Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals

Abstract

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.

Figure 1.

Intracellular signaling pathways recruited by leptin. The full-length isoform, ObRb, contains intracellular motifs required for activation of the JAK2/STAT3 signal transduction pathway. ObRb contains 4 important tyrosine residues that provide docking sites for signaling proteins with SHP2 domains. Activation of JAK2 occurs by transphosphorylation and subsequent phosphorylation of tyrosine residues in the cytoplasmic region of the receptor. Phosphorylation of STAT3 leads to their dissociation from the receptor and the formation of active dimers, which translocate to the nucleus to regulate gene expression, binding to the promoter regions of target genes. The leptin-regulated STAT3 signaling may interact with STAT5, which may regulate STAT3-dependent gene expression. The ability of SOCS3 to inhibit leptin-stimulated phosphorylation of JAK2 provides a negative-feedback mechanism on the leptin signaling system. The ERK members of the MAPK family are components of the well-defined AMPK-Ras/Raf/MAPK signaling cascade and have become activated by leptin. Leptin activates PI3K signaling via IRS-1 and/or IRS-2 phosphorylation. The PTP1B inhibits leptin-stimulated phosphorylation of IRS-1/2 and/or JAK2. Leptin administration results further in Akt/mTOR phosphorylation followed by regulation of FOXO and S6 expression.

Figure 2.

The effect of recombinant leptin administration in leptin deficiency or leptin excess states. Recombinant leptin may have beneficial effects when administered in leptin-deficiency states, but minimal benefit and/or mostly adverse effects when administered in leptin-excess states. In congenital leptin deficiency and congenital lipodystrophy, recombinant leptin administration results in metabolic and neuroendocrine improvement; improvement seems to be more limited in HIV-associated acquired lipodystrophy syndrome, in which coadministration of pioglitazone, which acts by up-regulating endogenous adiponectin, may increase the metabolic benefit. On the other hand, recombinant leptin administration in type 2 diabetes mellitus and/or common obesity and normal or high circulating leptin levels has minimal or null metabolic effect, whereas it increases circulating leptin-binding protein and antileptin antibodies. Coadministration of pramlintide, an amylin analog targeting leptin tolerance, or leptin administration after weight loss, when leptin's declined levels increase appetite, might prove to be of some benefit. Similarly, leptin up-regulation in animal models with NAFLD resulted in increased inflammation and fibrosis, thereby progression to NASH. Data on adverse effects, including renal impairrment or T-cell lymphoma, observed mainly in a minority of leptin-deficiency patients, are currently inconclusive. Data on carcinogenic effect of leptin, mainly observed in hyperleptinemic individuals, are also inconclusive but may be tissue-specific; however, hypoleptinemia itself may be also implicated in carcinogenesis in hypoleptinemic individuals, and thus this aspect of leptin physiology remains to be fully elucidated. *, Only experimental data.