormalities in the production of leptin, thecells that receive leptin’s signal, or the efferent pathwaysthat effect changes in weight. Thus the pathogenesis ofobesity can be inferred in a general way by measurementof the plasma leptin levels (Figure 5). An increase inplasma levels suggests that obesity is the result of leptinresistance. A low or normal plasma concentration ofleptin in the context of obesity suggests decreased pro-

duction of leptin. This interpretation is similar to thatrelating insulin to the pathogenesis of diabetes. However,this designation is quite general because a great numberof hormones as well as genetic, environmental factors,and even psychologic factors are likely to influenceleptin sensitivity and production.

Plasma leptin levels have been measured in rodentsand in humans using both RIA and ELISA.10,80 In allforms of rodent obesity studied, the obese animals havea higher leptin level than controls (not including ob/obmice).10,81 The data suggest that these forms of animalobesity are the result of leptin resistance. In each of threecases that have been tested, obese animals that arehyperleptinemic can be shown to be completely or par-tially resistant to exogenous leptin.11

Diet-induced obese mice (DIO) become obese onlyafter exposure to a high-fat diet. For example, Akr mice(and some other strains) remain lean when fed a standardchow diet but become obese only when fed a high-fatdiet. By contrast, other mouse strains do not becomeobese when exposed to an identical diet. DIO animalsdevelop hyperleptinemia and exhibit a partial response toexogenous leptin. The leptin resistance observed in suchmice emphasizes the fact that environmental factors can

Figure 5. Pathogenesis of obesity. There are three general ways in which alterations of the leptin regulatory loop could lead to obesity.(A) Failure to produde leptin, as occurs in ob/ob mice would result in obesity, as would (B) inappropriately low leptin secretion fora given fat mass. In the latter case, the fat mass would expand until “normal” leptin levels are reached, resulting in obesity. (C) Finally,obesity could result from relative or obsolete insensitivity to leptin at its site of action. Such resistance would be associated withincreased circulating leptin, analogous to the increased insulin levels seen with insulin-resistant diabetes. In general, high plasmaleptin levels are evident in obese rodents and humans. In a subset of cases, obesity is associated with normal levels of leptin.Differences in leptin production and leptin sensitivity could be the result of genetic, environmental, and psychologic factors.


modulate leptin sensitivity. This indicates that the patho-genesis of DIO and leptin resistance is the result of aninteraction between genetic and environmental factors.

A fuller understanding of the mechanisms by whichfat content in the diet modulates weight is likely to berelevant to human obesity. The incidence of obesityincreases in many populations when exposed to a high-fat “Western” diet.82 How might genes interact withenvironmental factors to cause obesity? As most peoplehave experienced first hand, exposure to a highly palat-able diet often leads to transient weight gain. In mostcases, the gained weight is eventually lost. However, it ispossible that in other cases, the induced increase inendogenous leptin level (which accompanies weightgain) leads to a down-regulation of the leptin responseand a failure to return to the starting weight. If tachy-phylaxis to increased levels of endogenous leptin isinfluenced by genetic factors, one might predict that asubset of individuals (and some populations) would beespecially susceptible to DIO. The observation that ani-mals that express constitutive levels of leptin are insen-sitive to a high-fat diet supports this possibility (unpub-lished). However, alternative explanations are possibleand additional studies are required. Studies to identifythe AKR alleles that predispose to DIO may illuminatethe underlying mechanism.83,84

Leptin and Human Obesity

In human subjects, a highly significant correlation be-tween body fat content and plasma leptin concentrationhas been observed and obese humans generally havehigh leptin levels.10,80 These data suggest that in mostcases human obesity is likely to be associated withinsensitivity to leptin. However, five to ten percent ofobese human subjects have relatively low levels of lep-tin.10,80 Low leptin levels also predispose to weight gainin pre-obese Pima Indians.85 These data suggest that insome instances obesity results from a subnormal secre-tion rate of leptin from fat.

The basis for leptin resistance in the overwhelmingmajority of obese hyperleptinemic human subjects isunknown. Data from studies of animals clearly indicatethat this condition is likely to be very heterogeneous andthat many factors are likely to influence the activity ofthe neural circuit that regulates feeding behavior andbody weight. It has also been suggested that entry ofleptin into the cerebrospinal fluid (CSF) may be limitingin some obese subjects thus leading to leptin resis-tance.86,87 If true, the development of morbid obesitycould result when the plasma leptin levels exceed thecapacity of the transport system. Treatment of humanswith recombinant leptin has been shown to result in anincrease in CSF leptin concentrations.88 Leptin uptakehas been demonstrated in the capillary endothelium of

mouse and human brain and is decreased in pre-obeseanimals.89–91 It is yet unknown whether this increase inCSF levels after treatment with recombinant leptin isvariable among different individuals. It has thus beenproposed that transport across the brain capillary endo-thelium is required for leptin to find its way to its site ofaction in the brain interstitial space and that Ob-Raand/or other proteins mediate leptin transport.89 More-over, defects anywhere in this transport pathway couldlead to the development of obesity.

Defects in leptin signal transduction could also beimportant in the development of leptin resistance. Stud-ies of the function of the leptin receptor in vitro haveconfirmed that Ob-Rb is capable of activating signaltransduction.25,92–94 Leptin activates the STAT transcrip-tion factor in hypothalamus within 15 minutes of a singleintraperitional injection.95 In vitro studies have indicatedthat activation of the leptin receptor is dependent onphosphorylation of the JAK2 kinase after ligand bindingto an Ob-Rb homodimer. Leptin also leads to the tyrosinephosphorylation of the SHP-2, a phosphotyrosine phos-phatase, which in turn decreases both the state of JAK-2phosphorylation and transcription of a leptin-induciblereporter gene.96,97 Thus SHP-2 may play a role in shut-ting off the leptin signal transduction pathway. SOCS-3,a suppressor of JAK signaling has been implicated inleptin signal transduction and may also play a role indown-regulating the response to leptin.98 The other com-ponents of the leptin signal transduction pathway havenot yet been identified.

Leptin resistance in humans is likely to be the resultof a complex interplay of many factors. In principle,leptin resistance could result from altered activity of anyof the aforementioned components of the leptin signaltransduction pathway in the cells that respond directly onany cells downstream in this neural circuit. Leptin’sactions are also likely to be influenced by psychologicfactors via connections between the higher cortical cen-ters, which modulate an animal’s motivational state andneural circuits within the hypothalamus.67 The neuroana-tomic and functional relationships between these brainregions are only now being elucidated.

Mutations Associated with Human Obesity

In almost all cases, obese subjects express at least someleptin. However, two cousins born from an extendedfamily have been found to be homozygous for a frameshift mutation in the leptin gene. These individuals donot have any circulating leptin.99 In these two subjects,the mutation is associated with profound obesity con-firming that leptin is of critical importance for the controlof body weight in humans. Affected members of Turkishkindred with a missense mutation in the leptin gene alsohave reduced leptin levels and manifest extreme obesity


and amenorrhea. These results further suggest that leptinplays a role in modulating reproductive function inhumans.100 Similar conclusions were reached in studiesof three massively obese members of a French familycarrying mutations in the leptin receptor.101 These threestudies also indicate that apart from severe obesity andabnormalities of reproductive function, the other abnor-malities identifiable in ob/ob and db/db mice such ashypertcortisolemia, cold intolerance, and severe diabetesare not necessarily apparent.

Mutations in other genes are also associated withhuman obesity. Approximately 1 to 2% of morbidlyobese humans have mutations in the human MC-4 re-ceptor.102 In these cases, the obesity is inherited in adominant mutation indicating that a 50% decrease in�MSH signaling can have important effects on bodyweight. A recent report also showed linkage of POMCand other loci on human chromosome 2 to leptin levelsand to a lesser extent body mass index (BMI, kg/m2) ina population of Mexican Americans.103 POMC is theprecursor of �MSH. Variation at this locus may contrib-ute to leptin resistance. The importance of MSH signal-ing is further confirmed by the development of obesity intwo individuals with mutations in the POMC gene.104

Obesity has also been observed in a woman with amutation in the PC-1 gene.105 PC-1 is a protease that isknown to cleave neuropeptide precursors includingPOMC and thus serves a similar function to CPE, thegene that is mutant in fat/fat mice.

