COMMEMORATIVE LECTURE

Leptin and the Regulation of Body Weight
Jeffrey M. Friedman

Rockefeller University, New York, USA(Received for publication on August 17, 2010)

The cloning of the ob gene and its gene product, leptin, has led to the elucidation of a robust
physiologic system that maintains fat stores at a relatively constant level. Leptin is a peptide
hormone secreted by adipose tissue in proportion to its mass. Recessive mutations in theleptin gene are associated with massive obesity in mice and humans, establishing a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall, stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels
increase, suppressing appetite until weight is lost. This system maintains homeostatic controlof adipose tissue mass. The discovery of leptin has advanced our understanding of metabolic
disease in a number of respects. Its identification has revealed a new endocrine system regulating body weight. This system provides a means by which changes in nutritional state regulate other physiologic systems. A number of leptin deficiency syndromes that are treatablewith leptin replacement have been identified. The majority of obese subjects are leptin resistant, which establishes that obesity is the result of hormone resistance. Leptin treatment results in weight loss in a subset of obese patients and can also synergize with other anti-obesity
agents to reduce weight in the general population. Leptin provides an entry point for studying
a complex human behavior. Finally, this research has established that there is a powerful biological basis for obesity, a fact that is (correctly) changing public perception about the pathogenesis of this medical condition. (Keio J Med 60 (1) : 1－9, March 2011)

Introduction

markably stable in animals and humans over long periods of time, especially when taking into account thelarge number of calories that are consumed, the elaboration of this principle by the Prussian surgeon Hermannvon Helmholtz, and others, suggested that organisms
would need a means for maintaining constancy of energy
stores by regulating energy balance (food intake vs. energy expenditure).5 A precise balance between energy intake and energy expenditure has been noted in humans
over as little as a 2-week time frame, which proved to belong enough to average out day-to-day fluctuations in intake.6 This stability is also observed in experimental settings in which the body weight of animals that were either overfed or starved returned to that of a control
group once food intake returned to normal.2, 7-11 Finally,
when animals are fed nutrients in varying dilutions, they
adjust their intake to maintain constancy of the number

The ob gene was cloned in 1994 using the methodology of positional cloning. Leptin, the protein encoded by
the ob gene, was identified in 1995 and shown to be ahormonal signal that regulates energy balance.1-4 Since
its discovery 15 years ago, 30,943 articles on leptin havebeen written (S Korres, personal communication, 2009),
providing an opportunity to assess, with some hindsight,
the impact of this research. What follows is a summaryof the conclusions that have emerged from this and subsequent research.
Historical Background
The first law of thermodynamics applies similarly toinanimate and biological systems. Because weight is re-

Dr. Friedman is the recipient of the 2009 Keio Medical Science Prize.
Presented at the Keio Medical Science Prize Commemorative Symposium, December 4-5, 2009.
Reprint requests to: Jeffrey M. Friedman, MD, PhD, The Rockefeller University, 1230 York avenue, New York, NY 10065, USA, E-mail: friedj@mail.rockef
eller.edu
Copyright © 2011 by The Keio Journal of Medicine
1

