Whats in a Name? In Search of Leptins Physiologic Role1
Jeffrey S. Flier
Department of Medicine, Division of Endocrinology, Beth Israel
Deaconess Medical Center, Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Jeffrey S. Flier, M.D., Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Research North Room 325C, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail:
jflier{at}bidmc.harvard.edu
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Introduction
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THE IDENTIFICATION of the ob gene (1) and
the discovery that its encoded protein, leptin, is an adipocyte-derived
hormone that is essential for normal regulation of body weight (2, 3, 4)
have permanently altered the field of metabolic physiology. Over a 3-yr
period, more than 800 papers on leptin have been published, creating a
substantial and rapidly changing body of knowledge. As often occurs,
however, the initial conception of the physiological role of a newly
discovered protein requires revision in the light of emerging
information. In this paper, I will review the relevant literature and
will propose a modified view of leptins physiological role. This
perspective, although respectful of the profound impact that leptins
discovery has had upon our understanding of obesity and on the field of
obesity research, will attempt to deemphasize the physiological status
of leptin as an anti-obesity hormone, stressing instead its roles as a
signal of energy deficiency and as an integrator of neuroendocrine
function. Although this field is expanding rapidly, and many of these
ideas are clearly works in progress, it is hoped that this perspective
will be of value to workers in the field.
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Initial conception of the physiological role of the ob gene product
leptin
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The identification of the ob gene through positional cloning (1)
and the discovery that its encoded product is a circulating hormone
that is deficient in the ob/ob mouse (2, 3, 4) set the stage
for leptin to be considered an "adipostatic hormone." That is, the
physiological role of leptin was seen as rising with increasing
adiposity, to generate a signal that limits further weight gain. This
view, repeated throughout the leptin literature, has much to recommend
it. First, it resonates well with the fact that total leptin
deficiency, although very rare, causes severe obesity in both rodents
(1) and man (5); and in the rodent (so far), obesity as a result of
mutation in the leptin gene is reversed by replacement with recombinant
leptin. Indeed, the view that leptins function is to resist obesity
and promote leanness led to the choice of the name "leptin" (2),
from the Greek root leptos, meaning thin. Second, this view of leptin
concords well with the postulation, based on substantial indirect
evidence, of an adipostatic system for weight control (reviewed in ref.
6). An adipostatic mechanism was proposed to explain the relative
stability of weight over time in many animals and their capacity to
respond to involuntary overfeeding with adaptations, including reduced
appetite and increased thermogenesis, which restore body weight and
composition to previous levels. According to this view, rising levels
of leptin signal the brain (and possibly other sites) that excess
energy is being stored (in the form of fat), and this signal brings
about adaptations that resist obesity. When this signal is deficient,
the brain perceives energy stores to be insufficient, and the
physiological response is to increase appetite and decrease energy
expenditure, both of which push energy balance towards energy storage
and weight gain.
This initial view, that leptin functions primarily as an anti-obesity
hormone, requires revision stimulated both by new data and by
theoretical considerations. The new data includes the demonstration
that leptin has numerous biological effects distinct from those
expected of an adipostatic, anti-obesity hormone, and the fact that
resistance to leptins anti-obesity action is observed in both
experimental animals (7, 8, 9) and in man (10, 11). On a theoretical
level, it seems likely that a potent anti-obesity adipostatic system
would be subject to negative genetic selection during the course of
evolution.
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Leptin action and the "thrifty genotype": an evolutionary
perspective
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Through evolution, as in much of the world today, it is almost
certain that chronically inadequate and/or intermittant energy
availability confronted terrestrial organisms for major periods of
their lives. The view of early man as a hunter-gatherer, for example,
suggests periods of inadequate food intake punctuated by the bounty of
the kill. In such an environment, we can hypothesize that strong
evolutionary pressure would select for traits promoting two adaptive
responses. The first would promote efficient storage of energy when
food was available. This would enhance survival by increasing energy
stores during periods of insufficient food. Such traits have previously
been referred to as constituting a thrifty genotype (12). A related but
distinct trait that would also confer survival advantage would produce
physiological adaptations during periods of insufficient energy intake.
