Site and mechanism of leptin action in a rodent form of congenital lipodystrophy.
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.
Asilmaz
Esra
E
Laboratory of Molecular Genetics, The Rockefeller University, New York, New York 10021, USA.
Cohen
Paul
P
Miyazaki
Makoto
M
Dobrzyn
Pawel
P
Ueki
Kohjiro
K
Fayzikhodjaeva
Gulnorakhon
G
Soukas
Alexander A
AA
Kahn
C Ronald
CR
Ntambi
James M
JM
Socci
Nicholas D
ND
Friedman
Jeffrey M
JM
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D020738:Leptin / Q000378:metabolism*; D008060:Lipodystrophy / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D010802:Phylogeny; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism
D020738:Leptin; D013230:Stearoyl-CoA Desaturase