Leptin in human physiology and therapeutics

Abstract

Leptin regulates energy homeostasis and reproductive, neuroendocrine, immune, and metabolic functions. In this review, we describe the role of leptin in human physiology and review evidence from recent "proof of concept" clinical trials using recombinant human leptin in subjects with congenital leptin deficiency, hypoleptinemia associated with energy-deficient states, and hyperleptinemia associated with garden-variety obesity. Since most obese individuals are largely leptin-tolerant or -resistant, therapeutic uses of leptin are currently limited to patients with complete or partial leptin deficiency, including hypothalamic amenorrhea and lipoatrophy. Leptin administration in these energy-deficient states may help restore associated neuroendocrine, metabolic, and immune function and bone metabolism. Leptin treatment is currently available for individuals with congenital leptin deficiency and congenital lipoatrophy. The long-term efficacy and safety of leptin treatment in hypothalamic amenorrhea and acquired lipoatrophy are currently under investigation. Whether combination therapy with leptin and potential leptin sensitizers will prove effective in the treatment of garden-variety obesity and whether leptin may have a role in weight loss maintenance is being greatly anticipated.

Figure 1

Leptin's action in the brain during states of energy excess and energy deficiency. During states of leptin and energy excess, leptin's access to the hypothalamus and other brain areas is impaired and leptin's action is blunted. In states of leptin and energy deficiency, neuropeptides that are normally inhibited by leptin are elevated (+) and neuropeptides stimulated by leptin are suppressed (-). A change in the concentrations of these neuropeptides leads to alterations in neuroendocrine function and energy homeostasis. Alterations in leptin levels may also affect the hedonic aspects of feeding behavior. The role of leptin in the brain is discussed in greater detail in the text. Adapted from references [31; 24; 18]. Abbreviations: ACTH, adrenocorticotropic hormone; AgRP, agouti-related peptide; ARC, arcuate nucleus; BDNF, brain-derived neurotrophic factor; CART, cocaine- and amphetamine- regulated transcript; CCK, cholecystokinin; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GLP-1, glucagon-like peptide 1; GnRH, gonadotropin-releasing hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; NST, nucleus of the solitary tract; PO, preoptic area; POMC, proopiomelanocortin; PVN, paraventricular nucleus; SN, substantia nigra; TRH, thyrotropin-releasing hormone; TSH, thyrotropin-stimulating hormone; VMH, ventromedial hypothalamus; VTA, ventral tegmental area.