These changes would promote survival by reducing energy expenditure, by
ensuring substrate fluxes to tissues such as brain that require energy
at constant rates and by increasing food seeking behavior.
The concept of a thrifty genotype was first introduced by Neel in 1963
(12), 32 years before the discovery of leptin. In his original
conception, he proposed that a "quick insulin trigger" would
promote increased energy storage when food was available, favoring
survival during the hunter-gatherer period. He further hypothesized
that this pattern of insulin secretion would engender insulin
resistance, which would then promote diabetes when food supplies were
abundant and continuously available. It is this aspect of the thrifty
genotype concept that has received the greatest attention. Although
several aspects of this scheme have not proven correct, the proposal
that genetically determined capacities that are favorable during hunter
gatherer existence may be detrimental under conditions of abundance was
profound. In 1991, Wendorf and Goldfine (13) proposed a revision of the
thrifty genotype hypothesis, wherein they proposed the key phenotypic
manifestation to be insulin resistant glucose uptake in skeletal
muscle. They hypothesized that the advantage of insulin resistance in
muscle would be to limit hypoglycemia during periods of starvation (by
limiting muscle glucose use), but that this same phenotype would
promote hyperglycemia and energy storage in fat during periods of
nutritional abundance. This paper extended the concept of the thrifty
genotype to starvation as well as feeding and is attractive on two
accounts. First, insulin resistance of muscle glucose uptake and
storage as glycogen is a risk factor for type II diabetes (14), and
second, transgenic mice with muscle-selective insulin resistance are
susceptible to obesity when placed on a high fat diet (15).
It is now necessary to update the thrifty genotype concept, relating it
to the emerging biology of leptin. It is clear that a thrifty genotype
(and phenotype) that promotes energy storage in response to feeding
opposes the function of a molecule such as leptin that limits energy
storage as fat. Stated another way, an effective role for leptin as an
adipostatic hormone would subvert this aspect of the thrifty genotype
and would be predicted to reduce survival when food is scarce. It is
likely, therefore, that a role for leptin as a potent anti-obesity
signal would be selected against under these environmental conditions.
In response to this analysis, it might be suggested that a thrifty
genotype would result when leptin was ineffective or partially
disabled. This fits with the observation that heterozygous ob/+ mice
survive starvation longer than do wildtype +/+ mice (16, 17) Although
true, it is unlikely that leptin evolved for the purpose of being
disabled or ineffective. Therefore we must consider the question: for
what physiological purpose did leptin actually evolve?
Leptin levels in the blood fall when energy intake is limited and
energy stores in fat are declining (18, 19). Might leptin have evolved
to signal the shift between sufficient and insufficient energy stores?
If falling leptin signaled the brain to initiate responses that would
reduce the risk of starvation and death, this would surely be an
important physiological role. Starvation evokes a number of responses,
including reduction in fertility, suppression of metabolic rate and
thyroid hormone levels, and activation of the
hypothalamic-pituitary-adrenal axis (reviewed in ref. 20), each of
which has survival value. Because falling leptin is experimentally
linked to each of these adaptations (21), at least in rodents, this
action of leptin is likely to be a key component of its physiology. The
same cellular mechanism (whatever it is) that causes leptin to fall
with insufficient energy intake/stores might raise leptin levels with
overfeeding and obesity. However, a survival advantage might accrue to
those individuals who had a limited response to this part of the leptin
dose response curve, thereby manifesting the thrifty genotype (Fig. 1
).