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of calories that are consumed, not the volume.1 2 In eachcase, it appeared that the animal had sensed a change inits body weight and in turn adjusted its recent food intake to return weight to control levels.
In aggregate, these data were interpreted to mean that
there must be a biologic system that regulated food intake and maintained homeostatic control of bodyweight.1 2 This premise was articulated often during thefirst half of the 20th century and was further advanced by
the demonstration that body weight could be altered, ineither direction, by introducing specific lesions in the
hypothalamus, with lesions of the ventromedial hypothalamus causing obesity and those of the lateral hypothalamus causing leanness.1 3 It was thus suggested thatbrain centers in the hypothalamus receive peripheral signals that reflect an organism’s nutritional state as part ofa feedback loop(s) that maintains homeostatic control ofbody weight.14, 15
The key question concerned the identity of these putative signals. It was proposed that glucose, fat and protein
stores were in some way sensed, as were core temperature, recent food intake and other variables.1 4, 1 5 Kennedy first proposed the possibility that one of these signals
might be derived from adipose tissue, although neither
the nature of this factor nor the mechanism by which it
acted was clear. Kennedy1 6 and later Hervey1 7 invoked amechanism whereby a fat-derived factor, perhaps a steroid hormone that increased appetite, was partitioned inboth the adipose tissue and aqueous compartments andwas diluted as adipose mass increased. That this factor
might be hormonal was first suggested by data fromparabiosis (cross circulation) experiments between
obese, ventromedial hypothalamic (VMH)-lesioned andcontrol rats. 1 8 The observation that the normal rats
paired to those with a VMH lesion ate less and lost
weight suggested that the lesioned rats overproduced anappetite-suppressing factor secondary to a lesion at itssite of action (i.e., the hypothalamus). Although the existence of this factor could be inferred from this and othersimilar studies, the intrinsic difficulty of implementing abiochemical purification using a behavioral assay of
feeding behavior impeded successful efforts to identify
it. In retrospect, with the identification of this factor as
leptin, it is clear how challenging such a purification
would be, even using modern methods, because of therequirement for chronic dosing of leptin to elicit an anorectic effect. A biochemical approach for identifying endogenous appetite suppressants is also complicated byfrequent false positives that arise because many compounds exert aversive effects to nonspecifically reduce
appetite.
A clue to the identity of this circulating factor was provided by parabiosis experiments pairing geneticallyobese ob/ob and db/db mice to wild-type mice, or toeach other; ob and db are recessive mouse mutations thatcause massive obesity as a result of profound hyperpha-

Friedman JM: Leptin Regulates Adipose Tissue Mass

gia and reduced energy expenditure. In addition, bothmutants manifest a pleiotropic set of numerous otherphysiologic abnormalities (see below).1 9 The phenotypesof both mutations are strikingly similar, which suggested
that the encoded genes might function in the same physiologic pathway. The results from the parabiosis experiments were consistent with this possibility and further
suggested that the ob gene encoded a circulating factor
that suppressed food intake and body weight and that thedb gene encoded its receptor. The aforementioned studies using the parabiotic union of mice with lesions of theventromedial hypothalamus to normal rats further suggested that this receptor was localized in the hypothalamus. In aggregate, these studies were consistent with theparsimonious hypothesis that a circulating factor produced in adipose tissue and encoded by the ob gene acted on a receptor in the hypothalamus that was encodedby the db locus.
These studies thus suggested that food intake and bodyweight–or, more precisely, adipose tissue mass–wereregulated by an endocrine system and provided a strong
impetus for the cloning of the ob and db genes.
The Cloning of the ob Gene and Identification of
Leptin Has Uncovered a New Endocrine System
Regulating Body WeightThe development of positional cloning, a methodologythat enabled the cloning of mutant genes based solely ona detailed knowledge of their position on a genetic map,
provided a means for identifying the ob and db genes.
In 1994 the ob gene was identified as an approximately
4.5-kb RNA that was expressed exclusively in adipose
tissue (Fig. 1).1
This RNA encoded a predicted 167-amino-acid polypeptide with a signal sequence, which indicated that it
was secreted and likely to circulate in plasma. The geneis disrupted in the two available alleles of ob in the original C57/Bl6J ob/ob mutation, a nonsense mutation disrupts protein function leading to a secondary increase in
the RNA, whereas in the second coisogenic ob 2j mutation, a retroviral insertion abrogates expression of thecoding sequence altogether.2, 20
The available data suggested the hypothesis that thepolypeptide encoded by the ob gene, now known as
leptin (derived from the Greek root leptos, meaning“thin”), functioned as the afferent signal in a negative
feedback loop that maintained stability of adipose tissuemass.1-4 If true, the following criteria had to be satisfied:leptin should circulate in plasma, its concentrations
should change proportionately with increases or decreases of fat mass, and the recombinant protein should reduce food intake and body weight in lean and ob but notin db mice. Finally, the db gene should encode the receptor for leptin and be localized in the hypothalamus (andpossibly elsewhere).

Keio J Med 2011; 60 (1): 1－9

3

Fig. 1 Leptin is a hormonal signal that maintain homeostatic control and adipose tissue mass.

