leptin and triciribine

Apart from controlling energy balance, leptin, secreted by adipose tissue, is also involved in the regulation of cardiovascular function. Previous studies have demonstrated that acutely administered leptin stimulates natriuresis and vascular nitric oxide (NO) production and that these effects are impaired in obese animals. However, the mechanism of resistance to leptin is not clear. Because obesity is associated with chronically elevated leptin, we examined if long-term hyperleptinemia impairs acute effects of leptin on sodium excretion and NO production in the absence of obesity. Hyperleptinemia was induced in lean rats by administration of exogenous leptin at a dose of 0.5mg/kg/day for 7 days, and then acute effect of leptin (1mg/kg i.v.) was studied under general anesthesia. Leptin increased fractional sodium excretion and decreased Na(+),K(+)-ATPase activity in the renal medulla. In addition, leptin increased the level of NO metabolites and cyclic GMP in plasma and aortic wall. These acute effects of leptin were impaired in hyperleptinemic animals. In both control and hyperleptinemic groups the effect of leptin on Na(+) excretion and renal Na(+),K(+)-ATPase was abolished by phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, but not by protein kinase B/Akt inhibitor, triciribine,. In contrast, acute effect of leptin on NO metabolites and cGMP was abolished by triciribine but not by wortmannin. Leptin stimulated Akt phosphorylation at Ser(473) in aortic tissue but not in the kidney, and this effect was comparable in control and hyperleptinemic groups. These results suggest that hyperleptinemia may mediate "renal" and "vascular" leptin resistance observed in obesity.

Topics: Androstadienes; Animals; Aorta; Blood Pressure; Cyclic GMP; Humans; Insulin; Kidney Medulla; Leptin; Male; Natriuresis; Nitric Oxide; Obesity; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Ribonucleosides; Sodium; Sodium-Potassium-Exchanging ATPase; Substance P; Wortmannin

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.

Topics: Animals; Carnitine O-Palmitoyltransferase; Dietary Fats; Disease Models, Animal; Heart Diseases; Leptin; Lipid Metabolism; Male; Malonyl Coenzyme A; Mice; Mice, Inbred C57BL; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribonucleosides; STAT3 Transcription Factor; Triglycerides