title: Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity.
abstract: Induction of skeletal muscle (SM) mitochondrial stress by expression of uncoupling protein 1 (UCP1) in mice results in a healthy metabolic phenotype associated with increased secretion of FGF21 from SM. Here, we investigated whether SM mitochondrial uncoupling can compensate obesity and insulin resistance in the NZO mouse, a polygenic diabesity model. Male NZO mice were crossed with heterozygous UCP1 transgenic (tg) mice (mixed C57BL/6/CBA background) and further backcrossed to obtain F1 and N2 offspring with 50 and 75 % NZO background, respectively. Male F1 and N2 progeny were fed a high-fat diet ad libitum for 20 weeks from weaning. Blood glucose was reduced, and diabetes (severe hyperglycemia >300 mg/dl) was fully prevented in both F1- and N2-tg progeny compared to a diabetes prevalence of 15 % in F1 and 42 % in N2 wild type. In contrast, relative body fat content and plasma insulin were decreased, and glucose tolerance was improved, in F1-tg only. Both F1 and N2-tg showed decreased lean body mass. Accordingly, induction of SM stress response including FGF21 expression and secretion was similar in both F1 and N2-tg mice. In white adipose tissue, expression of FGF21 target genes was enhanced in F1 and N2-tg mice, whereas lipid metabolism genes were induced in F1-tg only. There was no evidence for induction of browning in either UCP1 backcross. We conclude that SM mitochondrial uncoupling induces FGF21 expression and prevents diabetes in mice with a 50-75 % NZO background independent of its effects on adipose tissue.
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Voigt
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Katterle
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Kahle
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
authors.forename: Reinhart
authors.initials: R
authors.lastname: Kluge
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.affiliation: German Institute of Human Nutrition in Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany. klaus@dife.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Klaus
keywords: Body composition; Diabetes; Fibroblast growth factor 21; Gene expression; Glucose metabolism; Glucose tolerance test; Lipid metabolism; Polygenic obesity; Skeletal muscle; Uncoupling protein 1; White adipose tissue