Peripheral Signals In The Regulation Of Food Intake

The peripheral hormones that regulate food intake include several gastrointestinal, pancreatic, and adipocyte-derived peptides (Table 1.2). Based on extensive studies in rodents and limited human data, these peptides can be classified as having orexigenic (e.g., ghrelin) or anorexigenic (e.g., insulin, peptide YY, glucagon-like polypeptide, cholecystokinin, leptin) effects.

TABLE 1.1

Selected Central Neuropeptides that Modulate of Food Intake

Orexigenic Anorexigenic

Neuropeptide Y alpha-Melanocyte stimulating hormone

Agouti-related protein Corticotropin-releasing hormone

Orexins a Cocaine-amphetamine regulated transcript

Orexin b Serotonin

TABLE 1.2

Selected Peripheral Modulators of Food Intake

Signal

Main Targets

Anorexigenic

Leptin Peptide YY

Pancreatic polypeptide Insulin

Cholecystokinin GLP-1

Hypothalamus Hypothalamus Hypothalamus Hypothalamus

Brain stem/Vagus Local Gl/diverse

Orexigenic

Ghrelin

Hypothalamus

A. Adipocyte-Derived Signals

There is a mature and growing literature on the roles of several adipocyte products (including nonesterified fatty acids, adipocytokines, and leptin) in the regulation of metabolic fuel economy, energy balance, glucoregulation, food intake, and body weight. Products such as nonesterified fatty acids have long been proposed as mediators of obesity-associated insulin resistance and glucose dysregulation (33-35), as discussed elsewhere in this book.

B. Adipocytokines

The adipocytokine TNF-alpha (also known as cachectin, for its association with cachexia or wasting) is a mediator of insulin resistance and is secreted in higher amounts by adipocytes from obese subjects (36-41). Other circulating and adipose-derived proinflammatory cytokines also have been implicated in the pathogenesis of obesity-associated insulin resistance and diabetes (42, 43). On the other hand, adiponectin is secreted in abundant amounts by fat cells from insulin-sensitive persons and is deficient in persons with obesity or insulin resistance (44, 45). Thus, numerous adipose tissue products serve as markers, signals, or modulators of energy balance, fuel economy, intermediary metabolism, glucoregulation, and other metabolic events that intersect with food intake and body-weight homeostatsis. Of these numerous adipose tissue products, leptin is perhaps the best characterized in terms of its role in the regulation of food intake and related mechanisms.

C. Leptin

The positional cloning of the mouse (ob) gene and its human homologue (46) represents a major milestone in obesity research. Two separate mutations of the ob gene result in either a premature stop codon or complete absence of ob mRNA in the ob/ob mouse (46). The resultant absence of a normal ob gene product leads to overfeeding, massive obesity, delayed sexual maturation, and immune defects in ob/ob mice. The human ob or lep gene is transcribed and translated into a secreted protein mainly in white adipose tissue, but activity can also be reported in brown adipose tissue and gastric epithelium (47). Circulating leptin levels are increased by feeding, decreased during fasting or following weight loss, and are altered by a variety of hormonal and physiological factors (48, 49).

A pedigree with severe childhood obesity associated with deletion of a guanine nucleotide in codon 133 of the human lep gene was the first human example of congenital leptin deficiency to be identified (50). A missense lep mutation in codon 105 has also been identified in a Turkish pedigree (51). Three individuals (two female, one male) homozygous for this mutation have the phenotype of hypolep-tinemia, marked hyperphagia, massive obesity, and hypothalamic hypogonadism. Excluding these rare reports, common forms of human obesity do not appear to be caused by discernible lep mutations (52). Treatment with recombinant leptin results in a marked reduction in food intake and profound weight loss in ob/ob mice (53, 54). Leptin therapy also is remarkably effective in correcting obesity in humans with congenital leptin deficiency (55-57).

1. Mechanism of Leptin Action

Leptin exerts its effects through interaction with cognate cell membrane receptors (lep-r) (58). One full-length (isoform-b) and several alternatively spliced forms (a, c, d, e, f) of lep-r have been identified in brain and peripheral tissues (59, 60). Lep-r is a member of the class 1 cytokine receptor family (61). This receptor family mediates gene transcription via activation of the jak-stat pathway (42). The long isoform lep-r (b), expressed in the hypothalamus, mediates the central effects of leptin; the shorter isoforms are truncated in the cytoplasmic domain, but can bind leptin and probably mediate in some of its peripheral action (62).

Leptin-receptor activation results in decreased expression of NPY, thereby inhibiting the powerful orexigenic effects of NPY (63). Leptin's action to suppress food intake is mediated through an elaborate neuronal circuitory that involves suppression of orexigenic signals (NPY, AgRP, MCH, hypocretins 1 and 2/orexins a and b) and activation of anorexigenic (alpha-MSH, MC4, CRH, CART) neuronal pathways (23). Mutations in the lep-r gene result in obesity and leptin resistance in rodents (64, 65) and humans (66). Adipose tissue lep mRNA (67, 68) and circulating leptin (69) levels are elevated in obese subjects, suggesting that obese persons are not responding optimally to the weight-regulating effects of leptin. The basis of this leptin resistance is unclear, but may be related to impaired blood-to-brain leptin delivery

(70) or defects in leptin-receptor signaling, probably mediated by altered expression of the suppressor of the cytokine signaling (socs)-3 gene in leptin-responsive cells

2. Leptin and Insulin Action

Replacement doses of recombinant leptin, administered systemically, normalized plasma glucose and insulin levels in hyperglycemic, hyperinsulinemic ob/ob mice

(54) and leptin-deficient subjects with diabetes and insulin resistance (57). Low doses of leptin administered either i.v. or i.c.v. increased glucose utilization and decreased hepatic glycogen storage in wild-type mice (72). Furthermore, leptin therapy selectively depletes visceral fat stores and stimulates insulin sensitivity in rats (73). These findings indicate that leptin is a naturally occurring insulin sensitizer. Indeed, addition of leptin to cultured human hepatocytes stimulates signaling along the phosphatidyl inositol 3' kinase pathway, one of the mediators of insulin action (74). Reversal of lipotoxicity may be another mechanism for the insulin-sensitizing effects of leptin (75). There is a marked variability in plasma leptin levels (even among persons of comparable adiposity), at least part of which may relate to differences in insulin sensitivity (48, 76).

