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Tissue-Specific Effects of Central Leptin on the Expression of Genes Involved in Lipid Metabolism in Liver and White Adipose Tissue

Biochemistry Section (N.G., E.B.-K., E.M., P.B., A.A.), Nutrition and Food Technology Section (S.G.-A.), Faculty of Chemistry, and Regional Centre for Biomedical Research, University of Castilla-La Mancha, 13071 Ciudad Real, Spain; Health Sciences Faculty (T.F.-A., M.R.), University Rey Juan Carlos, 28922 Alcorcón, Madrid, Spain; and Centre of Molecular Biology "Severo Ochoa" (J.M.C.), Autonomous University, 28049 Madrid, Spain

Address all correspondence and requests for reprints to: Antonio Andrés, Area de Bioquímica, Facultad de Químicas, Regional Centre for Biomedical Research, Avda. Camilo José Cela, 10, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain. E-mail: antonio.andres{at}uclm.es.

Leptin reduces adiposity and exerts antisteatotic effects on nonadipose tissues. However, the mechanisms underlying leptin effects on lipid metabolism in liver and white adipose tissue have not been fully clarified. Here, we have studied the effects of central leptin administration on key enzymes and transcription factors involved in lipid metabolism in liver and epididymal adipose tissue. Intracerebroventricular leptin infusion for 7 d did not change leptin plasma levels but decreased triacylglyceride content in liver, epididymal adipose tissue, and plasma. In both tissues this treatment markedly decreased the expression of key enzymes of the de novo fatty acid (FA) synthesis such as acetyl-coenzyme A-carboxylase, FA synthase, and stearoyl-coenzyme A desaturase-1, in parallel with a reduction in mRNA expression of sterol regulatory element binding protein-1c in liver and carbohydrate regulatory element binding protein in adipose tissue. In addition, leptin also decreased phosphoenol-pyruvate carboxykinase-C expression in adipose tissue, an enzyme involved in glyceroneogenesis in this tissue. Central leptin administration down-regulates delta-6-desaturase expression in liver and adipose tissue, in parallel with the decrease of the expression of sterol regulatory element binding protein-1c in liver and peroxisome proliferator activated receptor in adipose tissue. Finally, leptin treatment, by regulating adipose triglyceride lipase/hormone sensitive lipase/diacylglycerol transferase 1 expression, also established a new partitioning in the FA-triacylglyceride cycling in adipose tissue, increasing lipolysis and probably the FA efflux from this tissue, and favoring in parallel the FA uptake and oxidation in the liver. These results suggest that leptin, acting at central level, exerts tissue-specific effects in limiting fat tissue mass and lipid accumulation in nonadipose tissues, preventing the development of obesity and type 2 diabetes.

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