Sensitivity of cardiac carnitine palmitoyltransferase to malonyl-CoA is regulated by leptin: similarities with a model of endogenous hyperleptinemia.
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.
Guzmán-Ruiz
Rocío
R
Departamento de Ciencias Farmacéuticas y de la Alimentación, Facultad de Farmacia, Universidad Ceu-San Pablo, Urbanización Montepríncipe, Boadilla del Monte, 28668 Madrid, Spain.
Somoza
Beatriz
B
Gil-Ortega
Marta
M
Merino
Beatriz
B
Cano
Victoria
V
Attané
Camille
C
Castan-Laurell
Isabelle
I
Valet
Philippe
P
Fernández-Alfonso
María S
MS
Ruiz-Gayo
Mariano
M
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D020738:Leptin / Q000008:administration & dosage / Q000097:blood*; D050356:Lipid Metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012263:Ribonucleosides; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D020738:Leptin; D012263:Ribonucleosides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014280:Triglycerides; C023764:triciribine; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D051057:Proto-Oncogene Proteins c-akt