Basal (fasting) plasma leptin levels are similar in patients with diabetes compared with body mass index (BMI)- and gender-matched nondiabetic subjects (77, 78), but dynamic leptin response to secretagogues is attenuated in patients with diabetes (78, 79) or morbid obesity (80). We have postulated that increased leptin secretory response to food (as well as insulin and glucocorticoids) represents a counterregu-latory attempt (48, 49, 81) to limit hyperphagia and weight gain (Figure 1.1). This adaptation may be of physiological relevance, because fasting abolishes the plasma leptin response to glucocorticoids (82, 83). Theoretically, a defect in leptin secretion could permit hyperphagia, promote weight gain, and aggravate insulin resistance. If impaired leptin secretion is confirmed as a general feature of diabetes, such diabetic dysleptinemia would provide a rationale for evaluation of leptin therapy. Indeed, patients with lipodystrophic diabetes and leptin deficiency respond remarkably well

Regulation Food Intake

FIGURE 1.1 Glucocorticoid-leptin interactions. Glucocorticoids stimulate hypothalamic neuropeptide Y (NPY) expression, which stimulates food intake. Leptin inhibits NPY expression and induces satiety. Local gastrointestinal signals from putative postprandial mediators, such as glucose, insulin, pancreatic polypeptide (PP), Peptide YY (PYY), or other gastrointestinal humors (broken lines) may play a role in satiety, besides the suppressive action of leptin on NPY. Glucocorticoids also stimulate leptin synthesis and secretion, which could counteract the orexigenic effect of NPY (+, stimulation; -, inhibition). (From Dagogo-Jack, S, Diabet. Rev., 7:23-38, 1999, with permission.)

FIGURE 1.1 Glucocorticoid-leptin interactions. Glucocorticoids stimulate hypothalamic neuropeptide Y (NPY) expression, which stimulates food intake. Leptin inhibits NPY expression and induces satiety. Local gastrointestinal signals from putative postprandial mediators, such as glucose, insulin, pancreatic polypeptide (PP), Peptide YY (PYY), or other gastrointestinal humors (broken lines) may play a role in satiety, besides the suppressive action of leptin on NPY. Glucocorticoids also stimulate leptin synthesis and secretion, which could counteract the orexigenic effect of NPY (+, stimulation; -, inhibition). (From Dagogo-Jack, S, Diabet. Rev., 7:23-38, 1999, with permission.)

to leptin replacement, and often achieve independence from insulin and oral hypogly-cemic agents (84). Leptin also potently reduced hepatic steatosis in these patients (84).

3. Exogenous Leptin Therapy for Human Obesity

Administration of low physiological doses of recombinant methionyl-human-leptin (0.01-0.04 mg/kg) produced dramatic results in morbidly obese leptin-deficient patients (55-57). Following daily subcutaneous injection of recombinant leptin, significant weight loss was reported within two weeks. The weight loss was maintained at a rate of approximately 1-2 kg per month, without evidence of tachyphylaxis, throughout the period of treatment. Daily food consumption (and food-seeking behavior) decreased within one week of initiation of leptin replacement, and 95 percent of the total weight loss was accounted for by selective body-fat depletion.

Basal energy expenditure decreased (due to weight loss), but dynamic energy expenditure increased during leptin treatment, the latter being due to increased physical activity (55). Thus, the major mechanisms of weight-loss following leptin replacement are sustained reduction in caloric intake and stimulation of physical activity. The stimulatory effect of recombinant leptin on physical activity was first noted in ob/ob mice (53, 54) and is probably mediated by activation of the sympathetic nervous system (85).

Similar but less dramatic benefits on weight reduction were observed following leptin augmentation in a cohort of 54 lean and 73 obese men and women with normal leptin genotype (as indicated by baseline serum leptin levels > 10 ng/ml) (86). The subjects were randomized to daily self-injection with placebo or different doses (0.01, 0.03, 0.10, or 0.30 mg/kg) of recombinant methionyl human leptin. The mean weight changes at 24 weeks ranged from -0.7 ±5.4 kg for the 0.01 mg/kg dose to -7.1 ± 8.5 kg for the 0.3 mg/kg dose.

As in patients with congenital leptin deficiency, loss of fat mass accounted for most of the weight loss following leptin treatment. However, there was a marked heterogeneity in the responses to recombinant leptin among subjects with normal leptin gene. Thus, leptin-deficient patients are exquisitely more sensitive to leptin therapy than patients with common obesity. Nonetheless, augmentation of circulating leptin levels induces variable but significant weight loss in leptin-replete obese subjects. This suggests that leptin resistance may be overcome by exogenous supplementation, similar to the experience with insulin therapy in type 2 diabetes. The currently known metabolic and behavioral effects of leptin are summarized in Table 1.3.

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