Although rare, the association of massive obesitywith mutations in leptin and its receptor in human con-firms their importance in regulating body weight. Thisassertion is supported by data from early clinical trialswith leptin in humans. However, because the mutationsin these genes, and POMC, PC-1, and the MC4 receptorare uncommon, the pathogenesis of most human obesityis unknown. It is likely that some of the genes respon-sible for human obesity in the general population will atsome level modulate either leptin secretion or leptinsensitivity. Both genetic and physiologic studies will berequired to confirm this prediction.

Prospects for New Treatments of HumanObesity

A recent prospective epidemiologic study of more thanone million individuals confirmed that obesity is anindependent risk factor for mortality.4 This finding am-plifies the need for efficacious and safe means for treat-ing this disorder. The health risk of obesity is greatlydiminished when even modest amounts of weight (i.e.,5% of total weight) are lost.106,107 This is the result of amarked improvement in the diabetic, hypertensive, andcardiovascular status of obese subjects affected by theseconditions.106 Dieting, by itself, is only rarely effective

for the long-term maintenance of weight loss emphasiz-ing the need for additional therapies.1 Clearly an impor-tant indication for such treatment would be for themanagement of the comorbidities associated with obe-sity.

The possible therapeutic benefit of leptin treatmentin humans is now being tested in several clinical settings.It is has been demonstrated that leptin therapy has potentweight-reducing effects in the two leptin-deficient indi-viduals that have been treated thus far.108 In addition toreducing food intake, weight, and body fat content, thehormone also stimulated cycling of gonadotrophins inone of the prepubescent 11-year-old children receiving it.The efficacy of treatment with exogenous leptin in thesesubjects confirms that leptin plays a physiologic role toregulate weight in humans and establishes a link betweenleptin signaling and reproductive capacity.108

Recent data from early clinical trials in the generalpopulation have demonstrated that 4 weeks of leptininjections are safe and cause small but significant weightloss in lean and obese subjects compared with placebo (P�0.02) (unpublished observation. Treatment of a subsetof eight obese subjects for a total of 6 months resulted inan average weight loss of 7.1 kg in a group receiving 0.3mg/kg leptin versus a loss of 1.7 kg in a group receivinga placebo. Some of the subjects in this group lost sub-stantial amounts of weight whereas others did not. Thislimited study suggests that leptin could ultimatelyemerge as an effective therapy for some, but not all,obese subjects although studies of more patients areclearly required.109

Further studies to determine the possible utility ofleptin for the treatment of type 2 diabetes are alsoindicated because animal studies have shown that leptincan increase glucose metabolism independently of itseffects on weight and can obviate the need for insulin inlipodystrophic mice.73,110,111 As mentioned, this effectcould be a result of leptin’s action to clear lipid fromperipheral sites. It is also possible that leptin could be oftherapeutic benefit for the maintenance of weight lossafter a diet (rather than as a means to induce weight loss).In humans, diet-induced weight loss results in a decreasein plasma leptin concentration.10 This provides a possi-ble explanation for the high failure rate of dieting; a lowleptin level is likely to be a potent stimulus for weightgain. Thus leptin treatment after a very low calorie dietcould, in principle, reduce the 95% failure rate of dietsfor long-term maintenance of weight loss.

Summary

Studies of the physiologic system that regulates weighthave identified several molecules that have potential astherapeutic targets. Leptin or leptin agonists may be ofuse for the treatment of obesity and other disorders such


as lipodystrophy. �MSH agonists and NPY antagonistsare also in development. The fact that patients withMC4R mutations exhibit an obese phenotype makes�MSH agonists particularly attractive as a potential ther-apeutic. MCH antagonists could be of potential benefitespecially in light of the lean phenotype of MCH knock-out mice. It is highly likely that as additional componentsof the system that regulate weight are identified, newtherapeutic modalities will be developed. Whether or notnew therapies emerge, the identification of leptin and itsreceptors has provided an intellectual framework inwhich to consider the regulation of food intake and bodyweight, the pathogenesis of obesity and other nutritionaldisorders, and the links between nutrition and physiol-ogy.