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Figure 1. A theoretical relationship between serum
leptin levels and leptin action. During starvation, as leptin levels
fall, withdrawal of leptin action results in increased appetite and
decreased thermogenesis, as well as other changes not noted here. As
feeding continues, two patterns can be seen. In one, (D) leptin rises
with increased feeding and fat stores, but leptin action fails to rise
further because of a limitation at some step in leptin transport,
action at the target cell, or at a later step in the pathways
regulating appetite. This apppears as "leptin resistance", and is
also a feature of the "thrifty genotype". In another (C), leptin
action to reduce appetite and increase thermogenesis continues to rise
as levels rise. As indicated by the arrow, this will
tend to prevent obesity from developing and may be viewed as the
"lean genotype".
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Two important points emerge from this paradigm. First, this view is not
inconsistent with the fact that severe obesity results from mutations
that disable leptin or its receptor. With continuous leptin deficiency,
the brain "perceives" starvation and promotes hyperphagia and
efficient metabolism despite adequate energy stores that progress to
obesity. Indeed, any defects that create such a starvation signal in
the midst of plenty, such as defects in producing leptin, delivering
leptin to its site of action, or responding to the leptin signal, would
be expected to promote obesity. This important fact does not imply,
however, that the physiological function of leptin is to prevent
obesity from overfeeding. Second, it is clear that a genotype/phenotype
that is adaptive when food intake is intermittant (e.g. a
limited physiological response to rising leptin that enhances capacity
for energy storage) may be maladaptive in the midst of continuous
caloric abundance by promoting obesity and its complications. This
underlines an important principle of genetics: that a particular
genotype/phenotype cannot always be viewed, per se, as adaptive or
maladaptive, without information about the environmental conditions to
which the affected individual is exposed.
To summarize this evolutionary perspective: the ability of falling
leptin during starvation to promote increased energy intake, to
decrease energy expenditure, and to promote partitioning of energy
towards fat suggests that leptin plays a role in defending the thrifty
phenotype by falling with starvation. Although transition from this low
leptin starved state to a fed state with restored leptin is likely to
be important to physiological health, a continuous rise in leptin
action as energy storage proceeds would subvert the thrifty phenotype
by limiting the capacity for energy storage. Thus I hypothesize that,
in an environment with periods of starvation punctuated by feeding,
evolution would favor a leptin dose response curve that functioned
briskly as a switch between some level of sufficient energy storage and
another level perceived as insufficient (e.g. between the
fed and fasted states) but that failed to limit further energy storage
as levels rose with increased energy stores. The latter state would
most likely be described as "leptin resistance" (Fig. 1
).
It is important to stress that this analysis does not disregard the
experimental evidence supporting a capacity of animals to respond to
overfeeding by increasing thermogenesis (i.e. inefficient
metabolism) and by decreasing spontaneous food intake (22). Indeed,
increased leptin action is perfectly suited for bringing these
adaptations about, because leptin can diminish food intake (2, 3, 4) and
increase heat production by activating thermogenesis in brown adipose
tissue (23), and possibly other sites, through induction of the newly
identified mitochondrial uncoupling proteins UCP-2 (24, 25) and UCP-3
(26, 27, 28). We can reformulate the question as follows: leptin has the
capacity to serve as a signal that prevents obesity when animals are
subjected to abundant food supplies, but whether or not this capacity
is realized depends upon the shape of the leptin biological dose
response curve. Whether or not the leptin dose response curve displays
increased activity at high leptin levels may have been determined by
the conditions that confronted the species over evolutionary time
scales. If the adverse consequences of obesity were more deleterious
than the inability to maximize energy stores, evolution would select
for the capacity to respond briskly to leptin and, thus, for avoidance
of leptin resistance. Variations between strains of animals or
individual members of a species in regard to this parameter would have
major implications for their susceptibility to obesity. Likewise,
variations in the steepness of the curve describing the relationship
between leptin secretion/levels and adipocyte size/fat stores would
influence the body fat mass that is obtained.
