title: Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice.
abstract: Dissecting exercise-mimicking pathways that can replicate the benefits of exercise in obesity and diabetes may lead to promising treatments for metabolic disorders. Muscle estrogen-related receptor gamma (ERRγ) is induced by exercise, and when over-expressed in the skeletal muscle mimics exercise by stimulating glycolytic-to-oxidative myofiber switch, mitochondrial biogenesis and angiogenesis in lean mice. The objective of this study was to test whether muscle ERRγ in obese mice mitigates weight gain and insulin resistance. To do so, ERRγ was selectively over-expressed in the skeletal muscle of obese and diabetic db/db mice. Muscle ERRγ over-expression successfully triggered glycolytic-to-oxidative myofiber switch, increased functional mitochondrial content and boosted vascular supply in the db/db mice. Despite aerobic remodeling, ERRγ surprisingly failed to improve whole-body energy expenditure, block muscle accumulation of triglycerides, toxic diacylglycerols (DAG) and ceramides or suppress muscle PKCε sarcolemmal translocation in db/db mice. Consequently, muscle ERRγ did not mitigate impaired muscle insulin signaling or insulin resistance in these mice. In conclusion, obesity and diabetes in db/db mice are not amenable to selective ERRγ-directed programming of classic exercise-like effects in the skeletal muscle. Other biochemical pathways or integrated whole-body effects of exercise may be critical for resisting diabetes and obesity.
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Badin
authors.affiliation: Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Isabelle K
authors.initials: IK
authors.lastname: Vila
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Danesh H
authors.initials: DH
authors.lastname: Sopariwala
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Yadav
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Sabina
authors.initials: S
authors.lastname: Lorca
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Inserm UMR 1048, Institute of Metabolic and Cardiovascular Diseases, and Paul Sabatier University, Toulouse, France.
authors.forename: Katie
authors.initials: K
authors.lastname: Louche
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Eun Ran
authors.initials: ER
authors.lastname: Kim
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA.|Graduate School of Biomedical Sciences at The University of Texas Health Science Center at Houston, Houston, USA.
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Song
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Inserm UMR 1048, Institute of Metabolic and Cardiovascular Diseases, and Paul Sabatier University, Toulouse, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Moro
authors.affiliation: Metabolic and Degenerative Diseases, Institute of Molecular Medicine, The University of Texas McGovern Medical School, Houston, USA.|Graduate School of Biomedical Sciences at The University of Texas Health Science Center at Houston, Houston, USA.|Integrative Biology and Pharmacology, The University of Texas McGovern Medical School, Houston, USA.
authors.forename: Vihang A
authors.initials: VA
authors.lastname: Narkar
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D006019:Glycolysis; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008820:Mice, Obese; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal; D011960:Receptors, Estrogen / Q000502:physiology*
chemical_list: C490916:Esrrg protein, mouse; D011960:Receptors, Estrogen