Acknowledgments

The author would like to thank Susan Korres for expertassistance in preparing this manuscript and Alex Soukasfor helpful comments. This work was supported by agrant from NIH/NIDDK (J.M.F.).

1. Wadden TA. Treatment of obesity by moderate andsevere caloric restriction. Results of clinical re-search trials. Ann Intern Med 1993;119:688–693

2. Friedman JM, Halaas JL. Leptin and the regulationof body weight in mammals. Nature 1998;395:763–770

3. Kennedy GC. The role of depot fat in the hypotha-lamic control of food intake in the rat. Proc R Soc(Lond) (B) 1953;140:578–592

4. Calle E, Thun M, Petrelli J, et al. Body-mass indexand mortality in a prospective cohort of U.S.adults. N Engl J Med 1999;341:1097–1105

5. Stunkard AJ, Harris JR, Pedersen NL, McClearnGE. The body-mass index of twins who have beenreared apart. N Engl J Med 1990;322:1483–1487

6. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded bythe obese gene. Science 1995;269:543–546

7. Zhang Y, Proenca P, Maffei M, et al. Positionalcloning of the mouse obese gene and its humanhomologue. Nature 1994;372:425–432

8. Coleman DL. Obese and diabetes: two mutantgenes causing diabetes-obesity syndromes inmice. Diabetologia 1978;14:141–148

9. Cohen SL, Halaas JL, Friedman JM, et al. Charac-terization of endogenous human leptin. Nature1996;382:589

10. Maffei M, Halaas J, Ravussin E, et al. Leptin levelsin human and rodent: measurement of plasmaleptin and ob RNA in obese and weight-reducedsubjects. Nat Med 1995;1(11):1155–1161

11. Halaas JL, Boozer C, Blair-West J, et al. Physio-logical response to long-term peripheral and cen-tral leptin infusion in lean and obese mice. ProcNatl Acad Sci U S A 1997;94:8878–8883

12. Spiegelman BM, Flier JS. Adipogenesis and obe-sity: rounding out the big picture. Cell 1996;87:377–389

13. Ahima RS, Prabakaran D, Mantzoros C, et al. Role

of leptin in the neuroendocrine response to fasting.Nature 1996;382:250–252

14. Lord G. Leptin modulates the T-cell immune re-sponse and reverses starvation induced immuno-suppression. Nature 1998;394:897–901

15. Frisch RE, McArthur JW. Menstrual cycles: fatnessas a determinant of minimum weight for heightnecessary for their maintenance or onset. Science1974;185:949–951

16. Chehab FF, Mounzih K, Lu R, Lim ME. Early onsetof reproductive function in normal female micetreated with leptin. Science 1997;275(5296):88–90

17. Mantzoros CS, Flier JS, Rogol AD. A longitudinalassessment of hormonal and physical alterationsduring normal puberty in boys. Rising leptin levelsmay signal the onset of puberty. J Clin EndocrinolMetab 1997;82(4):1066–1070

18. Tartaglia LA, Dembski M, Weng X, et al. Identifica-tion and expression cloning of a leptin receptor,OB-R. Cell 1995;83:1263–1271

19. Lee GH, Proenca R, Montez JM, et al. Abnormalsplicing of the leptin receptor in diabetic mice.Nature 1996;379:632–635

20. Li C, Ioffe E, Fidahusein N, et al. Absence ofsoluble leptin receptor in plasma from dbPas/dbPas

and other db/db mice. J Biol Chem 1998;273:10078–10082

21. Glaum SR, Hara M, Bindokas VT, et al. Leptin, theobese gene product, rapidly modulates synaptictransmission in the hypothalamus. Mol Pharmacol1996;50:230–235

22. Heisler LK, Cowley MA, Tecott LH, et al. Activationof central melanocortin pathways by fenfluramine.Science 2002;297:609–611

23. Sierra-Honigmann M, Nath A, Murakami C, et al.Biologic action of leptin as an angiogenic factor.Science 1998;281:1683–1686

