Portal de Periódicos da CAPES

Hepatic Cyclooxygenase-2 Expression Protects Against Diet-Induced Steatosis, Obesity, and Insulin Resistance

2014; American Diabetes Association; Volume: 64; Issue: 5 Linguagem: Inglês

10.2337/db14-0979

1939-327X

Daniel E. Francés, Omar Motiño, Noelia Agrá, Águeda González‐Rodríguez, Ana Julia Fernández-Álvarez, Carme Cucarella, Rafael Mayoral, Luis Castro‐Sánchez, Ester García-Casarrubios, Lisardo Boscá, Cristina E. Carnovale, Marta Casado, Ángela M. Valverde, Paloma Martín‐Sanz,

Adipokines, Inflammation, and Metabolic Diseases

Accumulation evidence links obesity-induced inflammation as an important contributor to the development of insulin resistance, which plays a key role in the pathophysiology of obesity-related diseases such as type 2 diabetes and nonalcoholic fatty liver disease. Cyclooxygenase (COX)-1 and -2 catalyze the first step in prostanoid biosynthesis. Because adult hepatocytes fail to induce COX-2 expression regardless of the proinflammatory stimuli used, we have evaluated whether this lack of expression under mild proinflammatory conditions might constitute a permissive condition for the onset of insulin resistance. Our results show that constitutive expression of human COX-2 (hCOX-2) in hepatocytes protects against adiposity, inflammation, and, hence, insulin resistance induced by a high-fat diet, as demonstrated by decreased hepatic steatosis, adiposity, plasmatic and hepatic triglycerides and free fatty acids, increased adiponectin-to-leptin ratio, and decreased levels of proinflammatory cytokines, together with an enhancement of insulin sensitivity and glucose tolerance. Furthermore, hCOX-2 transgenic mice exhibited increased whole-body energy expenditure due in part by induction of thermogenesis and fatty acid oxidation. The analysis of hepatic insulin signaling revealed an increase in insulin receptor–mediated Akt phosphorylation in hCOX-2 transgenic mice. In conclusion, our results point to COX-2 as a potential therapeutic target against obesity-associated metabolic dysfunction.