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 HIVrelated 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. adipokines; adipose tissue; leptin resistance; leptin deficiency; hypoleptinemia STUDIES OF GENETICALLY OBESE MICE serendipitously found in the Jackson Laboratories revealed that their phenotypes derive from homozygous mutations of either the obese (ob) or diabetic (db) genes that result in obesity and insulin resistance or diabetes as well as endocrine and immune dysfunction (53, 54,115,117,183,261). The gene mutation in the ob/ob mouse results in a complete deficiency of or a truncated and biologically inactive ob gene product (287); the latter subsequently was given the name leptin (95), from the Greek word "leptos" (meaning "thin"), because when this protein was given to the obese ob/ob mice they lost significant amounts of body weight. It was then recognized that the db gene codes for the leptin receptor (140). Consequently, exogenously administered leptin reduces body weight and resolves the metabolic, endocrine, and immune disturbances in ob/ob mice but has no effects in db/db mice (100, 111, 28...

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints

“…Leptin also plays important roles on lipid and glucose metabolism, the gonadal, adrenal, somatotropic and thyroid axes, sympathetic tone, biomarkers of cardiovascular disease, immunity, inflammation, and brain structure and function (5,6,(32)(33)(34). In humans, leptin deficiency is observed in cases of hypothalamic amenorrhea, anorexia nervosa, genetic deficiency due to mutations in the leptin gene, and LS.…”

Adipose tissue, obesity and adipokines: role in cancer promotion

“…The long form ObRb is a single transmembrane protein that is expressed throughout the central nervous system (CNS), but its function is most relevant in the hypothalamus [17]. Of the short forms identified, ObRa and ObRc are active in most tissues throughout the body [17].…”

“…The long form ObRb is a single transmembrane protein that is expressed throughout the central nervous system (CNS), but its function is most relevant in the hypothalamus [17]. Of the short forms identified, ObRa and ObRc are active in most tissues throughout the body [17]. Leptin and its long form receptor act in the fed state on appetite and metabolism through stimulation of proopiomelanocortin (POMC)/ cocaine and amphetamine-regulated transcript (CART) or suppression of neuropeptide Y/AgRP [18], these alterations ultimately result in an increase of α-melanocytestimulating hormone.…”

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“…Leptin, a product of the obesity (ob) gene secreted mainly from adipose tissue, regulates various reproductive, neuroendocrine, immune, and metabolic functions [39].…”