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Leptin as a starvation signal: the neuroendocrine connection
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Because starvation is a recurrent threat to survival, numerous
physiological systems have developed to defend against it. Among the
most important responses to starvation are behavioral changes,
including increased food-seeking behavior and hunger; metabolic
changes, including those that promote provision of energy to tissues
through a switch from carbohydrate to fat-based metabolism (29); and
reduction in metabolic rate, which along with initial size of the
energy storage pool, is expected to play a key role in determining the
total duration of survival. Does a single signal entrain and
orchestrate these complex responses? Insulin, the most critical hormone
of metabolic homeostasis, falls with fasting and rises with feeding and
has diverse actions across this entire dose response range. The fall of
insulin with starvation is critical to the metabolic switch from
carbohydrate to fat-based metabolism, through actions on numerous
biochemical processes in organs including fat, muscle, and liver (29).
Great effort has gone into studies aiming to determine whether insulin
has additional actions to influence appetite, energy expenditure, and
neuroendocrine status in response to over- or undernutrition. Because
insulin can apparently be transported across the blood brain barrier
(30) and, when injected centrally, can reduce appetite and expression
of hypothalamic neuropeptide Y (31), a role for insulin in the central
regulation of energy balance has been proposed. Taken as a whole,
however, these observations about insulin, although provocative and
logical, have left most investigators believing that one or more
additional signals linking the periphery and central control sites has
yet to be discovered.
Leptin is clearly such a molecule. First, it was shown that leptin
levels fall fairly rapidly (i.e. within hours) with energy
deprivation in rodents (18, 19), and they do so (initially) out of
proportion to the loss of fat stores. This suggests that, in addition
to being a readout of energy stores, the leptin level is a sensor of
energy balance or the relationship of energy intake to expenditure at a
point in time. Next, a classic replacement strategy was employed to
show that starvation-induced changes in neuroendocrine status were
blunted or prevented entirely when a starved animal was replete with
leptin. Thus, the activation of the hypothalamic-pituitary-adrenal
(HPA) axis, and suppression of the thyroid and reproductive axes, were
blunted or prevented by leptin repletion during starvation in rodents,
establishing that these effects are signaled, at least in part, by the
fall in leptin (21).
What are the consequences of these leptin-entrained endocrine
responses? The most critical product of the HPA axis is the
glucocorticoid hormone, corticosterone in the rodent and cortisol in
man. At least two of many beneficial functions of increased
glucocorticoid secretion in starvation can be cited. First,
glucocortocoids gained their name from their ability to promote the
shift to hepatic gluconeogenesis that is needed to supply the brain
with glucose when exogenous sources of nutrition are limited. They
accomplish this by numerous mechanisms including the stimulation of
proteolysis in muscle (to provide substrate) and the activation of
enzymes of gluconeogenesis in the liver. Second, as starvation is a
time of stress that is more likely associated with physical challenge
and struggle, the actions of glucocorticoids that relate to the stress
response would be advantageous. The fall in leptin is the first defined
mechanism to explain the activation of the HPA axis in response to
starvation.
All other things being equal, starvation is expected to produce death
more rapidly when the metabolic rate is higher. Because thyroid hormone
is a dominant regulator of basal metabolic rate, a fall in thyroid
hormone during starvation is likely to be advantageous, so long as
other potentially adverse consequences of hypothyroidism do not occur.
The metabolic rate falls during food restriction, as do levels of T3 in
humans (33) and T4 and T3 in rodents (21), but the contribution of
decreased thyroid hormone levels in producing the hypometabolism of
starvation has not been established. Starvation can lower metabolic
rate by lowering levels of thyroid hormone, but mechanisms may also
exist apart from the effects of decreasing levels of T3 and T4. These
include changes in lean body mass, reduction in brown adipose tissue
activity (34), and possibly changes in the expression or function of
new uncoupling proteins. It is noteworthy that changes in each of these
parameters (e.g. lean body mass, brown adipose tissue
activity, and UCP-3 expression) have been reported to respond to
changing leptin levels. Thus, leptin is capable of regulating metabolic
rate in starvation by several mechanisms, including changes in the
thyroid axis (35, 36, 37). Interractions between these mechanisms may also
exist. Thus, thyroid hormone increases the expression of UCP-3 in
skeletal muscle of the rat (28), and it is possible that some or all of
the action of leptin to induce UCP-3 is secondary to the leptin effects
to induce thyroid hormone levels.
