Leptin in human physiology and pathophysiology

Abstract

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.

Fig. 1.

States of energy excess are associated with hyperleptinemia, but the hypothalamus is resistant or tolerant to the effects of increased leptin (dashed line). Energy deficiency results in hypoleptinemia. As a result, a complex neural circuit comprising orexigenic and anorexigenic signals is activated to increase food intake (220). In response to decreased leptin levels, there is increased expression of orexigenic neuropeptides AgRP and NPY in the ARC (59) and orexin and MCH in the LHA. Furthermore, there is decreased expression of anorexigenic neuropeptides POMC and CART in the ARC (59) and BDNF in the VMH. In addition to neurons that project from the LHA to the VTA, leptin also acts at the VTA of the mesolimbic dopamine system to regulate motivation for and reward of feeding. Leptin activation of the NTS of the brain stem also contributes to satiety. In addition, leptin has direct and/or downstream effects on the PVN and PO that are important for neuroendocrine responses to energy deprivation, including reducing reproductive and thyroid hormones. For the sake of comparison, leptin acts only indirectly on the GnRH-secreting neurons in the hypothalamus, and it can act directly and indirectly on TRH-secreting neurons (220). The effect of leptin on cortisol levels during starvation differs in mice and humans. Unlike in normal mice (102), leptin administration does not reverse the elevated adrenocorticotropin levels associated with starvation in humans (37). The mechanism of leptin's effect on the growth hormone axis is unclear. Dashed arrows indicate how leptin directly and indirectly influences metabolism and insulin resistance. AgRP, agouti-related protein; ARC, arcuate nucleus; BDNF, brain-derived neurotropic factor; CART, cocaine- and amphetamine-regulated transcript; CRH, corticotropin-releasing hormone; GnRH, gonadotropin-releasing hormone; IGF-I, insulin-like growth factor I; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; PO, preoptic area; POMC, proopiomelanocortin; PVN, paraventricular nucleus; TRH, thyrotropin-releasing hormone; VMH, ventromedial hypothalamic nucleus; VTA, ventral tegmental area.