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Perspectives in DiabetesLeptin: The Tale of an Obesity GeneJose F. Caro, Madhur K. Sinha, Jerzy W.Kolaczynski, Pei Li Zhang, and Ro bert V. Considine

The discovery of a fat-melting horm one name dleptin (Greek root, leptos, meaning thin) byFriedman raised the hopes of one-third of theU.S.population that there is a simple solution

to cure the ir obesity (1). The dream of such a solution fora complex disease was broug ht closer to reality a fewmonths later by evidence of leptin resistance in humanobesity (2). The concept of leptin resistance has sincebeen extended to other studies in humans (3-6) and tothe animal models of obesity (7-14), except for the ob obmouse, in which mutations in the ob gene result in anabsolute leptin deficiency (1).LEPTIN: THE PASTIn 1958, G.R. Hervey (15) first dem onstra ted the pres enceof a hormone that regulated body weight through aninteraction with the hypothalamus. G.C. Kennedy (16)had suggested 5 years earlier that the site of this hor-mone production was the adipose tissue, giving birth tothe lipostatic theory of body weight control.The experiment performed by Hervey (15) remains oneof the best examples from the golden days of physiology.The production of obesity by the destruction of the ven-tromedial hypothalamus (VMH) in one member of a para-biotic rat pair led to death by starvation in the unlesionedanimal. Hervey proposed that a circulating satiety factorwas produced in excess by the lesioned parabiont asbody fat accumulated. This animal was rendered insensi-tive to the factor by VMH destruction; thus, the unle-sioned parabiont became hypophagic in response to thehigh level of the satiety signal transmitted across theparabiotic union.Parabiosis poses a barrier to the exchange of short-lived circulating hormones, such as the gastrointestinalhormones cholecystokinin, bombesin, insulin, glucagon,glucagon-like peptides, etc. We will show in the next sec-

From the Department of Medicine, Jefferson Medical College of ThomasJefferson University, Philadelphia, Pennsylvania.Address correspondence and reprint requests to Dr. JoseF.Caro , VicePresident, Diabetes Research and Clinical Investigation, Lilly ResearchLaboratories, Lilly Corporate Center, 0540, Indianapolis, IN 46285. E-mail:carojose@lilly.com.Received for publication 16 May 1996 and accepted in revised form 1August 1996.c/EBPa, CCAAT/enhancer binding protein a, DIO, diet-induced obe-sity; JAK, Janus protein-tyrosine kinase; NPY, neuropeptide Y; PPAR72,peroxisome proliferator-activated receptor 72; STAT, signal transdu cersand activators of transcription;VMH, ventromedial hypothalamus.

tion that Hervey's factor is leptin. But, as proposed byHervey, leptin is not a gastrointestinal terminating signal,since its concentration does not increase postprandiallyin humans (17).Parabiosis experiments performed in animals withgenetic obesity are also an important part of the historyofleptin.Hausberger (18) reported in 1959 that nonobesemice suppressed the weight gain ofob obmice in par a-biosis and interpreted this result to indicate that this typeof obesity is caused by the lack of a factor that can betransmitted by successful parabiosis. This prediction w ascorrect: theob obmouse does not produce leptin (1).The genetic mechanism of obesity in the db/dbmouseand thefa/fa rat was predi cted to be different from theob obmouse. Coleman and Hummel (19) reported in 1969that lean m ice in parabiosis with obese db/dblittermatesdied of starvation. Harris and coworkers found the samewithfa/fa rats (20). These results were strikingly similarto those obtained by Hervey (15), suggesting that db/dban dfa/fa animals became obe se because of central ner-vous system insensitivity to the circulating satiety factor.Again, these predictions proved correct. The db/dbmouse (21,22) and thefa/fa rat (23) wer e recently foundto have mutations in the leptin receptor (24).All the important work on body weight regulation pre-ceding the discovery of leptin was best reviewed by Wei-gle (25) in 1994. What is conceptu ally new?LEPTIN: THE PRESENTThe positional cloning of the mouse obese (pb)gene byZhang et al. (1) was the beginning of what will likelybecome known as the fat years of obesity research orthe golden years of modern endocrinology in action.Zhang et al. (1) reported in 1994 that they had identifiedthe gene responsible for obesity in one of the most inten-sively studied genetically derived rodent models of obe-sity, the ob/obmo use, homozygo us for a mu tant form ofthe obese {ob)gene.The mouse ob gene encodes a 4.5-kilobase adipose tis-sue messenger RNA with a highly conserved 167-aminoacid open reading frame and a 21-amino acid secretorysignal sequence. The predicted amino acid sequence is84%identical to that in hum ans and m ice and has fea-tures of a secreted protein. A non-sense mutation incodon 105 was found in the original congenic C57BL/6Job obmouse strain, which expressed a 20-fold increase inabnormalobmRNA. A second mu tation w as found in th ecoisogenic SM/Ckc-+Daco&2J/o&2J mouse that must be inthe promoter region of the ob gene, since it prevents thesynthesis ofobmRNA.