Chronic nutritional deficiency, leading to stunted linear growth,
results in large measure from insufficient nutrition for synthesis of
tissues that underlie growth. There is also a regulatory aspect to this
outcome. That is, there may be a disadvantage to increasing size (and
thereby metabolic needs) when calories are chronically scarce. This may
account for the suppression of the growth hormone axis during
starvation. Starvation causes suppression of both GH and IGF-I in
rodents, and this suppression may be prevented by leptin repletion
(38). In humans, GH is increased during starvation, but IGF-I is
suppressed (39), and the role of leptin in this has not yet been
studied.
An important connection between nutrition and reproduction has long
been noted. The development of live and healthy progeny requires a
large allotment of calories, and it would compromise both mother and
the fetus if the process began with insufficient calories stored in
fat. This is the likely teleological explanation for the ability of
caloric deprivation both to prevent full sexual maturation and to limit
reproductive competence in sexually mature females. It is less clear
what benefit derives from the reproductive axis being diminished in
starved males, but this is also well described to occur (36).
How does leptin influence these diverse endocrine effects of
starvation? Leptin most likely exerts its most important effects
through the central nervous system, specifically within the
hypothalamus. It is not yet established through what neural circuitry
these effects are brought about. An initial theory viewed hypothalamic
NPY as a key target (40). NPY containing cells in the arcuate nucleus
have leptin receptors (41), and leptin suppresses NPY expression at
this site (40, 42). Administration of NPY can activate the HPA axis
(43) and can also exert a variety of effects upon the
hypothalamic-pituitary-gonadal axis (44). However, the effects of
starvation to activate the HPA axis, suppress reproduction, and
activate the thyroid axis all occur normally in mice with knockout of
the NPY gene (45, 46), indicating that other, as yet unidentified
hypothalamic factors must be involved. Regarding the thyroid axis, we
have observed that starvation causes suppression of TRH expression in
the paraventricular nucleus of the hypothalamus in the rat, despite
falling levels of T4, which should increase TRH, and that leptin
treatment during starvation prevents this suppression (37). Whether
this effect is a direct action of leptin on TRH neurons or is mediated
by an indirect projection from leptin responsive neurons is presently
unknown. It should be noted that leptin has also been described to have
direct actions upon peripheral target organs such as the pituitary
(47), adrenals (48), and gonads (49), and the possible role of these
actions will await further study.
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Leptin and the metabolic response to starvation
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Although a role for falling leptin in the endocrine response
to starvation seems clear, it is not yet established to what degree
leptin plays a role in the metabolic adaptation to starvation, a
situation where falling insulin is the dominant hormonal change.
Falling insulin is thought to be the major factor bringing about
increased lipolysis, decreased uptake of glucose in muscle and fat, and
increased hepatic glucose production, which characterize starvation.
The falling insulin level may also play a direct and important role in
the fall in leptin production by the adipocyte during starvation, as
insulin has been observed to stimulate leptin gene expression in
vitro (50, 51, 52), and leptin levels rise in vivo during a
prolonged euglycemic insulin clamp (53). However, it is not yet clear
to what degree falling leptin might contribute, along with falling
insulin, to the metabolic adaptations to starvation. Repletion of
leptin alone in the starving mouse failed to prevent the rise in
ketones or the fall in glucose levels (36), suggesting that
insulin is the primary hormone in this adaptation, but such studies
need to be extended to evaluate the possibility of more subtle
metabolic effects of falling leptin that could be important. Given the
observation that leptin is capable of exerting potent metabolic effects
on peripheral target tissues (54, 55), at least some of which may be
direct rather than through the brain (56), further studies on the
metabolic physiology of leptin are warranted.
Interpretation of studies on the metabolic physiology of leptin
will require integration of biochemical observations with the
physiological context in which they occur. For example, during fasting,
when lipolysis is activated, both insulin and leptin levels fall, as
discussed above. The fall in insulin is clearly linked to this process.
