Metabolic Abnormalities and the Role of Leptin in Human Obesity
F-Xavier Pi-Sunyer and
Blandine Laferrère
Obesity Research Center
Columbia University College of Physicians and Surgeons
New York, New York 10025
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Introduction
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OBESITY is the most common
nutritional disease in the United States, affecting about one fourth of
the population (1). It leads to increased morbidity and mortality and
is associated with insulin resistance, dyslipidemia, diabetes mellitus,
hypertension, and cardiovascular disease (2). The morbidity and
mortality is increased in persons with abdominal or upper body fat
distribution independent of the obesity itself (2, 3, 4, 5, 6, 7, 8).
The treatment of obesity, even using comprehensive multidisciplinary
approaches, including drugs, is very difficult, with patients generally
losing 10 to 15% of their baseline obese body weight at the most,
plateauing after 46 months of weight loss effort, then beginning to
regain. A better understanding of the etiology and pathophysiology of
obesity is necessary in order to develop more effective prevention and
treatment measures.
The discovery of leptin (9) and its receptor (10) opened a new era in
obesity research and brought some hope to the obesity community.
Although leptin appears to be a key protein in energy balance in
rodents, its physiological role in humans is not fully known, and the
mechanism by which its secretion is regulated in humans is not clear.
Thus far, the role of leptin in metabolic abnormalities associated with
human obesity has not been studied extensively, although some data
suggest that hyperleptinemia could relate to the metabolic
syndrome.
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Background
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Leptin, encoded by the ob gene (9) is a 167-amino acid
protein produced and released exclusively by adipose cells (for review
see 11). It circulates in the blood mostly bound to a family of
proteins (12, 13). Crossing the blood-brain barrier (14) into the
central nervous system, it acts at the level of the hypothalamus by
binding to its receptor and activating secondary signals that inhibit
food intake and increase energy expenditure (15). When leptin is given
to leptin deficient ob/ob mice, which have a mutation in the ob gene
and do not make leptin, the obesity and metabolic abnormalities present
in these mice are corrected. An increase in energy expenditure, a
decrease in food intake, and a decrease in plasma glucose, insulin, and
cortisol levels (16, 17, 18) occur. Leptin injected into wild-type mice
also leads to weight loss (15, 16, 17, 18, 19, 20) and prevents the decrease in energy
expenditure usually seen with weight loss (18). The db/db mouse and the
fa/fa rat do not respond to leptin because they have an abnormal
leptin receptor (21). Hypothalamic brain lesions cause leptin
ineffectiveness, supporting the thesis that leptin acts in the
hypothalamus to regulate food intake and thermogenesis (22).
The leptin receptor was cloned from mouse choroid plexus (10) and has
been found in the cytokine family of receptors. At least five
alternatively spliced forms of the receptor have been found (23). One
of these, Ob-Rb, is heavily expressed in the hypothalamus and less so
elsewhere (23, 24). This receptor has been found to be abnormal in
db/db mice (23, 25). How the leptin receptor is activated and what its
subsequent signaling is have not yet been elucidated. But it is known
that the arcuate, the ventromedial, and lateral hypothalamic nuclei are
principal brain sites for Ob-Rb expression (26, 27, 28).
The receptor may respond differently to the high levels of leptin
secreted by a high fat mass and the low levels of leptin produced by
starvation. High leptin seems to inhibit neuropeptide Y messenger RNA
(mRNA) expression and thus shut off activity of this powerful
stimulator of food intake (29). It has also been shown that inhibition
of binding of MSH to the melanocortin receptor (MC4R) may be involved.
With hypocaloric dieting, leptin levels fall (30). This results in
highly expressed neuropeptide Y in the hypothalamus, leading to
increased food intake. Corticotropin releasing hormone (CRH) may also
be involved (31).
None of the normalizing metabolic effects that occur with the provision
of leptin to ob/ob mice have been shown in obese humans so far.
However, a long-acting modified ob protein caused a dose-dependent
suppression of spontaneous food intake in rhesus monkeys (32). The
pharmaceutical company Amgen, in a press release, has
stated that injected leptin had some effect on lowering body weight in
obese volunteers but did not give quantitative details about the weight
loss or about other metabolic effects (33).
In humans, leptin is secreted into the circulation in a pulsatile mode
(32 pulses in 24 h, with each pulse duration being about 33 min,
an interpeak interval of 43 min and a pulse height showing a 132%
increase over the preceding baseline). It follows a circadian rhythm,
peaking at night (34). Serum leptin levels are higher in women than in
men. The regulation of serum leptin levels in humans is not well
understood. The levels increase as body fat mass increases (35, 36).
