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

E Asilmaz, P Cohen, M Miyazaki… - The Journal of …, 2004 - Am Soc Clin Investig
E Asilmaz, P Cohen, M Miyazaki, P Dobrzyn, K Ueki, G Fayzikhodjaeva, AA Soukas…
The Journal of clinical investigation, 2004Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation