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Site and mechanism of leptin action in a rodent form of congenital lipodystrophy
Esra Asilmaz, … , Nicholas D. Socci, Jeffrey M. Friedman
Esra Asilmaz, … , Nicholas D. Socci, Jeffrey M. Friedman
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):414-424. https://doi.org/10.1172/JCI19511.
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Article Metabolism

Site and mechanism of leptin action in a rodent form of congenital lipodystrophy

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Abstract

Lipodystrophy is characterized by the complete or partial absence of adipose tissue, insulin resistance, hepatic steatosis, and leptin deficiency. Here, we show that low-dose central leptin corrects the insulin resistance and fatty liver of lipodystrophic aP2-nSREBP-1c mice, while the same dose given peripherally does not. Central leptin also repressed stearoyl-CoA desaturase-1 (SCD-1) RNA and enzymatic activity, which were increased in livers of lipodystrophic mice. aP2-nSREBP-1c mice homozygous for an SCD-1 deletion had markedly reduced hepatic steatosis, increased saturated fatty acids, decreased acetyl-CoA carboxylase activity, and decreased malonyl-CoA levels in the liver. Despite the reduction in hepatic steatosis, these mice remained diabetic. A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity. Leptin treatment at this dose improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2–associated PI3K activity, and Akt activity in liver. Together, these data suggest that CNS-mediated repression of SCD-1 contributes to leptin’s antisteatotic actions. Intracerebroventricular leptin improves glucose homeostasis by improving insulin signal transduction in liver, but in this case the effect appears to be independent of SCD-1.

Authors

Esra Asilmaz, Paul Cohen, Makoto Miyazaki, Pawel Dobrzyn, Kohjiro Ueki, Gulnorakhon Fayzikhodjaeva, Alexander A. Soukas, C. Ronald Kahn, James M. Ntambi, Nicholas D. Socci, Jeffrey M. Friedman

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Figure 1

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Effects of central and peripheral leptin in rodent lipodystrophy. Severa...
Effects of central and peripheral leptin in rodent lipodystrophy. Several metabolic parameters in aP2-nSREBP-1c transgenic mice treated with icv PBS, icv leptin (12 ng/h), and subcutaneous leptin (200 ng/h) are shown. (a, d, and e) Plasma levels of leptin, glucose, and insulin, respectively. (b) Average daily food intake for the 12-day treatment. (c) Percentage change in body weight. One hundred percent change indicates the weight of the mice on the day of pump insertion. Error bars indicate the SE for four mice per group for each treatment. *P < 0.05, icv leptin vs. icv PBS.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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