Obese individuals have very high levels, so they must be resistant to
the action of leptin on inhibition of food intake and increase in
energy expenditure. To see if obesity could be related to an
abnormality of leptin production, human ob gene mutations have been
sought. Thus far, only two mutations have been found; one is a mutation
in the coding sequence of the leptin gene in two members of a family in
the United Kingdom (37), and the other is a mutation of the
leptin-receptor gene in members of a family in France (38). Many other
obese patients have been studied with no such success (39). Thus, human
obesity is not due primarily to a lack of production of leptin or the
production of an abnormal leptin. Also, there is no evidence that
obesity in humans is due to the presence of abnormal leptin receptors
(40). Thus, if there is a defect in the leptin pathway in human
obesity, it could be due either to an inability of the leptin to
appropriately enter the central nervous system or to a
post-receptor defect in the subsequent leptin signaling cascade. It is
likely that the transmission of the signal will involve many other
molecules in the central nervous system. Particularly prominent studies
have focused on neuropeptide Y and the proopiomelanocortin (POMC) (MSH
precursor) pathway (41). Leptin could inhibit NPY, a peptide that is
stimulatory to feeding, or it could enhance the binding of MSH to the
MC4 receptor, thereby inhibiting food intake (42). But other
neurotransmitters may also be involved.
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Regulation of leptin production
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It is clear, however, that other regulatory factors besides fat
mass are involved in the secretion of leptin. At each level of fat
mass, leptin levels are quite variable from one individual to another
(43). Also, serum leptin levels can change independently of fat mass,
for example during fasting (44). At least two hormones have been
implicated in modulating serum leptin levels: insulin and
glucocorticoids. Both of these hormones are also implicated in the
"metabolic syndrome" (4). Low leptin levels have been reported to
predict weight gain in Pima Indians (45), suggesting that chronic
under-secretion could be a cause of obesity.
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Energy intake
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Plasma levels of leptin change with a change in energy intake.
Fasting induces a rapid decrease of leptin levels, but this can be
prevented if glucose and insulin are maintained at basal levels (44).
Administration of glucose after a prolonged fast induces an acute
increase in serum leptin levels in humans (46). Daytime feeding does
not produce any acute change of leptin in humans but may be responsible
for the nocturnal leptin surge that is prevented by a prolonged fast
(44, 46). Leptin increases between 5 and 10 h after massive
short-term overfeeding (47). The increase in leptin levels from nadir
to peak is related to insulin excursions in response to meals (48), and
shifting meal time by 6.5 h without changing the light and sleep
cycles will shift plasma leptin rhythm by 57 hours (49).
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Fat distribution and leptin
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Although the metabolic disturbances linked to obesity relate
closely to fat distribution, leptin secretion does not appear to be
affected by abdominal obesity. In human obesity, serum leptin levels
are correlated best to fat mass and to percent body fat, with a higher
expression of the ob gene in adipose tissue of severely obese compared
with lean individuals (43). This ob gene expression is related to total
body fatness (50) and to subcutaneous adiposity (51), but not to
intra-abdominal fat (52, 53).
The level of expression of leptin mRNA varies from one adipose tissue
depot to another, with some differences among reports. While one group
of investigators has found increased expression of ob mRNA in omental
fat cells from massively obese humans (54), most have found a higher
level of expression in subcutaneous as compared with
intra-abdominal adipose tissue (52, 53).
Further investigation is needed of leptin secretion in relation to fat
distribution and the differing biological functions of the subcutaneous
and intra-abdominal depots in this regard. In addition, two problems
remain. First, many of the metabolic abnormalities linked to obesity
are related to body fat distribution, especially intra-abdominal fat.
Yet except for one report (55), other studies have not shown any
correlation between intra-abdominal fat and leptin levels. According to
Lonnqvist (56), only 40% of leptin variability can be explained by fat
mass. The other factors responsible for the variability of leptin at
each level of fat mass are unknown.
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Insulin
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Animal data have documented that ob mRNA is up- or down-regulated
by a rise or fall in insulin levels. Longitudinal study of the
development of obesity in fa/fa rats shows a parallel increase in white
adipose tissue ob mRNA levels and plasma insulin levels. However, in
adult obese rats, ob mRNA does not respond to insulin (57).
In humans, there is some evidence suggesting a potential role for
insulin in leptin regulation. Serum leptin correlates with fasting
insulin levels (50, 58, 59), and a few studies have found a positive
relationship between insulin resistance and hyperleptinemia (60, 61).
