title: Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs.
abstract: Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. robert.frost@utsouthwestern.edu
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Frost
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001823:Body Composition; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse; D005947:Glucose