Hepatic cyclooxygenase-2 expression protects against diet-induced steatosis, obesity and insulin resistance

DANIEL ELEAZAR FRANCÉS; OMAR MOTIÑO; NOELIA AGRÁ; ÁGUEDA GONZÁLEZ-RODRÍGUEZ; ANA 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

DIABETES

AMER DIABETES ASSOC

Año: 2015 vol. 64 p. 1522 - 1531

0012-1797

Accumulation evidence links obesity-induced inflammation asan important contributor to the development of insulin resistance, which playsa key role in the pathophysiology of obesity-related diseases such as type 2diabetes and nonalcoholic fatty liver disease. Cyclooxygenase (COX)-1 and -2catalyze the first step in prostanoid biosynthesis. Because adult hepatocytesfail to induce COX-2 expression regardless of the proinflammatory stimuli used,we have evaluated whether this lack of expression under mild proinflammatoryconditions might constitute a permissive condition for the onset of insulinresistance. 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 decreasedhepatic steatosis, adiposity, plasmatic and hepatic triglycerides and freefatty acids, increased adiponectin-to-leptin ratio, and decreased levels ofproinflammatory cytokines, together with an enhancement of insulin sensitivityand glucose tolerance. Furthermore, hCOX-2 transgenic mice exhibited increasedwhole-body energy expenditure due in part by induction of thermogenesis andfatty acid oxidation. The analysis of hepatic insulin signaling revealed anincrease in insulin receptor-mediated Akt phosphorylation in hCOX-2 transgenicmice. In conclusion, our results point to COX-2 as a potential therapeutictarget against obesity-associated metabolic dysfunction.