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

FRANCÉS, DANIEL; MOTIÑO, OSCAR; AGRA ANDRIEU, NOELIA; GONZÁLES-RODRIGUEZ, A; FERNÁNDEZ ALVAREZ, ANA JULIA; CUCARELLA, CARME; MAYORAL MONIBAS, RAFAEL; CARSTRO-SANCHEZ, L; GARCÍA-CASARRUBIOS, E; BOSCÁ, LISARDO; CARNOVALE, CRISTINA E; CASADO PINNA, MARTA; VALVERDE, M; MARTÍN-SANZ, PALOMA

DIABETES

AMER DIABETES ASSOC

Año: 2015 vol. 64 p. 1 - 11

0012-1797

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 mellitus and non- alcoholic fatty liver disease. Cyclooxygenase (COX)-1 and -2 catalyze the first step in prostanoid biosynthesis. Since adult hepatocytes fail to induce COX-2 expression regardless of the pro-inflammatory stimuli used, we have evaluated whether this lack of expression under mild pro-inflammatory 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 high fat diet as demonstrated by decreased hepatic steatosis, adiposity, plasmatic and hepatic triglycerides and free fatty acids, increased adiponectin/leptin ratio and decreased levels of pro-inflammatory 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-Tg. In conclusion, our results point to COX-2 as a potential therapeutic target against obesity-associated metabolic dysfunction.