Leptin is an adipocyte-secreted hormone that has been proposed to
regulate energy homeostasis as well as metabolic, reproductive,
neuroendocrine, and immune functions. In the context of open-label
uncontrolled studies, leptin administration has demonstrated
insulin-sensitizing effects in patients with congenital lipodystrophy
associated with relative leptin deficiency. Leptin administration has
also been shown to decrease central fat mass and improve insulin
sensitivity and fasting insulin and glucose levels in HIV-infected
patients with highly active antiretroviral therapy (HAART)-induced
lipodystrophy, insulin resistance, and leptin deficiency. On the
contrary, the effects of leptin treatment in leptin-replete or
hyperleptinemic obese individuals with glucose intolerance and diabetes
mellitus have been minimal or null, presumably due to leptin tolerance
or resistance that impairs leptin action. Similarly, experimental
evidence suggests a null or a possibly adverse role of leptin treatment
in nonlipodystrophic patients with nonalcoholic fatty liver disease. In
this review, we present a description of leptin biology and signaling;
we summarize leptin’s contribution to glucose metabolism in animals and
humans in vitro, ex vivo, and in vivo; and we provide insights into the
emerging clinical applications and therapeutic uses of leptin in humans
with lipodystrophy and/or diabetes