LIPID METABOLISM Leptin, and Lipid Oxidation Through AMPK

One of the serious effects of diabetes is the excess storage of fat not only in adipocytes, but also in other tissues (termed lipotoxicity). Type II diabetes patients are insensitive to treatment with insulin, and it is hypothesized that insulin resistance results from an excessive accumulation of lipids in nonadipocytes such that the lipids interfere with the action of insulin on those cells. The hormone leptin, which can regulate food intake and neuroendocrine activity, now appears to regulate lipid oxidation in the mitochondria of nonadipocytes. Minokoshi et al. found that leptin injection in mouse muscle in vivo resulted in increased intracellular concentrations of adenosine 5'-monophosphate (AMP), and activated the 2 adenosine 5'-monophosphate-activated kinase (AMPK)--a protein that regulates cellular energy metabolism--in mouse muscle. However, not only did leptin activate 2 AMPK immediately in muscle, it also indirectly caused long-term activation of AMPK (for several hours) as mediated through the hypothalamus. The hypothalamus-dependent activation of AMPK was mediated by the -adrenergic pathway. Leptin-mediated activation of AMPK led to the phosphorylation (and inactivation) of acetyl coenzyme A carboxylase (ACC), an enzyme that inhibits the import of lipids into and the oxidation of lipids in the mitochondria, and led to increased lipid oxidation in vivo. Leptin failed to increase phosphorylation of ACC in cells that overexpressed a dominant-negative form of AMPK, suggesting that leptin acts through AMPK to inhibit ACC and increase lipid oxidation. Thus, designing therapeutic drugs that target the leptin-AMPK pathway may prove useful for some diabetic patients.

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