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100.0 -

cQ .

E10.0 -

1.0 -

' s * . . '

* . . : V ^ - ' ' .

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0 10 20 30 40 50 60 70Body Fat (%)

FIG. 1. Relation between percent body fat and serum leptin inhumans.

We asked if humans with obesity were like the oblobmouse and cloned and sequenced the human OBcDNAfrom subcutan eous adipose tissue (2). There were no dif-ferences in the sequence of the coding region of thehuman OB gene among a small group of lean and obesesubjects (2). We have recently screened 106 subjects formutations using conformation-sensitive gel electrophore-sis (26).Afirst-base substitution (G to A) was detected inone individual that changed a valine to a methionine atposition 94 (26). The nature of this amino acid substitu-tion is conservative, and the immunoreactive circulatingleptin in the patient is consistent with the degree of obe-sity. Furthermore, we found a positive correlationbetween the weight of our subjects and the am ount ofOBmRNA in their adipose tissue (2). The latter finding wasconfirmed in huma ns independently by two other labora-tories (3,4). Thus, assuming that the OB gene productdoes indeed code for a satiety factor, our observationsuggests that the adipocyte is functioning normally andthe defect in human obesity lies elsewhere. In otherwords, we propose that most obese humans are resistantto their endogenous produ ction of leptin.The next major discovery was the unequivocal demon-stration that the product of the obese gene, leptin, wasable to induce weight loss in mice (27-32). Daily admin-istration of recombinant leptin produces a strikingweight loss in the oblobmouse (27-32). Furthermo re,weight loss after leptin administration in animals is notonly due to decreased appetite and food consumption,but also to an increase in thermogenesis and activitylevel (27-29). Normalization of hyperglycemia and hyper-insulinemia also occurred before any significant weightloss (27-29). Although theoblobmouse has myriad meta-bolic abnormalities, it seems that leptin improved notonly obesity, but all the metabolic abnormalities thathave been studied so far (27-33).

Campfield et al. (27) showed that leptin can alter feed-ing behavior and energy balance when placed directly inthe lateral ventricle of the brain ofobloband lean (+/?)mice. This suggests that one or more brain areas are

among the target sites for leptin. Indeed, Stephens et al.(31) demonstrated high-affinity leptin binding in rathypothalamic plasma membranes. Furthermore, chronicleptin administration decreased hypothalamic neuropep-tide Y (NPY) mRNA expression and directly suppressedNPY release from isolated perfused normal rat hypothal-amus (31). Hypothalamic NPY stimulates food intake,decreases thermogenesis, and increases plasma insulinand corticosteroid level (34). Therefore, NPY appears tobe a logical transducer system for leptin action.The administration of leptin also proves the conceptsof leptin resistance in animals. The db/db mouse wastotally refractory to leptin (27-29), as predicted by Cole-man and Hummel (19). A model of diet-induced obesityin the mouse was insensitive to leptin, requiring 5-10times more leptin to achieve the equivalent weight loss ofthat produced in theoblobmouse (27).The next important step was the development of aradioimmunoassay for the quantitative determination ofleptin levels in the human circulation (5). Figure1showsthe relationship between serum leptin and percentagebody fat from 500 individuals with a wide range of bodyweights, an expanded database from t hat previously pub-lished (5). The data demonstrate a strong positive corre-lation between serum leptin concentration and body fat.Therefore, serum leptin concentrations reflect theamount of adipose tissue in the body, a finding that holdstrue in almost every study performed in humans (3-6)and anim als (7-14) . This conc ept is illustrated in Fig. 2, inwhich an imaginary scale measures the amount of adi-pose tissue. The units here are not in kilograms but inleptin units. Figure 2 illustrates the serum leptin concen-tration in two theoretical patients: 5 ng/ml (lean level)and 50 ng/ml (obese level), respectively. In thes e two su b-jects, the values coincide with their set point of bodyweight, energy intake and energy expenditure are in bal-ance, and body weight will not change. But, what hap-pens if the lean or obese person loses weight because ofeither illness or voluntary diet? As the amount of adiposetissue in the pan in Fig. 2 decreases, the leptin indicatorwill move to the left of the set point. The response of thebody will be to increase appetite and decrease energyexpenditure to restore adipose tissue mass. As theamount of fat increases, leptin levels will increase untilthe original set point is reached. It is easy to see how ben-eficial this mechanism for preserving a predeterminedbody weight could be for the lean subject recoveringfrom an illness. It is even easier to see how problematicthis mechanism can be for the obese person who is vol-untarily attempting to lose weight.

