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

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 3

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Computational analyses of the hepatic transcription profile after icv an...
Computational analyses of the hepatic transcription profile after icv and subcutaneous leptin treatment. Cluster analysis, correlation analysis, and the distribution of correlations of liver gene expression from mice treated with icv leptin versus icv PBS and subcutaneous leptin versus subcutaneous PBS are shown. (a) Standard hierarchical clustering of 30 microarray experiments, including icv leptin and subcutaneous leptin treatments, show that the transcription profiles of icv and subcutaneous leptin are more similar to each other than to any other sample. (b) A pairwise comparison of icv and subcutaneous leptin gene expression is shown for genes regulated by both treatments (the intersection set). In the first quadrant, gene expression is increased in subcutaneous treatment and decreased in icv treatment; in the second quadrant, gene expression is increased in both treatments; in the third quadrant, gene expression is decreased in both treatments; and in the fourth quadrant, gene expression is decreased in subcutaneous treatment and increased in icv treatment. In almost all cases, gene expression is similarly regulated by both treatments. ρ denotes the correlation value. (c) The logarithm of fold changes of subcutaneous leptin versus PBS and icv leptin versus PBS for genes regulated by either treatment (the union set) is shown. (d) The distribution of correlations of 3,962 pairwise comparisons from our database is shown. The arrow shows the correlation of the icv leptin versus PBS treatment and the subcutaneous leptin versus PBS treatment. This shows that gene expression after icv and subcutaneous leptin is more highly correlated than for the other comparisons (P < 0.002).