Insulin has a stimulatory effect on serum leptin after 6 h at high
physiological concentration (62) and at supraphysiological
concentration (63) or when given for a prolonged period of time during
an hyperinsulinemic hyperglycemic clamp (64). A recent study showed
that physiological levels of insulinemia can increase plasma leptin in
a dose-dependent manner (65). One study has reported that the increase
in leptin levels from nadir to peak is related to insulin excursions in
response to meals (48).
However, in humans, most studies have been unable to detect an effect
of insulin on leptin, and the increase in plasma insulin secondary to
feeding does not increase serum leptin (58, 59, 66, 67, 68). The presence
of diabetes does not affect leptin (60), and diabetes does not alter
the relationship of leptin and body mass index. Leptin levels are not
different between diabetic and nondiabetic subjects (69).
Because ob/ob mice develop insulin resistance in the absence of leptin,
it is unlikely that leptin is a major factor responsible for the
induction of insulin resistance in obesity. Nevertheless, some recent
reports indicate that leptin could be a mechanism by which increased
adiposity increases insulin resistance (70). Leptin antagonizes insulin
signaling in hepatoma cells, decreasing insulin-induced tyrosine
phosphorylation of IRS-1, a step leading to many of the metabolic
actions of insulin (glucose transport, kinase pathway). Leptin also
antagonizes the ability of insulin to decrease mRNA encoding PEPCK, the
enzyme catalyzing the rate-limiting step in gluconeogenesis. However,
many unanswered questions remain about how leptin might affect insulin
action (71). There is no effect of in vitro leptin on
glucose transport in muscle or adipocytes (72).
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Glucocorticoids
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The permissive role of glucocorticoid hormones in the genesis and
maintenance of obesity is well demonstrated in animal models (73, 74).
Human obesity is associated with a relative hypercortisolism,
especially in central or upper body obesity (75, 76, 77, 78, 79, 80). The
hypercortisolism of Cushings disease is associated with obesity. Both
of these hypercortisolemic states are associated with hyperleptinemia
(81). Also, oral administration of glucocorticoid has been shown to
increase human leptin plasma levels (82, 83, 84, 85, 86) as well as leptin mRNA in
adipose tissue in vivo (85). It has recently been shown that
glucocorticoids inhibit the action of central leptin (87) in rodents.
It is possible, therefore, that the relative hypercortisolism of
obesity could generate glucocorticoid-induced leptin resistance and
play a role in the pathogenesis of obesity (87).
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Hypertension
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Some animal data suggest that leptin may have actions influencing
the autonomic cardiovascular system, with sympathoexcitatory action.
However, acute leptin administration does not increase arterial blood
pressure or heart rate (88). In humans, leptin levels show a positive
correlation with mean arterial, systolic, and diastolic blood pressure
in men but not in women (60) and a positive correlation with mean blood
pressure (89). Potential mechanisms of action, if there is a direct
causal effect, need to be explored.
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Dyslipidemia
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The relationship between leptin and circulating lipid particles
does not seem strong. One study found no relation between leptin and
lipids or lipoproteins (90). A correlation was found between leptin,
triglycerides, HDL-cholesterol (89) or HDL-C, and apo B (91), but the
association lost its significance after adjustment for fat mass in both
studies. A positive association has been reported between leptin and
two measures of HDL, HDL-TG and HDL-apo A-1, but not with HDL-C
(92).
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Energy expenditure
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In contrast to rodents, no relationship has been found between
leptin and energy expenditure in humans (60). This lack of correlation
between changes in leptin and changes in energy expenditure suggest
that leptin is not the primary signal that mediates the changes of
energy expenditure that accompany altered body weight in humans (36).
Leptin has had an effect on the expression of UCP3 mRNA in brown
adipose tissue and muscle (93). Future research will bring new insight
on the role of leptin in energy balance.
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Summary
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While the hyperleptinemia of obesity is likely to be associated
with the metabolic complications of obesity/hyperinsulinemia/insulin
resistance, it is not associated with diabetes, with the relative
hypercortisolism of upper body obesity, with hypertension in women, (it
is in men), or with dyslipidemia. Overall, the correlations between
leptin and the metabolic diseases associated with obesity are weak. The
equivocal results of an association of leptin with components of the
metabolic syndrome make it unlikely that leptin affects these directly.
(On the other hand, these correlations, when found, preclude any causal
relationship between leptin and metabolic diseases.) There are
experimental data showing a definite role for insulin and
glucocorticoids in the regulation of leptin, and of leptin in the
regulation of insulin. More data are required on the effects of leptin,
but it is likely that leptin will not be a major link between obesity
and the metabolic syndrome. Certainly, however, when leptin is
available for clinical use, its effect on different aspects of the
metabolic syndrome will be worth studying.
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