Leptin and Clinical Medicine: A New Piece in the Puzzle of Obesity
George A. Bray and
David A. York
Louisiana State University, Pennington Biomedical Research Center,
Baton Rouge, Louisiana 70808
Address all correspondence and requests for reprints to: George A. Bray, M.D., 6400 Perkins Road, Baton Rouge, Louisiana 70808.
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Introduction
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THE DISCOVERY of leptin in 1994 has
provided a major new piece in the puzzle of obesity. Leptin is a
167-amino acid peptide made exclusively in adipose tissue. Its absence
produces the obese (ob/ob) mouse, which is characterized by
obesity, hyperphagia, hyperglycemia, hyperinsulinemia and insulin
resistance, hypothermia, and infertility. Leptin corrects these
defects. The leptin receptor is a member of the cytokine family of
receptors with several splice variants. The intracellular signaling
system for leptin appears to involve activation of the Jak-Stat system,
with Stat-3 being the phosphorylated intermediate. Genetic defects in
the leptin receptor produce the diabetes (db/db) mouse,
which is phenotypically identical with the ob/ob mouse when
the genes are expressed on the same background strain, and the obese
fa/fa Zucker rat. The levels of leptin are directly related
to the quantity of body fat, suggesting that it is a signal to the
brain and other tissues about the adequacy or inadequacy of fat stores.
Leptin receptors are distributed widely, including brain and many
peripheral tissues, suggesting that this peptide may provide a wide
range of tissues with information about fat stores. Although human
obesity may not be a direct result of low leptin activity,
understanding gained from the animal models may help in the development
of new pharmacotherapeutics for human obesity.
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I. The background: the first piece in the puzzle
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The year was 1950. The place was the Jackson Laboratory in Bar
Harbor, ME, where George W. Snell was a leader in mouse genetics. In
that year Dickie et al. (1) reported the appearance in their
colony of a recessive mutant associated with massive obesity. The
genetic defect in the obese or ob/ob mouse is a recessively
inherited disease manifested early in life that is associated with
diabetes. Shortly after discovery of the ob/ob mouse, a
second recessively inherited form of obesity, called diabetes or
db/db, was described by Hummel and Coleman (2). Rounding out
the discovery of recessively inherited forms of obesity were the
discovery of the fatty rat (3) and, somewhat later, tub and fat mice
(4).
The fact that ob/ob and db/db mice are
phenotypically identical when expressed on the same genetic background
yet genetically different was initially interpreted as a genetic defect
at two different steps in an enzymatic cascade (5). The search for a
biochemical or physiological mechanism for the genetic basis in these
obese animal models occupied many scientists (5), but has provided only
one major piece to the puzzle of obesity. This piece of the puzzle was
the finding that carboxypeptidase E, which cleaves propeptides to
biologically active peptides, was defective in the fat mouse (6).
The observation that all animal models of obesity have high levels of
insulin and insulin resistance lead to extensive studies of
insulin-responsive tissues and insulin receptors (5). The possibility
of a fat storage disease similar to the glycogen storage diseases was
also explored. Whatever the defect that was eventually identified, it
had to account not only for the metabolic abnormalities of hyperphagia,
hyperlipidemia, hyperglycemia, insulin resistance, and diabetes, but
also for the infertility and hypothermia that characterize these
animals (2, 5).
One of the intriguing questions that followed the discovery of the
ob/ob mouse was its differences from the obesity produced by
damage to the medial hypothalamus. Hetherington and Ranson (7) added
another piece to the puzzle when they showed that damage to the
ventromedial hypothalamus (VMH) would routinely produce obesity. The
paraventricular nucleus and central nucleus of the amygdala are other
key sites. In addition to lesions, local anesthesia of the ventromedial
nucleus (VMN) with procaine will produce hyperphagia and obesity.
Similarly, injection of colchicine, which inhibits the cell cycle, or
injection of monosodium glutamate, goldthioglucose, or ibotenic acid,
which damage cells in the VMH, will all produce obesity (5).
The next piece of the puzzle came from the observation that the obesity
would develop in the VMH-lesioned rat and in the ob/ob mouse
even when food intake was precisely matched to that of lean controls
(2, 5). If hyperphagia were allowed, the obesity was of greater
magnitude, but clearly hyperphagia was not essential for obesity in
either model.