24. Wang MY, Koyama K, Shimabukuro M, et al.OB-Rb gene transfer to leptin-resistant islets re-verses diabetogenic phenotype. Proc Natl AcadSci U S A 1998;95(2):714–718

25. Ghilardi N, Ziegler S, Wiestner A, et al. DefectiveSTAT signaling by the leptin receptor in diabeticmice. Proc Natl Acad Sci U S A 1996;93:6231–6235

26. Fei H, Okano HJ, Li C, et al. Anatomic localizationof alternatively spliced leptin receptors (Ob-R) inmouse brain and other tissues. Proc Natl Acad SciU S A 1997;94:7001–7005

27. Ioffe E, Moon B, Connolly E, Friedman JM. Abnor-mal regulation of the leptin gene in the pathogen-esis of obesity. Proc Natl Acad Sci U S A 1998;95:11852–11857

28. Choi SJ, Sparks R, Clay M, Dallman M. Rats withhypothalamic obesity are insensitive to central lep-tin injections. Endocrinology 1999;140:4426–4433

29. Hoggard N, Mercer JG, Rayner DV, et al. Localiza-tion of leptin receptor mRNA splice variants inmurine peripheral tissues by RT-PCR and in situhybridization. Biochem Biophys Res Commun1997;232(2):383–387

30. Luiten PGM, Horst GJ, Steffens AB. The hypothal-amus, intrinsic connections and outflow pathwaysto the endocrine system in relation to the control of


feeding and metabolism. Prog Neurobiol 1987;28:1–54

31. Friedman JM. The alphabet of weight control. Na-ture 1997;385:119–120

32. Stephens TW, Bashinski M, Bristow PK, et al. Therole of neuropeptide Y in the antiobesity action ofthe obese gene product. Nature 1995;377:530–534

33. Erickson JC, Hollopeter G, Palmiter RD. Attenua-tion of the obesity syndrome of ob/ob mice by theloss of neuropeptide Y. Science 1996;274(5293):1704–1707

34. Pedrazzini T, Seydoux J, Kustner P, et al. Cardio-vascular response, feeding behavior, and locomo-tor activity in mice lacking the NPY Y1 receptor.Nat Med 1998;4:722–726

35. Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD.Role of the Y5 neuropeptide Y receptor in feedingand seizures. Proc Natl Acad Sci U S A. In press

36. Naveilhan P, Hassani H, Canals J, et al. Normalfeeding behavior, body weight and leptin responserequire the neuropeptide Y Y2 receptor. Nat Med1999;5:1188–1193

37. Huszar D, Lynch CA, Fairchild-Huntress V, et al.Targeted disruption of the melanocortin-4 receptorresults in obesity in mice. Cell 1997;88:131–141

38. Fan W, Boston BA, Kesterson RA, et al. Role ofmelanocortinergic neurons in feeding and the ag-outi obesity syndrome. Nature 1997;385:165–168

39. Hakansson M-L, Brown H, Ghilardi N, et al. Leptinreceptor immunoreactivity in chemically definedtarget neurons of the hypothalamus. J Neurosci1998;18:559–572

40. Cowley M, Smart J, Rubinstein M, et al. Leptinactivates anorexigenic POMC neurons through aneural network in the arcuate nucleus. Nature2001;411:480–484

41. Ollmann MM, Wilson BD, Yang Y, et al. Antago-nism of central melanocortin receptors in vitro andin vivo by agouti-related protein. Science 1997;278:135–138

42. Shutter JR, Graham M, Kinsey AC, et al. Hypothal-mic expression of ART, a novel gene related toagouti, is up-regulated in obese and diabetic mu-tant mice. Genes Dev 1997;11:593–602

43. Qu D, Ludwig DC, Gammeltoft S, et al. A role formelanin-concentrating hormone in the central regu-lation of feeding behavior. Nature 1996;380:243–247

44. Shimada M, Tritos N, Lowell B, et al. Mice lackingmelanin-concentrating hormone are hypophagicand lean. Nature 1998;396:670–674

45. Gibbs J, Young RC, Smith GP. Cholecystokininelicits satiety in rats with open gastric fistulas.Nature 1973;245:323–325

