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Induction of Cardiac Uncoupling Protein-2 Expression and Adenosine 5'-Monophosphate-Activated Protein Kinase Phosphorylation during Early States of Diet-Induced Obesity in Mice

Departamento de Farmacología, Tecnología y Desarrollo Farmacéutico (B.S., R.G., V.C., B.M., C.D.-F., M.R.-G.) and Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Farmacia (P.R.), Universidad San Pablo-Ceu, 28668 Madrid, Spain; and Unidad de Cartografía Cerebral, Instituto Pluridisciplinar (M.S.F.-A.), Universidad Complutense, 28040 Madrid, Spain

Address all correspondence and requests for reprints to: Mariano Ruiz-Gayo, Departamento de Farmacología, Tecnología y Desarrollo Farmacéutico, Facultad de Farmacia, Universidad San Pablo-Ceu, Urbanización Montepríncipe, Carretera de Boadilla del Monte km 5,3 Boadilla del Monte, 28668 Madrid, Spain. E-mail: ruigayo{at}ceu.es.

The objective of this work was to characterize the adaptation of cardiac metabolism to a lipid overload in a model of diet-induced obesity (DIO) in mice. After 8 wk dietary treatment, mice receiving a high-fat diet exhibited an increase in the amount of adipose tissue, accompanied by a surge in plasma leptin concentration (from 5.4–16.0 ng/ml). This was associated with: 1) an induction of uncoupling protein-2 (120%), 2) an increase in the phosphorylated form of AMP-activated protein kinase (120%), and 3) a reduction in lactate concentration and lactate dehydrogenase activity in myocardial tissue (40%). Because DIO induces leptin resistance, we analyzed leptin receptor functionality by measuring phospho-signal transducer and activator of transcription 3 in response to acute leptin (1 mg/kg). We observed that leptin receptor signaling remained unaltered within the heart but was fully impaired within the hypothalamus. Taken together, these data show that during DIO development, there is a metabolic shift in the heart aimed at increasing fatty acid oxidation to the detriment of carbohydrates. This effect seems to be leptin-dependent, suggesting that the increased adiposity observed during the onset of obesity might contribute to impairing ectopic lipidic deposition in the heart.

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