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Leptin and Clinical Medicine: A New Piece in the Puzzle of Obesity

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.

	Introduction

Top Introduction I. The background: the... II. The discovery of... III. The biology of... IV. Regulation of leptin... V. Physiological effects of... References

 
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.

	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.

	II. The discovery of leptin

Top Introduction I. The background: the... II. The discovery of... III. The biology of... IV. Regulation of leptin... V. Physiological effects of... References

 
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.

	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.

View larger version (21K): [in this window] [in a new window]   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.

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 glutamineproline 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.

	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 2–4 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 12–14 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 12–14 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.

	V. Physiological effects of leptin: a model for obesity

Top Introduction I. The background: the... II. The discovery of... III. The biology of... IV. Regulation of leptin... V. Physiological effects of... References

 
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.

View larger version (15K): [in this window] [in a new window]   Figure 2. Model of hypothalamic effects of leptin and other experimental maneuvers that produce obesity.

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 25–40% 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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