Leptin circulates in the plasma of all mammals tested,
including humans and rodents, as an approximately
16-kDa protein with a single disulfide bond that is required for bioactivity.2 Leptin levels increase with accretion of adipose tissue mass and decrease when adipose
mass is lost.2 1 Injections or infusions of leptin reducefood intake and body weight of wild type and ob mice
but have no effect on db mice.2- 4, 2 2 The failure of recombinant leptin to alter food intake or weight in db
mice established specificity of the effect by excluding
the possibility that the protein reduced weight as a resultof an aversive or “toxic” effect that made animals feelsick.2The leptin receptor was identified biochemically andshown to be a cytokine family receptor that is expressedbroadly.2 3 It was subsequently shown that leptin receptor
RNA was alternatively spliced and that only one of the
splice variants, referred to as ObRb (also known as
LepR-l or LepRb), was mutant in C57Bl/Ks db/db
mice.2 4, 2 5 These mutant mice show an identical phenotype to animals with null mutations of the leptin receptor
or leptin itself.2 4, 2 5 This genetic evidence established thecritical importance of this receptor isoform in leptin signaling.
ObRb is the only receptor isoform that expresses all
the protein motifs required for cytokine receptor signaling. More importantly, while the other receptor isoforms
were expressed broadly, ObRb was highly enriched in
the hypothalamus in precisely those nuclei that alter
body weight when lesioned. 2 4, 2 6 These data thus suggested that leptin acted directly on the hypothalamus toregulate food intake and body weight. Consistent with a
CNS site of action, infusions of low-dose leptin centrally
replicate all the effects of peripheral leptin even at intracerebroventricular doses that do not alter plasma leptin
levels.2 It is now known that the leptin receptor also signals at other CNS sites outside the hypothalamus, in-cluding reward centers in the nucleus accumbens, andthat its expression at these other brain sites contributes tothe broad panoply of leptin’s effects (see below). Thereis compelling evidence that leptin also acts directly on
cells of the immune system, but the importance of possible direct effects of leptin on other peripheral cell types
is less clear.2 7, 2 8 The critical role of leptin’s actions directly in the CNS have been established with the findings that a brain-specific knockout of the leptin receptor
causes obesity similar to that of db/db mice and brainspecific expression of a LepRb transgene can suppress
the obesity of db mice.29, 30
In aggregate, these data established that leptin is a
novel hormonal signal in a negative feedback loop thatmaintains homeostatic control of adipose tissue mass bymodulating the activity of neural circuits that regulate
food intake, energy expenditure and metabolism. These
conclusions are important not only because key elementsof the homeostatic system regulating weight were identified but also because the identification of leptin and its
receptor confirmed the very existence of a homeostatic
system that many believed did not exist at all.
Changes in Nutritional State Regulate
Other Physiologic Systems
Leptin-deficient ob mice develop a complex phenotype that includes abnormalities in most, perhaps all,physiologic systems. 3 1 These pervasive abnormalities
are distinct from those typically manifest in human obesity. In retrospect, it has been appreciated that all of theabnormalities of massively obese ob/ob mice (paradoxically) resemble those that normally develop during starvation of normal animals and humans. This apparent
paradox can be most easily understood if one considers
the normal response to starvation. With weight loss, fat
mass is lost and leptin levels fall.2 1 This low leptin level4Friedman JM: Leptin Regulates Adipose Tissue Massis sensed and induces a state of positive energy balance
by increasing appetitive behavior and also by reducing
energy expenditure as part of a biologic response aimed
at restoring fat mass. This same starvation signal (i.e.,
low leptin) also modulates the function of other biologic
systems that are elements of the adaptive response to
starvation. These responses include, but are not limited
to, cessation of female ovulation, reduced immune function, a decrement in insulin signaling, alterations of hemostasis, and the development of a euthyroid sickstate.2 7, 3 2, 3 3 A role for leptin in ovulation was consistent
with the suggestion by Rose Frisch that an adipose tissue-derived factor was required to develop and maintainreproductive capacity in females, see below.34
In the absence of leptin production as a result of a genetic mutation, leptin-deficient animals and humans live
in a state of perceived starvation. In this state, the absence of leptin not only increases food intake but also
triggers additional biologic responses that reduce energy
expenditure as a means to conserve adipose tissue mass.
Despite the fact that leptin-deficient individuals become
obese, the absence of leptin prevents the generation of aleptin-mediated signal that would otherwise suppress a
set of physiologic responses act to conserve energy when
nutrient is limiting. Thus by down-regulating metabolism, thyroid function, immune function and suppressing
menstruation, energy is conserved.
In normal animals and humans, this response is active
only in the starved state after plasma levels fall. A key
result in support of this conclusion was provided bystudying fasted animals coincident with injections of recombinant leptin.3 2 In this experiment, leptin was able tosuppress the effect of starvation on ovulation, thyroid
function and other neuroendocrine responses. Analogous
studies have also shown that recombinant leptin can also
suppress the immune abnormalities that develop in fasted animals.27
In humans, the role of low leptin in inducing this set ofalterations has been confirmed by demonstration of thebeneficial effect of leptin treatment in a number of statesof leptin deficiency. Overall, these human and animal
data identify adipose tissue as a bona fide endocrine organ and further confirm that leptin plays a key role in theadaptive response to starvation by modulating the function of other physiologic systems. It is widely acceptedthat changes in nutritional state alter the function of other physiologic systems and it is now clear that leptin is a
key means by which the change in nutritional state iscommunicated.
Many Leptin Deficiency Syndromes are Treatablewith Leptin Replacement
Leptin mutations in humans are associated with massive obesity that is remediable by leptin treatment.3 5
While leptin mutations are rare, the demonstration of a