A fourth piece of the puzzle of obesity was the demonstration that a
disturbance of the autonomic nervous system appeared to be essential
for the development of obesity in most animal models, including the
ob/ob/mouse, the fa/fa rat, the VMH-lesioned
animal, and probably humans as well (8). Each model has low levels of
sympathetic activity to brown adipose tissue, a thermogenic tissue.
They all show an increased activity of the parasympathetic nervous
system, which may play a key role in the development of obesity. When
pancreatic islets of rats were removed from vagal innervation by
transplanting them under the renal capsule, the hyperphagic effect of
VMH lesions was almost entirely prevented. Thus was born the autonomic
hypothesis (5), which suggested that reduced activity of the
sympathetic nervous system and increased activity of the
parasympathetic nervous system played central roles in the development
of obesity in the fatty (fa/fa) rat, the VMH-lesioned rat,
and the ob/ob mouse (8). This hypothesis has received
subsequent support from both animal and human studies. The low levels
of sympathetic activity supplying brown adipose tissue offered a
plausible explanation for the lowered body temperature in
ob/ob mouse and fa/fa rats (5).
A sixth piece of the puzzle came from studies of the endocrine system
and has been called the endocrine hypothesis (5), although the
glucocorticoid hypothesis might be more appropriate. Removal of the
adrenal cortex is sufficient to impair the development of all
experimental obesities. The obesity of the ob/ob mouse, the
db/db mouse, and the fatty rat does not progress after
adrenalectomy. More striking, food intake returns to normal, muscle
mass increases, body growth resumes, insulin resistance is eliminated,
and hyperglycemia abates after adrenalectomy. Thus, the metabolic
components of the ob/ob mouse, db/db mouse,
fa/fa rat, and yellow mouse are dependent on adrenal
glucocorticoids. The infertility, however, is not restored by
adrenalectomy, suggesting that there is another function of the
ob/ob and db/db gene products.
Another piece in the puzzle of obesity was the demonstration that
estrogens altered body fat. Castration of the female rodent increases
food intake and decreases the activity of the sympathetic nervous
system (9). Injection of estrogens or their direct application to
hypothalamic structures will reduce food intake. Estrogen may thus
serve as a modulator of the messages produced by the medial
hypothalamus that control feeding signals, as part of the integration
of feeding and the reproductive axis. It is noteworthy that
adrenalectomy prevents the obesity of castration just as it does in
leptin deficiency and VMH-lesioned induced obesity (9).
Based on his studies of parabiotic animals, Coleman proposed that the
ob/ob mouse might be deficient in a circulating factor and
that the db/db mouse might not respond to this factor (2).
These prescient experiments were given a plausible biochemical basis by
the discovery of leptin and the leptin receptor.
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II. The discovery of leptin
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The identification of leptin shows the power of molecular cloning
techniques in identifying additional pieces to the puzzle of obesity.
Large numbers of animals carrying the ob or db
gene were mated with the Mus castaneus, a distantly related
mouse. With these large numbers of crosses and backcrosses, it was
possible to narrow the genomic distance to within centimorgans of the
gene. This essential preliminary work allowed Friedman and his
colleagues to complete the cloning of the ob gene by using
yeast artificial chromosomes (10). This major piece in the puzzle of
obesity was published in December 1994. The importance of the initial
work by Leibel and his colleagues to the eventual cloning of the
ob gene deserves greater recognition than it has generally
been given to date.
The primary product of the ob gene, now known as leptin, is
a 167-amino acid protein. Northern blot or reverse transcription-PCR
analysis of the messenger ribonucleic acid (mRNA) for the ob
gene showed that it was expressed only in adipose tissue (10, 11). This
was an important piece in this puzzle because it provided the basis for
a selective message arising in adipose tissue that could signal other
tissues and the brain about the state of the body fat, as proposed
initially by Coleman (2). Although such a factor may regulate food
intake, it may also be particularly important in the modulation of
reproduction. Such a hypothesis was suggested initially by Frisch
et al. (12) as the critical fat level hypothesis for the
onset of puberty and menstruation.
