BUSCADOR RECOLECTA

Digital.CSIC. Repositorio Institucional del CSIC

oai:digital.csic.es:10261/124929

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., This work was supported by Financing Program for Short Stays Abroad (Consejo Nacional de Investigaciones Científicas y Técnicas-Argentina) to D.E.F., by a Post-Doctoral fellowship from Consejo Nacional de Ciencia y Tecnología, México, SAF2012-39732 (Ministerio de Economía y Competitividad [MINECO], Spain) to L.C.-S., by CIBERehd (Instituto de Salud Carlos III [ISCIII], Spain) to M.C., by BFU2011-24760 (MINECO, Spain) to L.B., by S2010/BMD-2378 (Comunidad de Madrid) to L.B. and P.M.-S., by RD12/0042/0019 (ISCIII, Spain) and CIBERehd (ISCIII, Spain) to L.B. and P.M.-S., by SAF2010-16037, SAF2013-43713-R (MINECO, Spain) to P.M.-S., and by SAF2012-33283 (MINECO, Spain), S2010/BMD-2423 (Comunidad de Madrid), European Foundation for the Study of Diabetes and Amylin Paul Langerhans Grant, and CIBERDEM (ISCIII, Spain) to Á.M.V., Peer Reviewed