Because addition of leptin is described as activating lipolysis in
adipose tissue directly (56), it is unclear what role this might play
in the physiology of starvation. Does the fall of leptin during
starvation act as a brake on lipolysis to counter the action of falling
insulin? Studies aimed at addressing questions such as this are
required if the role of leptin in metabolic adaptation to the fed and
fasted states is to be understood.
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Endocrine actions of leptin independent of starvation or feeding
per se
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The effects of leptin on endocrine function as its levels fall
during starvation fit easily within the paradigm of leptin as a
molecule that signals the switch between sufficiency and insufficiency
of energy stores. These findings have led, however, to discovery of
additional actions of leptin on endocrine function that are further
removed from the energy sufficiency paradigm. The first example relates
to the adrenal axis. There is a diurnal rhythm of leptin levels that is
entrained by eating. In rodents, leptin levels rise during the dark
cycle when rodents do most of their eating (36); in man, levels rise
throughout the day and peak in the early morning (57). Individual meals
are not associated with an increased leptin level in man (58). These
diurnal patterns of leptin are the inverse of the typical patterns of
the HPA axis in both rodents (21) and man (58). Correlations do not
prove causal connections, and much is known about the central
mechanisms for regulation of circadian rhythms, including the critical
input from the suprachiasmatic nucleus. However, it is reasonable to
consider whether leptin may be one of several influences over the
pattern of the diurnal rhythm of the HPA axis. An anatomic substrate
for a possible pathway by which leptin responsive neurons might
influence the output of the suprachiasmatic nucleus has recently been
described (58a). The possible interaction between leptin and the HPA
axis extends further. It appears that leptin has a pulsatile pattern
apart from the diurnal rhythm (59). Given that leptin is secreted by
widely dispersed adipose cells that are unlikely to have any
coordination, this finding was quite surprising. This pulsatility is
seen only when frequent samples are taken, and whether the pattern
results from pulsatility at the level of secretion or clearance is not
known. Interestingly, this pattern is inversely correlated with the
pulsatile pattern of ACTH and cortisol (59). Because acute leptin
injection in vivo can suppress the rise in the HPA axis
induced by stress (60) in rodents, and because leptin has been seen to
acutely suppress hypoglycemia-induced secretion of CRH from
hypothalamic slices (60), it is reasonable to hypothesize that leptin
may have a role in the normal negative feedback function of the HPA
axis. Such a relationship would explain the fact that states of severe
leptin deficiency or resistance are associated with activation of the
HPA axis. It has also been suggested that leptin may inhibit the HPA
axis by a direct action on the adrenal gland to inhibit cortisol (48).
Thus, the inverse relationship between leptin and glucocorticoids may
derive from action at two sites in the HPA axis (48).
On the other hand, leptin has been reported to increase expression of
CRH messenger RNA (mRNA) in the paraventricular nucleus of the
hypothalamus (PVN) (42), and this pathway has been hypothesized to
represent a mechanism for the central actions of leptin (61), given
that CRH administered centrally reduces food intake (62) and increases
sympathetic output to brown adipose tissue (63, 64), two actions of
leptin. These disparate observations can be reconciled, however. The
PVN is a complex nucleus, and CRH neurons in the PVN have distinct
anatomic and functional identities (65). One population projects to the
median eminence, where released CRH gains access to the pituitary gland
to regulate secretion of ACTH and, thereby, adrenal glucorticoids. We
believe that in this population of cells, leptin is likely to be
inhibitory. A second population of CRH neurons in the PVN projects to
other sites, including the autonomic preganglionic centers in the
brainstem. It is likely, although as yet unproven, that leptin
activates these neurons. Such a model may account for the existing data
in this area.
Regarding the thyroid axis, it is of interest that a diurnal rhythm of
TSH has been seen (66, 67), with levels peaking in the early morning
hours, when leptin levels are at their highest. Given the observation
on the action of leptin to stimulate TRH gene expression in the
hypothalamus during starvation (37), it is possible that leptin may be
involved in this process.