46. Smith GP, Jerome C, Cushin BJ, et al. Abdominalvagotomy blocks the satiety effect of cholecysto-kinin in the rat. Science 1981;213:1036–1037

47. Matson CA, Wiater MF, Kuijper JL, Weigie DS.Synergy between leptin and cholecystokinin (CCK)to control daily caloric intake. Peptides 1997;18:1275–1278

48. Kristensen P, Judge ME, Thim L, et al. Hypotha-lamic CART is a new anorectic peptide regulatedby leptin. Nature 1998;393:72–76

49. Ohi-Hamazaki H, Watase K, Yamamoto K, et al.

Mice lacking bombesin receptor subtype-3 de-velop metabolic defects and obesity. Nature 1997;390:165–169

50. Woods AJ, Stock MJ. Leptin activation in hypo-thalamus. Nature 1996;381:745

51. Sakurai T, Amemiya A, Ishii M, et al. Orexins andorexin receptors: a family of hypothalamic neu-ropeptides and G protein–coupled receptors thatregulate feeding behavior. Cell 1998;92:573–585

52. Siegel J. Narcolepsy: a key role for hypocretins(orexins). Cell 1999;98:409–412

53. Gray TS, Carney ME, Magnuson DJ. Directprojects from the central amygdaloid nucleus tothe hypothalamic paraventricular nucleus: possiblerole in stress-induced adrenocorticotropin release.Neuroendocrinology 1989;50:433–446

54. Cummings S, Elde R, Ells J, Lindall A. Corticotrop-in-releasing factor immunoreactivity is widely dis-tributed within the central nervous system of therat: an immunohistochemical study. J Neurosci1983;3:1355–1368

55. Merchenthaler I, Hynes M, Vigh S, et al. Cortico-tropin releasing factor (CRF): origin and course ofafferent pathways to the median eminence (ME) ofthe rat hypothalamus. Neuroendocrinology 1984;39:296–306

56. Arase K, York D, Shimizu H, et al. Effects of corti-cotropin-releasing factor on food intake and brownadipose tissue thermogenesis in rats. Am J Physiol1988;255:E255–E259

57. Rohner-Jeanrenaud F, Walker C-L, Greco-PerottoR, Jeanrenaud B. Central corticotropin-releasingfactor administration prevents the excessive bodyweight gain of genetically obese (fa/fa) rats. Endo-crinology 1989;124:733–739

58. Schwartz MW, Baskin DG, Bukowski TR, et al.Specificity of leptin action on elevated blood glu-cose levels and hypothalamic neuropeptide Ygene expression in ob/ob mice. Diabetes 1996;45(4):531–535

59. Elmquist JK, Ahima RS, Maratos-Flier E, et al.Leptin activates neurons in ventrobasal hypothal-amus and brainstem. Endocrinology 1997;138(2):839–842

60. Heiman ML, Ahima RS, Craft LS, et al. Leptininhibition of the hypothalamic-pituitary-adrenalaxis in response to stress. Endocrinology 1997;138:3859–3863

61. Pepin MC, Pothier F, Barden N. Impaired type IIglucocorticoid-receptor function in mice bearingantisense RNA transgene. Nature 1992;355:725–728

62. Langley SC, York DA. Effects of antiglucocorticoidRU 486 on development of obesity in obese fa/faZucher rats. Am J Physiol 1990;259:R539–R544

63. Freedman MR, Horwitz BA, Stern JS. Effect ofadrenalectomy and glucocorticoid replacement ondevelopment of obesity. Am J Physiol1986;250:R595–R607

64. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in main-taining food intake. Nature 2001;410:822–825

65. Yamada M, Miyakawa T, Duttaroy A, et al. Micelacking the M3 muscarinic acetylcholine recep-


tor are hypophagic and lean. Nature 2001;410:207–212

66. Nakazato M, Murakami N, Date Y, et al. A role forghrelin in the central regulation of feeding. Nature2001;409:194–198

67. DeFalco J, Tomishima M, Liu H, et al. Virus-as-sisted mapping of neural inputs to a feeding centerin the hypothalamus. Science 2001;291:2608–2613