profound phenotype in these patients confirms the roleof this hormone in human physiology. Note that the low
incidence of leptin mutations is similar to that observedfor other key hormones such as insulin; a complete lossof hormone function is often catastrophic in an evolutionary context (for example, leptin-deficient humans
and animals are infertile and leptin-deficient animals arelikely to be more susceptible to predation) and thus
strongly selected against.
Leptin-deficient patients, as mentioned above, also
show a set of abnormalities in other physiologic systems
and these too are remediated by leptin treatment. 3 5, 3 6
The realization that leptin deficiency is associated withalterations in the function of other organ systems suggested the possibility that low leptin levels associatedwith other pathological conditions might also havepathologic consequences that would be ameliorated byleptin replacement therapy. Several such conditions havebeen identified, the first of which was lipodystrophy.
Lipodystrophy (LD) is a heterogeneous disorder that is
associated with the absence or a profound reduction in
adipose tissue mass.3 7 Lipodystrophy can be complete orpartial and is often the result of mutations in genes normally required for adipose tissue development. Lipodystrophy can also be acquired as a result of (presumed) immune alterations or more recently in chronic HIV patients.3 8, 3 9 Indeed a substantial number of HIV patients,
generally those on HAART triple therapy, develop lipodystrophy with metabolic abnormalities severe enoughto require medical treatment.
In this condition, the reduction of adipose tissue mass
(whatever the cause) results in the secondary depositionof lipid in other organs, in particular the liver, and a severe, often intractable insulin resistance develops. Because of the reduced adipose tissue mass, leptin levels
are pathologically low in lipodystrophic patients. The
contribution of the low leptin level to the consequencesof this disease has been clearly established by the profound effect of leptin treatment to correct the hepatic steatosis and insulin resistance in patients with this condition.3 7, 4 0, 4 1 The response to leptin therapy was most pronounced in patients with complete lipodystrophy, but
beneficial effects were also evident in some patients withpartial and HIV lipodystrophy. Finally, leptin also ameliorated the neuroendocrine abnormalities that developin LD patients despite the fact that a significant loss of
adipose tissue mass was observed.3 7 This finding and ananalogous finding in patients with hypothalamic amenorrhea (see below) uncouple the normal relationship between fat mass and the response to starvation and thus
confirm that it is a low leptin level that conveys nutritional information that an individual is pathologicallythin, not the fat mass itself.
Hypothalamic amenorrhea (HA) is another condition
associated with low leptin levels. Female patients whoare extremely thin frequently enter puberty late or some-Keio J Med 2011; 60 (1): 1－9times fail to enter puberty at all. In addition, adult females who develop extreme leanness, often associatedwith protracted vigorous exercise, frequently stop menstruating.3 4 Women with this condition show a prepubertal pattern of gonadotrophin secretion and also manifest
other neuroendocrine and metabolic abnormalities including premature, severe osteoporosis that in most cases cannot be treated adequately with hormone replacement therapy.4 2 This condition is not uncommon and affects 4%–8% of women of reproductive age, accounting
for as many as one in three visits by women to an infertility clinic (personal communication, Chris Mantzoros).
The contribution of hypoleptinemia to this condition was
confirmed by the demonstration that leptin replacement
therapy can restore reproductive function in women with
HA, some of whom had not menstruated for years.4 2 It is
this result, as first suggested by Frisch, that confirmedthat a fat-derived factor is essential for the development
and maintenance of normal reproductive function in
women,
HA patients also develop a set of neuroendocrine abnormalities typically associated with starvation, andthese too are ameliorated by leptin treatment. Premature
osteoporosis is a major problem for HA patients, andthere is evidence from serum markers that leptin mightalso improve the bone pathology that often develops inthese patients, though further studies will be necessary toconfirm this. Similar to the results for lipodystrophy,
these patients show endocrine and metabolic improvement despite losing adipose mass, thus confirming the
key role of hypoleptinemia, not of adipose mass itself, in
the activation of the set of physiologic responses to starvation.43
These data further suggest that leptin might have beneficial effects in other conditions associated with extremely low leptin levels. As noted by Frisch, delayed
puberty is often associated with extreme leanness, andfailure to enter puberty in the correct temporal window
can have significant, life-long consequences.3 4 Femaleswith leptin mutations typically do not enter puberty evenwhen at an appropriate bone age; leptin therapy rapidly
induces a prepubertal pattern of gonadotrophin secretion
which reverts when leptin therapy is stopped. 3 5 In thissetting, leptin is permissive for the onset of puberty, as
leptin treatment does not induce puberty in young women or in animals who have not reached the appropriatebone age.4 4 Thus, it is possible that in some cases leptin
therapy might be of benefit for inducing puberty.
Women with anorexia nervosa and patients with cachexia resulting from cancer or severe chronic infections
also show many of the same abnormalities observed inmalnourished individuals, including prominent immune
abnormalities. These immune alterations often contributeto the high ratio of infectious disease and mortality inthese conditions. Consistent with this, patients withleptin mutations also show abnormalities in immune

