Leptin, a 16-kDa
protein secreted from white adipocytes, has been implicated in the regulation of food intake, energy expenditure, and whole-body energy balance in rodents and humans. The gene encoding
leptin was identified by positional cloning and is the mutation leading to the profound obese phenotype of the ob/ob mouse. Exogenous administration of
leptin to ob/ob mice leads to a significant improvement in reproductive and endocrine status as well as reduced food intake and
weight loss. The expression and secretion of
leptin is highly correlated with body fat mass and adipocyte size.
Cortisol and
insulin are potent stimulators of
leptin expression, and expression is attenuated by
beta-adrenergic agonists, cAMP, and
thiazolidinediones. The role of other
hormones and
growth factors in the regulation of
leptin expression and secretion is emerging.
Leptin circulates specifically bound to
proteins in serum, which may regulate its half-life and
biological activity.
Isoforms of the
leptin receptor, members of the
interleukin-6 cytokine family of receptors, are found in multiple tissues, including the brain. Many of
leptin's effects on food intake and energy expenditure are thought to be mediated centrally via
neurotransmitters such as
neuropeptide Y. Multiple peripheral effects of
leptin have also been recently described, including the regulation of insulin secretion by pancreatic beta cells and regulation of
insulin action and energy metabolism in adipocytes and skeletal muscle.
Leptin is thought to be a metabolic signal that regulates nutritional status effects on reproductive function.
Leptin also plays a major role in hematopoeisis and in the
anorexia accompanying an acute
cytokine challenge. The profound effects of
leptin on regulating body energy balance make it a prime candidate for
drug therapies for humans and animals.