When energy intake and energy output are equal, or inbalance, leptin reflects the amount of triglyceride storedin the body as adipose tissue. However, what happens insituations of negative energy balance, such as fasting, orpositive energy balance, su ch as overfeeding?Areductionof 10% in body weight is associated with a53%reductionin serum leptin (5). This large decrease in serum leptinconcentration in the presence of a relatively small changein body weight suggests that leptin is regulated by otherfactors than the size of the adipose tissue depot. One ofthese factors may be caloric intake. In fact, fasting inhumans (35) and animals (36,37) results in a dramatic

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sion. Small fat cells expressed less OBmRNA than largefat cells even when obtained from the sam e individual (4).This suggests the possibility tha t cell wall stretching itselfmay initiate the signal, since exogenously applied tensionto the plasma membrane has been demo nstrated to lead tothe induction of gene expression in other cell systems(55). It is also possible that products of intracellularadipocyte metabolism, free fatty acids, diacylglycerol,lysophosphatidic acid, etc., could ac t as modifiers to regu-late obese gene transcription. In fact, these candidates areknown to regulate a variety of important pathways inother cell systems (56). Second, at least 5% of obesehumans have decreased leptin production relative to theamount of body fat (5,6). Though this percentage ofhypoleptinemic obesity may appear sm all, it represents5%of 30 million people in the U.S. alone. The most logicaltherapy for these patients will be an oral drug that wouldstimulate OBgene transc ription.The second major question to answer relates to themechanism of leptin action. This is of paramount impor-tance, since the majority of human obesity is character-ized by hyperleptinemia. Because the expec ted responseto elevation in leptin is decreased caloric intake andincreased energy expenditure, it appears that most obesehumans are insensitive to their endogenous leptin pro-duction. Here, the mo st logical therapy would be an oraldrug that improves leptin action.The concept that human obesity is a leptin-resistantstate assumes that leptin is as important in human obe-sity as it is in some m ouse m odels. Until leptin is given tohum ans, it is pruden t to consider th at leptin is either notinvolved in human obesity or high plasma leptin concen-trations are unable to overcome other causative factors.The first step to understand leptin action has beentaken when Tartaglia et al. (24) discovered the leptinreceptor. This structure belongs to the class I cytokinereceptor family. Indeed, the primary structure of leptin isunique, while the secondary structure resembles tha t of acytokine (57). Its receptor has an extracellular bindingdomain of 840 amino acids, a transmem brane domain of34 amino acids, and a variable intracellular domain.Beyond Lys 889, which includes 29 amino acids of theintracellular domain, the leptin receptor splices intothree forms with totally different intracellular domains. Ashort leptin receptor, named ob Ra, has a 34-amino acid