Demonstration that the Ob protein or leptin was biologically active was
the next step. Three laboratories simultaneously reported the results
of administering leptin (13, 14, 15), a word derived from the Greek word
leptos, meaning thin. Administration of leptin to ob/ob mice
reduced food intake and body fat, reduced glucose, and decreased
insulin and has recently been shown to increase the activity of the
sympathetic nervous system (16). Thus, leptin was acting, as do other
peptides, to regulate reciprocally the activity of the sympathetic
nervous system and food intake (17). Of particular importance for the
viability of leptin as the key to the obesity in the ob/ob
mouse was the fact that the db/db mouse was completely
resistant to leptin (15), as Coleman had predicted, and that leptin
cured the hypothermia and infertility of ob/ob mice. With
these data confirming that leptin was the ob gene product, a
big piece of the puzzle was in hand as the search for the biological
realities of leptin began.
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III. The biology of leptin
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Leptin is produced exclusively in fat cells across a wide range of
animal species, including humans (10, 18). This finding has added to
the growing literature showing that the fat cell is an important
secretory organ in addition to its role as a storage organ for fat.
Figure 1
shows a cartoon of leptin
secretion and action.

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Figure 1. Diagram showing the release and action of
leptin. Leptin is made exclusively in fat cells. Glucocorticoids and
insulin enhance this process. Circulating leptin is bound to receptors
that may be the extracellular part of the leptin receptor, which is
shown here in the brain. Leptin may act on the brain receptors or be
transported into the brain, where it alters NPY, food intake, the
sympathetic nervous system, and the reproductive system.
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The leptin that is secreted by the fat cell appears to bind to one or
more proteins in the circulation (19) (Fig. 1
). The percentage of free
leptin is higher in obese than in lean individuals (19). Indeed, plasma
leptin levels are closely correlated with body fat in both humans and
rodents (18, 19, 20, 21, 22, 23, 24, 25), although there is a wide range of individual leptin
values at a specific level of body fat. To date, no obesity in humans
has been found to result from a defect in the reading frame of this
gene (26, 27). However, linkage of obesity to the human leptin gene
region or to regions flanking the leptin gene have been reported
in massively obese subjects (28, 29). The increase in leptin levels
with increasing body fat and obesity suggests that obesity may be
associated with leptin resistance.
Complementing the discovery of leptin was the new piece to the puzzle
of obesity obtained by cloning of the leptin receptor. Initially, the
short form (Ra) of the receptor was identified from a complementary DNA
library of choroid plexus (30), but subsequently the long form (Rb) and
a number of other splice variants were cloned and sequenced by several
groups (31, 32, 33, 34, 35). The receptor for leptin is a member of the cytokine
receptor family (36, 37, 38). A mutation in the intracellular signaling
domain of the receptor was identified in db/db mice (31, 32)
to confirm the original experimental data from parabiosis (2) and
identify the molecular basis for a failure of db/db mice to
respond to either endogenous or exogenous leptin. The db and
fa mutations were thought to be syntenic. However, the
fa mutation was shown to be a glutamine
proline
substitution in the extracellular domain of the receptor. In contrast,
the db mutation is a G to T substitution that produces a new
consensus splice donor site. This results in the insertion of a
106-base sequence of the terminal exon of the short form of the
receptor into the mRNA of the long form of the receptor and introduces
a premature stop codon that results in a receptor protein lacking the
intracellular signaling domain (33, 34, 35). The fa/fa rat, but
not the db/db mouse, will respond to exogenous leptin when
it is delivered intracerebroventricularly (39). The fa
mutation may either impair transport of leptin or reduce the number of
receptors that are localized in the plasma membrane.
The biological effects of leptin are thought to result from the
activation of a Jak-Stat signaling pathway, with specific involvement
of Stat-3 protein (36, 40). However, it is not clear whether this is
the only signaling pathway that is activated by leptin. The long form
of the receptor (Rb) has been identified in several brain regions and
may also be present in a range of peripheral tissues, including the
liver and pancreas (31, 32, 34, 41, 42). Within the brain this receptor
is expressed in a number of brain regions that have been associated
with the regulation of feeding behavior and energy balance, such as the
arcuate nucleus and VMH (43, 44). The latter observations may fit two
pieces of the puzzle together by explaining the similarities between
syndromes of leptin deficiency and the syndrome that results from VMH
lesions. However, the predominant form of the receptor in peripheral
tissues is the short splice variant (Ra). The high level of expression
of this receptor in the choroid plexus (30) led to the suggestion that
its major function may be the transport of leptin into the brain. If
this is so, it is not clear why this form of the receptor is so widely
distributed in peripheral tissues.