5function, and in one extended pedigree segregating
leptin mutations, there was a high incidence of premature death from infectious disease. 3 6, 4 5 While leptin
would have the undesirable effect of inducing weightloss in the setting of cachexia, there is evidence from animals that leptin treatment administration can suppress
these immune abnormalities at lower doses than are required to suppress food intake or body weight.4 6 Thus it
is conceivable that very low dose, carefully titrated
leptin treatment could have beneficial effects on immune
function and other abnormalities in anorectic or cachectic patients, a possibility would require further, controlled clinical testing.
Most Obese Patients are Leptin ResistantPlasma leptin levels in human are highly correlatedwith adipose tissue mass and most obese patients havehigh leptin levels.2 1 The presence of a high endogenous
hormone level in the absence of an evident hormone effect (in this instance, leanness) suggests that there is resistance to that hormone. Thus, the initial data indicating that endogenous leptin levels are elevated in animaland human obesity suggested that obesity is most often
the result of leptin resistance and that the response ofobese subjects to exogenous leptin was thus likely to bevariable.2 2 Leptin’s efficacy was first shown to be variable in rodents with different obese strains showing aspectrum of leptin sensitivity with leptin-deficient ob/ob
mice being the most leptin sensitive and animals withleptin receptor mutations being the most resistant.2 2 Animals with obesity induced by a cafeteria or highly palatable diet, often a reliable predictor of drug responses inhumans, showed a partial response to leptin administration.
A similar variability in the response to leptin has been
seen in obese humans where leptin-deficient patients are
extremely sensitive to the effects of leptin treatment. In
obese patients in the general population, there was a statistically significant effect of leptin to reduce weight in asmall cohort of obese patients. 4 7 However, in further
studies, only a subset of obese humans (approximately
one-third) showed a clinically significant degree of
weight loss on leptin therapy (personal communication,
Alex DePaoli).4 7 These data indicated that the utility of
leptin as a monotherapy for the treatment of obesity was
likely to be limited to a subset of patients. It is yet unclear whether the individuals that respond to leptin havelower starting leptin levels than nonresponders. At agiven body mass index or percent fat, there is substantial
variability of leptin levels, and approximately 10%–15%of obese subjects have endogenous levels of leptin thatare indistinguishable from lean patients.2 1 The demonstration that leptin can have potent weight-reducing effects in some patients with low leptin levels such as
those with lipodystrophy and HA, see above, has sug-