68. Verploegen S, Plaetinck G, Devos R, et al. A hu-man leptin mutant induces weight gain in normalmice. FEBS Lett 1997;405(2):237–240

69. Loten EG, Rabinovitch A, Jeanrenaud B. In vivostudies in obese hyperglycaemic (ob/ob) mice:possible role of hyperinsulinaemia. Diabetologia1974;10:45–52

70. Chen G, Koyama K, Yuan X, et al. Disappearanceof body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad SciU S A 1996;93(25):14795–14799

71. Levin N, Nelson C, Gurney A, et al. Decreased foodintake does not completely account for adiposityreduction after ob protein infusion. Proc Natl AcadSci U S A 1996;93:1726–1730

72. Soukas A, Cohen P, Socci ND, Friedman JM. Lep-tin-specific patterns of gene expression in whiteadipose tissue. Genes Dev 2000;14(8):963–980

73. Pelleymounter MA, Cullen MJ, Baker MD, et al.Effects of the obese gene product on body weightregulation in ob/ob mice. Science 1995;269:540–543

74. Chinookoswong N, Wang J, Shi Z. Leptin restoreseuglycemia and normalizes glucose turnover ininsulin-deficient diabetes in the rat. Diabetes 1999;48:1487–1492

75. Shimomura I, Hammer R, Ikemoto S, et al. Leptinreverses insulin resistance and diabetes mellitus inmice with congenital lipodystrophy. Nature 1999;401:73–76

76. McGarry JD. What if Minkowski had been ageusic?An alternative angle on diabetes. Science 1992;258:766–770

77. Randle PJ, Garland PB, Newsholmer EA, HalesCN. The glucose fatty-acid cycle in obesity andmaturity onset diabetes mellitus. Ann N Y Acad Sci1965;131:324–333

78. Shulman GI. Cellular mechanisms of insulin resis-tance. J Clin Invest 2000;106:171–176

79. Kim J, Fillmore J, Chen Y, et al. Tissue specificoverexpression of lipoprotein lipase causes tissuespecific insulin resistance. Proc Natl Acad Sci U SA 2001;98:7522–7527

80. Considine RV, Considine EL, Williams CJ, et al.The hypothalamic leptin receptor in humans: iden-tification of incidental sequence polymorphismsand absence of the db/db mouse and fa/fa ratmutations. Diabetes 1996;45(7):992–994

81. Frederich RC, Hamn A, Anderson S, et al. Leptinlevels reflect body lipid content in mice: evidencefor diet-induced resistance to leptin action. NatMed 1995;1:1311–1314

82. Zimmet P, Arblaster M, Thoma K. The effect ofwesternization on native populations. Studies on aMicronesian community with a high diabetes prev-alence. Aust N Z J Med 1978;8(2):141–146

83. York B, Lei K, West DB. Inherited non-autosomaleffects on body fat in F2 mice derived from an AKR/Jx SWR/J cross. Mann. Genome 1997;8:726–30

84. West DB, Boozer CN, Moody DL, Atkinson RL.Obesity induced by a high fat diet in nine strains ofinbred mice. Am J Physiol 1992;262:R1025–R1032

85. Ravussin E, Pratley RE, Maffei M, et al. Relativelylow plasma leptin concentrations precede weightgain in Pima Indians. Nat Med 1997;3:238–240

86. Schwartz MW, Peskind E, Raskind M, et al. Cere-brospinal fluid leptin levels: relationship to plasmalevels and to adiposity in humans. Nat Med 1996;2:589–593

87. Caro JF, Kolaczynski JW, Nyce MR, et al. De-creased cerebrospinal-fluid/serum leptin ratio inobesity: a possible mechanism for leptin resis-tance. Lancet 1996;348(9021):159–161

88. Fujioka K, Patane J, Lubina J, Lau D. CSF leptinlevels after exogenous administration of recombi-nant methionyl human leptin. JAMA 1999;282:1517–1518

89. Golden PL, Maccagnan TJ, Pardridge WM. Humanblood-brain barrier leptin receptor. Binding andendocytosis in isolated human brain microvessels.J Clin Invest 1997;99:14–18