intracellular domain and is believed to function as atransporter. A long leptin receptor, named ob Rb, has a304-amino acid intracellular domain and is believed tofunction as the first leptin signaling step. The long intra-cellular domain contains putative motifs for Janus pro-tein-tyrosine kinase (JAK) and signal transducers andactivators of transcription (STAT) binding. JAK and STATbinding are key steps for cytokine class I receptor signal-ing (57). Another leptin receptor, ob Re, with an intra cel-lular domain of 32 amino acids, may also function as atransporter (22). The final leptin receptor, ob Re, is iden-tical to the o thers up to histidine 796, at which point thenucleotide sequences diverged. At only 808 amino acids,this receptor is the shortest and lacks transmembranedomain; therefore, it may be a soluble receptor (22).An unexpected finding is the wide distribution of thedifferent leptin receptor isoforms. They are not present

in the hypothalamus alone but have a wide distribution inthe brain, choroid plexus, liver, lungs, heart, kidney,testes, adipose tissue, spleen, etc. (22,24).To ascertain the role of leptin in all these tissues willcertainly provide a fertile area for investigation. Indeed,leptin can restore fertility in the female ob/obmouse,independent of any effect on body weight (33). It is notknown yet where the site, or sites, of leptin action islocated in the hypothalamic-pituitary-gonadal axis. How-ever, it is now possible to speculate why extreme thin-ness or fatness in women, which results in eitherhypoleptinemia or leptin resistance, might result inreproductive difficulties. Also, the requirement of a criti-cal amount of fat accumulation to initiate puberty may berelated to reaching a sufficient concentration of leptin tostimulate the hypothalamic-pituitary-gonadal axis.The third and final question is the most important toanswer from the clinical perspective. What is the mecha-nism of leptin resistanc e in hum an obesity? Figure 3 illus-trates several of the possible sites of abnormal leptinaction in humans.Wenow know that the great majority ofobese subjects do not have a defect in the production ofleptin. However, there may exist intravascular defects,such as leptin antibodies, leptin antagonists, or increasedproduction of leptin binding proteins to limit the concen-tration of free leptin that reaches the brain. Furthermore,because circulating leptin is a 146-amino acid protein, itwill be excluded from the blood-brain barrier and theblood cerebro spinal fluid barrier unless a trans porte r facil-itates this step (58). Therefore, leptin resistance could bedue to a defect in this putative transporter system.Even if leptin transport proves to be normal, the defectcould still lie in the leptin receptor. In the db/dbmouse, asingle nucleotide change in the leptin receptor results inthe aberrant splicing of the receptor transcript and theinsertion of a prem ature stop codon (21,22). Also, the genethat encodes the leptin receptor and the gene that causesobesity in the Zucker rat (fa/fa)are the same (23).It is possible that both leptin transp ort and its receptorare normal, and the defect lies in the signaling mecha-nism. At present, nothing is known about leptin signaling.However, based on our solid understanding of cytokinereceptor type I signaling, it is expected that data on lep-tin signaling will soon be forthcoming. In the end, itmight turn out tha t transport, receptor, and signaling cas-cade are all normal and the defect resides in the leptintransducer system.Neuropeptide Y-ergic neurons of the hypothalamicarcuate nucleus that project into the paraventricular anddorsomedial nuclei control energy balance in part bystimulating feeding and inhibiting thermogenesis (31,59).It has already been proven that leptin decreases NPY innormal animals (31,59): though, how decreases in NPYsuppress appetite is not known. The increase in thermo-genesis is likely due to an increase in sympathetic out-flow that ultimately activates the release of norepineph-rine from sympathetic nerve terminals. This, in turn acti-vates the 33adrenergic recepto r in brown adipose tissue.When norepinep hrine binds to the (33 adrenerg ic recep -tors on fat cells, it raises their metabolic rate by increas-ing expression of the gene that enc odes uncoupling pro-tein. This protein, present in the inner membrane of the

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TransportDefect2 S lood5 5 Brain2 R Barrier

FIG. 3. Possible def ect(s) of leptin in human obesity.