The effect of leptin on the reproductive axis may also extend beyond
the paradigm of starvation and feeding. In mice, leptin administration
from the time of weaning accelerates the onset of puberty (35, 68, 69).
In boys, leptin levels appear to peak at or before the time of pubertal
onset when studied in a longitudinal fashion through the peripubertal
years (70). These findings are consistent with the possibility that
leptin may be one of several signals that acts on the GnRH system,
either directly or indirectly, to influence the timing of the pubertal
program. The essential nature of this signal is demonstrated by the
fact that ob/ob mice without leptin fail to undergo pubertal
development, a process that is restored by administering leptin (71).
Whether leptin acts as a metabolic gate by reaching a necessary level,
or actually peaks to produce a signal is currently unresolved, as a
study of puberty in monkeys revealed no increase in leptin levels
before puberty (72). It is obvious that observations on leptin action
on the endocrine system in rodents require careful study in subhuman
primates and humans. Important differences between leptin action among
these species may be present.
While pursuing this issue in mice, we sought to determine whether
leptin levels peaked just before puberty in this species. When we
measured leptin levels post-weaning, days before the physical signs of
puberty, no peak was found. We then measured leptin levels from day 3
after birth to the post-weaning period and found that leptin levels
underwent a marked surge between days 5 and 15, peaking sharply at day
10. This was associated with an increased expression of leptin mRNA in
subcutaneous adipose tissue and was unrelated to any variation of
adipose tissue as a percent of body mass during this period. These
findings raise the possibility that leptin plays a developmental role
in addition to the functions related to energy balance and
neuroendocrine function. In this regard, it is important to note that
the brains of leptin deficent ob/ob and leptin resistant
db/db mice weigh substantially less than those of lean
littermates, and this differences increases with age (73). The
mechanistic basis for these striking differences in brain size (and
probably function) brought about by leptin deficiency is unknown.
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Actions of leptin on other organ systems
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When considering the biological role of a molecule such as leptin,
it is necessary to mention actions of leptin on other organ systems,
apart from the nervous system and endocrine/metabolic realms. Leptin
has been reported to act on hematopoeitic cells (74) and to alter renal
function (75), an effect that could be indirect via the sympathetic
nervous system, or direct on renal cells. The reason why leptin should
have been selected to exert these actions, as wellas other
unanticipated actions certain to be discovered in the ensuing years, is
not yet evident.
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Summary and conclusions
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I have tried to review the rapidly emerging evidence that leptin
is an adipocyte-derived hormone that is a powerful regulator of
metabolism and neuroendocrine function. Because leptin levels parallel
changes in nutritional status and energy storage across a broad range
from starvation to obesity, leptin is well-positioned to signal energy
insufficiency or energy excess, causing responses that could counter
the adverse consequences of either starvation or obesity. I have
reviewed some of the reasons why a response to starvation might be
retained, whereas the response to limit obesity, despite its value in a
world of nutritional excess, might have been selected against by
evolution, accounting for the high prevalence of obesity in the modern
world. Once the mechanism for this resistance is unlocked, new
treatments for obesity are likely to emerge. I have also reviewed the
evidence that leptins regulatory effects are not limited to
signalling the state of energy stores.
This perspective, it should be emphasized, in no way diminishes the
importance of leptins discovery for obesity research, which has been
nothing short of profound. Rather, these ideas suggest that the
importance of leptin includes, but extends substantially beyond, the
physiology of obesity avoidance. Indeed, the physiological significance
of leptin is just beginning to unfold.
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Acknowledgments
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I would like to acknowledge Drs. Eleftheria Maratos-Flier, Brad
Lowell, Rex Ahima, Christos Mantzoros, and Joel Elmquist for
helpful discussions of many of the ideas presented here.
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Footnotes
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1 This work was supported by NIH Grant R37 28082. 
Received December 16, 1997.
Accepted January 21, 1998.
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