title: 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.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, New York, New York 10021, USA.
authors.forename: Esra
authors.initials: E
authors.lastname: Asilmaz
authors.forename: Paul
authors.initials: P
authors.lastname: Cohen
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Pawel
authors.initials: P
authors.lastname: Dobrzyn
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Gulnorakhon
authors.initials: G
authors.lastname: Fayzikhodjaeva
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Soukas
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: James M
authors.initials: JM
authors.lastname: Ntambi
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: 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
chemical_list: D020738:Leptin; D013230:Stearoyl-CoA Desaturase