Molecular mechanism of leptin-induced increase in glucose and lipid metabolism

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We have demonstrated that transgenic overexpression of leptin can rescue the insulin-resistant diabetes and hepatic steatosis in a mouse model of lipoatrophic diabetes (A-ZIPTg mice), suggesting the potential usefulness of leptin as an antidiabetic agent. However, the molecular mechanisms underlying the leptin-induced increase in glucose and lipid metabolism is not clear. In this study, we examined the effect of sympathetic blockade on the leptin-induced increase in glucose metabolism in LepTg/A-ZIPTg mice obtained through genetic cross between transgenic skinny mice overexpressing letpin (LepTg) and A-ZIPTg mice. We also characterized the profile of hepatic gene expression in LepTg/A-ZIPTg mice using cDNA microarray analysis. Intraperitoenal injection of α-adrenoceptor blocker (bunazasin) did not affect the improved glucose metabolism in LepTg/A-ZIPTg mice. However, β-adrenoceptor blocker (propranolol) did aggravate the glucose metabolism in the animals. Those observations suggest the involvement of β-adrenoceptor activation in the lepitn's antidiabetic effect.Microarray analysis showed the upregulation in mRNAs encoding genes involved in glycolysis, respiratory chain, and insulin signal transduction in the liver from LepTg. By contrast, the expression of a wide variety of genes involved in fatty acid synthesis and oxidation programs was increased in A-ZIPTg mice. However, transgenic overexpression of leptin restored the expression of a large subset of genes, which are altered in A-ZIPTg mice, in LepTg/A-ZIPTg mice. Exogenous administration of leptin that elevates plasma leptin concentrations to those of LepTg/A-ZIPTg mice also resulted in the normalization of hepatic expressions of these genes in A-ZIPTg mice. These observations suggest that leptin alters hepatic gene expression in lipoatrophic diabetes, which leads to a change in energy metabolism from glucose utilization and fatty acid synthesis to fatty acid oxidation and increased respiration.