6gested that leptin may be efficacious in obese patientswith low plasma leptin levels.4 6 While leptin has beenshown to have potent weight-reducing effects in experimental obese animals with low leptin levels, this possibility has not been directly tested in humans.46
A key issue for future studies will be to elucidate themolecular mechanisms responsible for leptin resistance.
Leptin activates signal transduction in specific neural
populations in the hypothalamus and other brain regions.4 8 The leptin receptor signals via the JAK-Stat signal transduction pathway, which depends in part on
phosphorylation of tyrosine residues of specific protein
substrates including Stat3. 4 8 Signaling by this class ofreceptors is generally turned off as a consequence of thesecondary activation of SOCS proteins, which inhibit
JAK kinase, and specific tyrosine phosphatases whichshut off cytokine signaling after the signal transduction
pathway is initially activated. Consistent with this, thecellular effects of leptin have been amplified in cells
lacking either SOCS3 or PT1b, a phosphotyrosine phosphatase. Importantly, mice with haploinsufficiency for
either of these genes are resistant to obesity and remainlean on a high-fat diet and retain leptin sensitivity. 4 9, 5 0
While the contribution of these proteins to the development of leptin resistance is as yet unclear, these data doshow that the enhancement of leptin sensitivity can protect against obesity. These results also suggest thatchemical inhibitors of SOCS3 or PT1b could have potential as anti-obesity agents, either alone or in combination with leptin. Efforts to develop inhibitors of these
proteins are underway.
Recently, the hormone amylin has also been shown toameliorate leptin resistance, though the molecular mechanism has not been fully established.5 1 Amylin is a peptide hormone secreted from pancreatic β cells that has anumber of effects to reduce plasma glucose that are synergistic with insulin. This agent is approved for the treatment of diabetes as an adjunct to insulin treatment. Amylin reduces glucose absorption, suppresses glucagon secretion and reduces food intake.51
Amylin therapy is also associated with a durable
weight loss of approximately 5% in humans, establishing it as one of a number of gastrointestinal signals that
regulate nutrient intake and disposition. The possibility
that amylin could interact with leptin to achieve evengreater weight loss was first assessed in diet-induced rats
where it was shown that doses of leptin that had no discernible effect as a monotherapy in this setting, could
significantly enhance the response to amylin.5 1 The data
further suggested that there was true synergy between
leptin and amylin, and that amylin could restore leptin
signal transduction in the hypothalamus of DIO rats. The
clinical significance of these findings was also assessedin humans, where the combination of leptin and amylin
resulted in a substantial weight loss of 12.9% that wassignificantly greater than that for either agent alone.5 1