90. Banks WA, Kastin AJ, Huang W, et al. Leptinenters the brain by a saturable system indepen-dent of insulin. Peptides 1996;17:305–311

91. Banks W, DiPalma C, Farrell C. Impaired transportof leptin across the blood-brain barrier in obesity.Peptides 1999;20:1341–1345

92. Tartaglia LA. The leptin receptor. J Biol Chem1997;272(10):6093–6096

93. White DW, Kuropatwinski KK, Devos R, et al. Lep-tin receptor (OB-R) signaling. Cytoplasmic domainmutational analysis and evidence for receptorhomo-oligomerization. J Biol Chem 1997;272:4065–4071

94. Bjorbaek C, Uotani S, da Silva B, Flier JS. Diver-gent signaling capacities of the long and shortisoforms of the leptin receptor. J Biol Chem 1997;272(51):32686–32695

95. Vaisse C, Halaas JL, Horvath CM, et al. Leptinactivation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. NatGenet 1996;14:95–97.

96. Carpenter LR, Farruggella TJ, Symes A, et la. En-hancing leptin response by preventing SH2-con-taining phosphatase 2 interaction with ob receptor.Proc Natl Acad Sci U S A 1998;95:6061–6066

97. Li C, Friedman J. Leptin receptor activation of SH2domain protein tyrosone phosphatase 2 modu-lates ob receptor signal transduction. Proc NatlAcad Sci U S A 1999;96:9677–9682

98. Bjorbaek C, Elmquist JK, Frantz JD, et al. Identifi-cation of SOC-3 as a potential mediator of centralleptin resistance. Mol Cell 1998;1:619–625

99. Montague CT, Farooqi IS, Whitehead JP, et al.Congenital leptin deficiency is associated with se-vere early-onset obesity in humans. Nature 1997;387:903–908

100. Strobel A, Camoin TIL, Ozata M, Strosberg AD. Aleptin missense mutation associated with hypogo-nadism and morbid obesity. Nat Genet 1998;18:213–215


101. Clement K, Vaisse C, Lahlou N, et al. A mutation inthe human leptin receptor gene causes obesityand pituitary dysfunction. Nature 1998;392:398–401

102. Yeo G, Farooqi I, Aminian S, et al. A frameshiftmutation in MC4R associated with dominatly in-herited human obesity. Nat Genet 1998;20:111–112

103. Comuzzie AG, Hixson JE, Almasy L, et al. A majorquantitative trait locus determining serum leptinlevels and fat mass is located on human chromo-some 2. Nat Genet 1997;15:273–276

104. Krude H, Biebermann H, Luck W, et al. Severeearly-onset obesity, adrenal insufficiency and redhair pigmentation caused by POMC mutations inhumans. Nat Genet 1998;19:155–157

105. Jackson RS, Creemers JW, Ohagi S, et al. Obesityand impaired prohormone processing associatedwith mutations in the human prohormone conver-tase 1 gene. Nat Genet 1997;16:303–306

106. Blackburn G. Effect of degree of weight loss onhealth benefits. Obes Res 1995;3:211s–216s

107. Sjostrom CD, Lissner L, Sjostrom L. Relationshipsbetween changes in body compostition andchanges in cardiovascular risk factors: the SOSIntervention Study. Obes Res 1997;5:519–530

108. Farooqi I, Jebb S, Langmack G, et al. Effects ofrecombinant leptin therapy in a child with congenitalleptin deficiency. N Engl J Med 1999;341:879–884

109. Heymsfield S, Greenberg A, Fujioka K, et al. Re-combinant leptin for weight loss in obese and leanadults. JAMA 1999;282:1568–1575

110. Kamohara S, Burcelin R, Halaas JL, et al. Acuteintravenous and intracerebroventricular leptin infu-sion increases glucose uptake and glucose turn-over by an insulin independent mechanism. Nature1997;389:374–377

111. Sivitz WI, Walsh SA, Morgan DA, et al. Effects ofleptin on insulin sensitivity in normal rats. Endocri-nology 1997;138:3395–3401


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