mitochondria, releases energy from fatty acids as heat(60). The relevance of leptin's regulation of thermogene-sis in human s, if any, is unknow n at this time. This is par-ticularly true, since humans have little brown fat com-pared with rodents.From the previous discussion, it appears that NPY isthe leptin transducer system. However, this simple ideamay prove to be far from true. It is more likely that sucha fundamental physiological function as maintenance ofenergy balance is regulated by a multidimensional sys-tem with overlapping control pathways. Finally, thedefect in leptin action might be far from leptin itself.T hedistal biochemical and behavioral mechanisms that con-trol appetite, physical activity, and thermogenesis mayturn out to be the critical defect(s).The crucial question of practical relevance relates toleptin as a therapy for human obesity. Clinical trials arein preparation, and therefore, the answ er to this questionwill not be long in coming. Meanwhile, we can only spec-ulate on their outcome based on the lessons learned intreating obese mice (27-29). The weight loss achieved byexogenous leptin administration to mice varies tremen-dously (Fig. 4). The most sensitive animals are the ob/obmice, since they do not have endogenous leptin (1). Thedb/db mice are totally refractory to exogenous leptin,since they lack functioning leptin receptors (21-23). Inbetween are the normal mice and those with diet-inducedobesity (DIO). We believe that the majority of obese

hum ans will respond to leptin administration in a similarmanner to the DIO mice. A very small subgroup ofhumansthose with mutations in the leptin receptorwill be totally refractory to leptin. Another small fraction

will be very sensitive to leptin, mainly those with relativehypoleptinemia.Why do we believe the preponderance of obese sub-jects to be responsive to exogenous leptin administra-tion? Leptin resistance in humans is likely not to be anall-or-none phenomenon, but rather a reset of the leptinsensor in the hypothalamus (leptinstat). We previouslyproposed (61) that leptin resistance might in fact be theresult of the thrifty gene, and the developm ent of suchresistance provided a survival advantage to our ances-tors. In short, during periods of food availability, thosewith leptin resistance consumed large amounts andstored the excess as fat to be used during periods of

A moment for speculation...LeptinEffect inHumans

db/dbMice

Most Sensitive Most ResistantFIG. 4. The wide range of leptin response in mice and the predic-tion that most obese humansw llrespond like the DIO mice.

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famine. Unfortunately, today, with plenty of food, theprogeny of those people who survived in the past,become obese in the present.Administration of exogenous leptin to obese individu-als,w hose m ain genetic defect m ay be a reset of the lep-tinstat, should increase leptin above the level needed totrigger a change in appetite and thermogenesis. Thus, theextra exogenous leptin would deceive the hypothalamusinto believing the body has a greater fat m ass than it actu-ally does. It is more difficult to predict, however, howlong the hyp othalamu s would remain fooled. Beca use, asillustrated in Fig. 2, the leptinstat can move, the adapt-able brain might then make the regrettable decision toreset the leptinstat and render further leptin injectionsineffective. Only the results of the leptin clinical trialscan provide the answer.ACKNOWLEDGMENTSBecause human obesity is characterized by leptin resis-tance , this wor k is in hon or of Fuller Albright, who devel-oped the concept of hormone resistance and taught the Do's and DoNot's of clinical investigation. Do No.9:Do develop a theory... Do Not No. 7: Do not be a slaveto you r theory. Do feel hu rt if your facts are w rong; not ifyour theories are wrong. (Fuller Albright, J Clin Invest23:921,1944)REFERENCES

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protein reduces feeding and body weight in the ob/ob mouse. J ClinInvest 96:2065-2070, 199531 . Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG,Craft L, Hale J, Hoffman J, Hsiung HM, Kriaciunas A, MacKellar W, Ros-teck PR Jr, Schoner B, Smith D, Tinsley FC, Zhang XY, Heiman M: Therole of neuropeptideYin the antiobesity action of the obese gene prod-uct.Nature 377:530-532, 199532.Schwartz MW, Baskin DG, Bukowski TR, KuyperJL,Foster D, Lasser G,Prunkard DE, Porte D, Woods SC, Seeley RJ, Weigle DS: Specificity ofleptin action on elevated blood glucose levels and hypothalamic neu-ropeptideY gene expression in 06/06 mice.Diabetes 45:531-535, 199633 . Chehab FF, Lim ME, Ronghua L: Correction of the sterility defect inhomozygous obese female mice by treatment with the human recombi-nant leptin.Nature Genet 12:318-320, 199634. Dryden S, Williams G: The role of hypothalamic peptides in the controlof energy balance and body weight. Curr Opin Endo Diabetes 3:51-58,

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