Leptin secreted from adipocytes may be bound to a number of different
proteins in the circulation (19), including a splice variant of the
receptor (Re) that has no transmembrane domain and is soluble. However,
only approximately 50% of total leptin is bound in lean individuals,
and the level of free leptin is higher in obese individuals than in
their lean counterparts (19). This discounts the possibility that any
leptin resistance might result from excessive binding of leptin to
circulating proteins. However, leptin resistance does appear to be
peripheral, as dietary obese mice retain their sensitivity to central
leptin but lose the response to peripheral leptin (45).
The studies of leptin physiology have used two major approaches. The
first has been the regulation of leptin production, measured as tissue
mRNA levels (mainly in rodents) or circulating leptin levels (mainly in
humans). The second approach has examined the responses to exogenous
leptin. These studies have focused principally on food intake, body
composition, insulin secretion, and the reproductive system, although
effects on adipose tissue, the hematopoietic system, and other targets
are now being studied.
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IV. Regulation of leptin production
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Both human and animal studies have demonstrated the close
association among body fat, leptin mRNA, and plasma leptin levels
(18, 19, 20, 21, 22, 23, 24, 25). The level of expression of the leptin gene varies from one
fat depot to another. The circulating leptin levels increase with
percent body fat (r =
0.9), but not with visceral fat.
Plasma leptin levels are higher in men than in women (15, 20, 46, 47)
and show a diurnal rhythm in both sexes (48). Leptin production is
affected by several hormones. Leptin gene transcription and circulating
leptin levels are modulated by adrenal steroids (49, 50). Both in
vivo and in vitro studies in rodents and man have shown
that glucocorticoids enhance leptin gene transcription and leptin
levels (49, 50). The generally higher levels of leptin in human females
than males suggest that sex steroids might also affect leptin
production. These effects are generally similar in rodents and humans.
Similarly, insulin stimulation of leptin production has been
demonstrated in rodents (51, 52) in a range of studies that have
included cultured adipocytes and streptozotocin-diabetic rats. In human
studies, leptin levels have been correlated with basal insulin levels
(46, 47, 54). In man, insulin increases plasma leptin after a delay of
24 h (Saad, M. F., unpublished observation), although not all
investigators have observed this acute response (21, 55, 56). Plasma
leptin levels respond slowly to fasting (22, 57) and do not begin to
decrease in humans for 1214 h. Leptin gene transcription and plasma
leptin are severely reduced by longer starvation (24, 58). Conversely,
the increase in leptin after feeding is delayed. The nighttime increase
in leptin that was initially described by Considine and colleagues (18)
appears to be a delayed response to the last meal of the day and
probably reflects insulin changes (59).
It has been assumed that secreted leptin acts as a signal to the
central nervous system to indicate the level of body fat and induce the
appropriate responses of food intake and energy expenditure. However,
Flier et al. (60) suggested that leptin may act as a
starvation signal, such that low levels trigger the
hypothalamic-pituitary axis to respond to undernutrition. In a similar
vein, the effects of leptin on the reproductive system suggest that it
may act to trigger the hypothalamic-pituitary axis to initiate
reproductive cycling and induce a fertile state (61, 62, 63).
Leptin has a half-life in the serum of approximately 90 min, a
characteristic that would be consistent with it being the parabiotic
factor proposed by Coleman (2, 64). This 90-min half-life relative to
that of 1214 h in plasma may reflect differences in renal handling.
The interpretation of high levels of leptin in obesity as a reflection
of leptin resistance arises if one views the effects of leptin as
primarily concerned with regulation of food intake. If the leptin
signal is, rather, a reflection of the quantity of fat needed for
initiation of the reproductive system, and the hyperphagia of leptin
deficiency results from an effort to increase fat stores for fertility,
then the high levels of leptin would be anticipated to influence a
different system. This system is the reproductive system. It is
possible that the high levels of leptin produce their effects on the
reproductive system that, in turn, influence the feeding system.
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V. Physiological effects of leptin: a model for obesity
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When leptin is injected either peripherally or into the brain, it
will reduce food intake, particularly in the leptin-deficient animal
(13, 14, 15). One explanation for the effects of leptin on the brain may be
through the reduction in the levels of neuropeptide Y (NPY). The
observation that NPY stimulated food intake and produced obesity with
chronic administration is another piece in the puzzle of obesity (65).
