title: Hepatic cyclooxygenase-2 expression protects against diet-induced steatosis, obesity, and insulin resistance.
abstract: 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.
authors.affiliation: Institute of Experimental Physiology (Instituto de Fisiología Experimental), Consejo Nacional de Investigaciones Científicas y Técnicas, Rosario, Argentina.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Francés
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Omar
authors.initials: O
authors.lastname: Motiño
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Agrá
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.affiliation: Institute of Experimental Physiology (Instituto de Fisiología Experimental), Consejo Nacional de Investigaciones Científicas y Técnicas, Rosario, Argentina.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Álvarez
authors.affiliation: Biomedical Institute of Valencia, Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Cucarella
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Castro-Sánchez
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: García-Casarrubios
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.affiliation: Institute of Experimental Physiology (Instituto de Fisiología Experimental), Consejo Nacional de Investigaciones Científicas y Técnicas, Rosario, Argentina.
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Carnovale
authors.affiliation: Biomedical Institute of Valencia, Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Científicas, Valencia, Spain CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain pmartins@iib.uam.es avalverde@iib.uam.es.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
authors.affiliation: Institute of Biomedical Research Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain CIBERehd, Instituto de Salud Carlos III, Madrid, Spain pmartins@iib.uam.es avalverde@iib.uam.es.
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005234:Fatty Liver / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D007328:Insulin; D051546:Cyclooxygenase 2