Friedman JM: Leptin Regulates Adipose Tissue Mass

Further studies will establish the safety and efficiency ofthis combination for the treatment of obesity.
Leptin Provides an Entry Point
for Studying a Complex Human Behavior
Leptin treatment of leptin-deficient animals or humans
has extremely potent effects on food intake. In one instance, the food intake of a leptin deficient child wasmonitored before and after the first series of leptin injections. Prior to the first injection, this 3-year-old child ate
at least 1300 KCal at a single test meal (personal communication, Stephen O’Rahilly). This is approximately
one-half the number of calories a full-grown adult might
eat in an entire day. After a short period of leptin treatment, this child ate 180 KCal at an identical test meal,
which is the age-appropriate intake of a 4 year old.
Marked effects of leptin to reduce food intake in lipodystrophic patients and others have also been noted.37
The mechanism by which leptin reduces food intake
has been partially elucidated. Leptin activates neuralpathways that inhibit food intake and inhibits pathways
that activate food intake. Some of leptin’s actions appear
to result from inhibition of NPY/AGRP-expressing neurons in the arcuate nucleus of the hypothalamus, which
stimulate appetite, and activation of POMC neurons,
which reduce appetite by activating the postsynaptic
MC4 receptor in other parts of the brain.5 2 However, it islikely that other neural pathways also play a role and it is
not clear what aggregate set of pathways accounts forthe full effect of leptin treatment. Moreover, it is also not
clear whether leptin resistance abrogates leptin signalingby the NPY or POMC neurons or by as yet unknown
neural circuits. The identification of the specific circuitsthat are altered in the leptin-resistant state would provide
key entry points for delineating the pathophysiologic
molecular mechanisms that lead to obesity.
Leptin signaling also has important modulatory effects
on dopaminergic neurons that are part of reward pathways that provide input to the nucleus accumbens. 5 3, 5 4Consistent with this, fMRI imaging of leptin-deficient
subjects has revealed a marked increase in activity in the
nucleus accumbens in response to images of food evenin the fed state.55-57 Normal individuals typically show
this activity only in the starved state and do not show
this response in the fed state. The neural activity that isseen in the accumbens in fed leptin-deficient patientswas normalized by leptin therapy. 55 - 57 In addition,
leptin-deficient patients show markedly different foodpreferences and perception of food than do normal individuals.55-57 These data establish that leptin plays an important role to regulate feeding, a typical complex motivational behavior. The further delineation of the neuralcircuit activated by leptin may provide an opportunity todissect the way in which complex, behavioral decisions
are made. Feeding is regulated by many factors includ-Keio J Med 2011; 60 (1): 1－9

ing leptin, other hormonal and metabolic signals, sensory inputs, emotional factors and volitional factors suchas the conscious motivation to diet or in other cases gain
weight. It is not known how or even where in the brain
these multiple sensory inputs are represented. The full
spectrum of the downstream neuroanatomic sites towhich leptin-responsive neurons project are largely unknown, and their delineation could help lead to a fuller
understanding of how the decision to eat (or not eat) is
generated.
Biologic Basis for Obesity
The relevance of specific hypothalamic neural circuits
for human obesity has been established in a series of genetic studies in which it has been shown that single gene(i.e., Mendelian) defects account for 10% of cases ofmorbid human obesity, perhaps more;58-66 in one cohort,
15% of individuals with severe, early onset obesity weremembers of consanguineous pedigrees (personal communication, Stephen O’Rahilly). Thus, in addition to
mutations in the leptin and leptin receptor genes, significant obesity is also demonstrable in patients with
POMC, MC4R and TrkB mutations. This high incidence of Mendelian inheritance exceeds that for most,perhaps all, other complex traits which are commonly
accepted to have a genetic basis. Consistent with this,twin studies and other approaches have established asubstantial genetic basis for obesity with a hereditabilityof 0.7–0.9, a level exceeded only by height. 6 7 While asubset of these individuals show Mendelian inheritance,
the majority of these cases appear to be the result of
polygenes interacting with environmental factors.
The identification of genetic factors that cause obesity
is inconsistent with the widely held notion among thegeneral public that obesity is a personal failing. In theUS, the obese are often stigmatized to an extent thatwould be unacceptable for any other condition (see http://www.newsweek.com/id/215115). In addition, obese individuals on average make less money than their no-better-qualified lean counterparts and are promoted lessreadily.68, 69
The identification of human mutations that cause obesity requires that we modify the explanation that is often
invoked to explain the pathogenesis of obesity: the obese
eat too much and exercise too little. Although this is undoubtedly true, the deeper question is why do the obese
eat more and exercise less? The answer appears to beless about the conscious choices that obese people makeand more about their biologic makeup. The identificationof leptin and other components of a physiologic systemthat maintains energy balance has established that feeding is, at its core, a basic biologic drive analogous tothirst, breathing and reproduction.6 8 Although one canconsciously override the basic drive to eat over the shortterm and transiently lose weight, over the long term this7

basic drive dominates the conscious drive to eat less.
There are innumerable instances in each of our common
experience when basic drives overwhelm a conscious
desire. The world would be a fairer place if the people
who are inclined to deride the obese kept this in mind.
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