Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance

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Abstract

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, α-MSH, NT, and CRH. In addition to the conventional JAK2–STAT3 pathway, it has become evident that PI3K–PDE3B–cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2–STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2–STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K–PDE3B–cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.

Introduction

Obesity is one of the major health hazards in humans, particularly in western society. Remarkably in most humans body weight is maintained in stable condition. Positive energy balance as a result of less energy expenditure as compared to energy intake leads to the storage of energy in the form of fat. Although cumulative evidence gathered mostly over the last two decades suggest that body weight is regulated by a complex circuitry involving both central and peripheral factors working primarily in the brain, particularly in the hypothalamus; the idea that some factors originating in the periphery relay the status of body fat stores to the brain has originated from the days of Kennedy, almost 50 years ago [160]. In 1953, Kennedy hypothesized that the hypothalamus senses some peripheral factors that provide the information about the body fat stores, and the hypothalamus would then transduce this information to change food intake to compensate for changes in body fat content. Subsequent studies using parabiosis experiments in rats, Hervey showed that when one of the parabiotic partner made obese by a lesion in the ventromedial hypothalamus, the intact partner became anorexic and lean [132]. These results suggested that some blood-borne factor produced by the increased fat mass acted to induce satiety in the intact partner. Furthermore, its lack of effect in the lesioned animals also suggested that the action of this factor(s) in the hypothalamus is essential for the maintenance of normal body weight.

In the 1970s, Douglas Coleman’s finding that recessive mutations in the mouse ob and db genes resulted in obesity and diabetes [60], provided a critical clue about this peripheral factor that regulates body weight. Using parabiosis experiments with ob/ob and db/db mice, Coleman concluded that the blood-borne factor was encoded in the ob gene and the receptor for this factor was encoded in the db gene [60]. However, the product of the ob gene was not discovered until 1994, when Jeffrey Friedman’s team, using positional cloning, identified and characterized the ob gene and its product, leptin (from the Greek leptos=thin). They identified leptin as a 16 kDa protein produced primarily in white adipose tissue [367]. Although subsequent studies have demonstrated that leptin is produced in small amount in other tissues such as the placenta [207], stomach [10], pituitary [148], [251] and the hypothalamus [221], the role of this extra adipose tissue-derived leptin is not clearly understood. After the discovery of leptin receptor by Tartaglia’s group in 1995 [327], physiological role of leptin has been the subject of intensive investigation and has been appreciated not only in regulation of body weight, but also in a variety of physiological functions such as reproduction, bone formation, and cardiovascular systems, etc.

As expected, cumulative evidence suggests that leptin signals nutritional status to key regulatory centers in the hypothalamus [92], [153], [294], [357] and it has emerged as an important signal regulating body weight homeostasis and energy balance [42], [102], [124], [243], [347]. Mutations that result in leptin deficiency are associated with massive obesity in humans as well as rodents [102], [220]. Central or peripheral administration of leptin decreases food intake and body weight in a variety of animals, including rats, mice, and monkeys [102], [267], [326]. In normal mice, leptin administration reduces weight and corrects diet-induced obesity [42], [124], [243]. Leptin treatment has been shown to normalize feeding, reduce body weight and initiate puberty in a leptin deficient girl [99]. It is well established that leptin plays an important role in the long-term maintenance of body weight. In addition, the evidence that leptin mRNA levels are decreased following food deprivation and return to normal after refeeding [200], [277]; and a rapid decrease of plasma leptin levels after a short-term fast followed by a rapid recovery after refeeding in man [34], [65], [165], [166]; the existence of diurnal rhythm of plasma leptin entrained to meal timing in man [288]; and the evidence that circulating leptin levels increase within 4 h of natural feeding in rat [359] suggest that leptin may be involved in daily food intake and short-term regulation of body weight. Paradoxically, in the majority of cases, human obesity cannot be attributed to defects in leptin or its receptor [58], [65], [66], [115], [209], [220], and serum leptin levels are significantly higher in obese humans relative to non-obese humans [43], [64], [65], [129], [193], [202], [292], and leptin administration shows very limited effects in obese people [134], suggesting a state of leptin-resistant in obese individuals.

