Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 113, Issue 3, Pages 414-424Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200419511
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Funding
- NIDDK NIH HHS [R01-DK41096, R01 DK062388, R01 DK041096, R01-DK62388] Funding Source: Medline
- NIGMS NIH HHS [GM07739, T32 GM007739] Funding Source: Medline
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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. Intracere-broventricular leptin improves glucose homeostasis by improving insulin signal transducrion in liver, but in this case the effect appears to be independent of SCD-1.
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