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Sensitivity of cardiac carnitine palmitoyltransferase to malonyl-CoA is regulated by leptin: similarities with a model of endogenous hyperleptinemia.

Abstract：

:Acute leptin increase as well as endogenous hyperleptinemia evoked by high-fat diets (HF) activate fatty acid metabolism in nonadipose tissues. This supports the notion that hyperleptinemia is pivotal to prevent/delay steatosis during periods of positive energy balance. We have previously shown that long-term HF spares ectopic accumulation of lipids specifically in the miocardium. Because carnitine palmitoyltransferase I (CPT-I) allows mitochondrial uptake/oxidation of fatty acids, we have hypothesized that leptin drives cardiac CPT-I activity. In the current study, hyperleptinemia was induced in C57BL/6J mice either by exogenous leptin administration or by means of HF, and the ability of malonyl-coenzyme A (malonyl-CoA) (the main endogenous inhibitor of CPT-I) to inhibit cardiac CPT was analyzed. IC(50) values of malonyl-CoA were 8.1 +/- 1.5 micromol/liter in controls vs. 69.3 +/- 5.2 micromol/liter (P < 0.01) in leptin-treated mice. This effect was also observed in cardiac explants incubated with leptin and was blocked by triciribine, a compound shown to inhibit protein kinase B (Akt) phosphorylation (pAkt). In accordance, acute leptin evoked an increase of cardiac pAkt levels, which correlated with CPT sensitivity to malonyl-CoA. Otherwise, the inhibitory effect of malonyl-CoA was hindered in HF hyperleptinemic mice, and in this case, pAkt levels also correlated with CPT sensitivity to malonyl-CoA. Our data show that leptin reduces the sensitivity of cardiac CPT-I to malonyl-CoA and suggest the involvement of an Akt-related signaling pathway in this effect. This mechanism appears to be sensitive to both acute and chronic hyperleptinemia. We conclude that this action of leptin is pivotal to drive cardiac metabolism under situations associated to hyperleptinemia.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Guzmán-Ruiz R,Somoza B,Gil-Ortega M,Merino B,Cano V,Attané C,Castan-Laurell I,Valet P,Fernández-Alfonso MS,Ruiz-Gayo M

doi

10.1210/en.2009-1170

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

1010-8

issue

eissn

0013-7227

issn

1945-7170

pii

en.2009-1170

journal_volume

151

pub_type

杂志文章

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Sensitivity of cardiac carnitine palmitoyltransferase to malonyl-CoA is regulated by leptin: similarities with a model of endogenous hyperleptinemia.