In addition to its role in normal regulation of food intake and body weight, leptin treatment corrects obesity related disorders, including hyperglycemia, hyperinsulinemia, and sterility in ob/ob mice [14], [42], [49], [124], [243], and blunts the starvation-induced abnormalities in the gonadal, adrenal, and thyroid axes in lean mice [1]. Furthermore, leptin’s role in reproduction is becoming increasingly apparent. For examples, leptin has been shown to accelerate puberty in mice [2], [50]. Also transgenic mice over expressing leptin display accelerated puberty [364]. Leptin reverses the suppression of sexual maturation induced by fasting in rodents [54], and the effects of fasting on pulsatile secretion of luteinizing hormone [226]. Leptin also stimulates gonadotropin-releasing hormone secretion in vivo [346]. However, leptin’s role in primate puberty appears to be permissive, because there is no evidence of increased circulating leptin before the onset of puberty [247], [248], [249], [250], [274]. In a recent study, we have shown that continuous peripheral infusion of leptin failed to induce gonadotropin-releasing hormone secretion in pre-pubertal monkeys [15]. Other central action of leptin includes regulation of bone formation [83], [157] and angiogenesis [36], [309].

In most part, leptin’s role in various physiological functions, including food intake and body weight regulation, reproduction, bone formation, and angiogenesis appears to be mediated through the hypothalamus. In this review, I will however focus on the mechanisms of leptin action in the hypothalamus with regard to food intake and body weight regulation, obesity, and leptin resistance.

Section snippets

Hypothalamus as the major site of leptin action

From the lesion studies by Hetherington and Ranson [133], and by Anand and Brobeck [7], it has been established that lesion in the ventromedial hypothalamus causes hyperphagia and obesity, and lesion in the lateral hypothalamus causes aphagia and even death by starvation. These studies clearly suggested the hypothalamus as the primary center for regulation of food intake and body weight with the ventromedial nucleus as the “satiety center” and the lateral hypothalamus as the “feeding center.”

Neuronal targets of leptin action

The hypothalamus produces an array of orexigenic and anorectic peptides that constitute a major part of the neural circuitry regulating ingestive behavior and body weight [153], [272], [294], [357]. Evidence accumulated during the last several years suggest that leptin’s effects are mediated through the activity of several neuropeptidergic neurons of both orexigenic and anorectic in nature in specific site of the hypothalamus. Leptin sensitive neurons include those that produce neuropeptide Y

Leptin receptor

Leptin receptor is a member of the class I cytokine receptor family [327], [328]. Of the several alternative spliced isoforms (a–f, as well as others) of the leptin receptor (Ob-R), the Ob-Rb, which has the longest cytoplasmic domain (302 amino acids), is expressed in high levels in the hypothalamus [51], [182], [214], [328], and has been clearly demonstrated to be capable of initiating signal transduction [51], [102], [107], [182], [213], [335]. Other forms of the Ob-R appear to have no

Mechanisms underlying the central Leptin resistance

Because human obesity, in the majority of cases, cannot be attributed to defects in leptin or its receptor [54], [64], [65], [115], [209], and because obese humans are hyperleptinimic [43], [57], [64], [129], [193], [202], [292], it is suggested that obese individuals are, in general, leptin-resistant [57], [202]. Obese humans, and mice made obese by dietary manipulation, have elevated levels of circulating leptin but maintain a normal food intake [57], [125], [202]. Thus, it is likely that an

Summary and conclusion

In this review, available data on the mechanisms of leptin signaling in the hypothalamus in regulation of food intake and body weight in normal condition and that during the development of leptin resistance in DIO, ageing-associated obesity and following continuous central leptin infusion have been summarized. It appears that in addition to the conventional JAK2–STAT3 pathway, an alternative insulin-like signaling pathway, involving activation of PI3K and PDE3B and reduction in cAMP levels,

Acknowledgments

The author is indebted to Drs. Allan Zhao and Robert O’Doherty for their collaboration in some studies. This work was supported by US Public Health Service Grants DK 54484 and DK 61499.

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