NPY arises from neurons in the arcuate nucleus and is released in the
paraventricular nucleus (66). The decreases in NPY synthesis and
secretion (67) produced by leptin or a change in sensitivity to NPY
(68) could account for the decrease in food intake, the increased
sympathetic activity, and the restoration of fertility in the
ob/ob mouse. However, leptin is still effective in
transgenic animals with a knockout of NPY, suggesting that NPY is not
essential for the action of leptin (69). Alternatively, leptin may
decrease food intake through release of other peptides, of which CRH
and urocortin are prime examples.
Previous studies of leptin-deficient rodents (ob/ob and
db/db/fa/fa) identified the pathways and targets
that must be affected by leptin. In addition to food intake, an
autonomic imbalance that promoted insulin secretion and impaired brown
adipose tissue (BAT) thermogenesis was evident, such that the mutant
rodent would become obese before the onset of hyperphagia or when
hyperphagia was prevented. Thus, leptin must enhance the sympathetic
drive to a number of tissues, including BAT, must reduce the
parasympathetic vagal drive to the endocrine pancreas, and must restore
fertility. A reduction in insulin levels by leptin, in excess of that
related to the reduction in food intake (70), has been reported, as has
an increase in sympathetic activity in BAT (71). Restoration of
fertility in ob/ob mice has also been demonstrated (61, 72).
Other studies have shown the ability to induce precocious puberty with
leptin and suggest that leptin may act to block the estrogen inhibition
of pituitary gonadotropin secretion (62, 63).
Figure 2
is an effort to integrate leptin
into a broader picture. The absence of leptin, or the leptin receptor,
VMH lesions, NPY infusions, norepinephrine infusions, and removal of
estrogen have similar effects. They increase food intake, reduce
sympathetic activity, increase parasympathetic activity, and modify
reproductive function. It has long been known that the metabolic
defects in the ob/ob mouse and other rodent obesities,
including that caused by castration, could be corrected by removing or
blocking the effects of adrenal glucocorticoids (5, 73, 74). The
similarity of these differing experimental models suggests that they
all act to reduce the functional output from the ventromedial
hypothalamus.

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Figure 2. Model of hypothalamic effects of leptin and
other experimental maneuvers that produce obesity.
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As adrenalectomy is effective in reversing or blocking the progression
of all of these syndromes of obesity, including lesions of the PVN and
VMN, the effects of glucocorticoids must be further downstream from the
VMN/PVN (Fig. 2
). This model also suggests that the downstream effects
of the sympathetic nervous system, the parasympathetic nervous system,
estrogen levels, and glucocorticoid levels may modulate the peripheral
level of leptin mRNA in white and brown adipose tissue. Current
insights into the role of adrenal steroids suggest that they might
either inhibit leptin transport into the brain (75) or inhibit the
signaling pathways associated with leptin responses.
Despite the focus on the CNS, it is becoming apparent that leptin may
have direct effects on other target tissues. These may include adipose
tissue, as leptin inhibits preadipoycte differentiation and lipogenesis
in cultured cells (76) and the endocrine pancreas (41, 42). The
apparently ubiquitous expression of leptin receptors in all peripheral
tissues suggests that it may be important in the regulation of tissue
metabolism independently of its central effects to modulate
hypothalamic function.
In addition, we should recognize, as with other hormones, that there
may be a pathology associated with excessive levels of leptin. Indeed,
Cohen et al. (77) suggested recently that the hepatic
effects of leptin may contribute to insulin resistance. The
significance of these observations is unclear, as leptin consistently
reduces blood glucose in animal studies, suggesting an improvement in
insulin sensitivity.
The identification of genes that cause obesity in rodents has added
several new pieces to the puzzle of obesity and has provided an impetus
to the search for human obesity genes. Although no human obesitites
have yet been related to mutations in the coding regions of the rodent
obesity genes, alterations in the regulation of these genes is
possible. The heritable component of human obesity has been estimated
to account for 2540% of the variance in body fat, but the number of
genes may be large. Nevertheless, understanding of the rodent obesity
genes and identification of human obesity genes may well prompt the
development of new pharmacotherapies for the treatment of obesity.
Received February 7, 1997.
Revised May 13, 1997.
Accepted June 5, 1997.
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