Clin Res Cardiol 101, Suppl 1, April 2012

V130 - Control of glucose homeostasis and insulin sensitivity by Let-7
R. J. A. Frost1, E. N. Olson1
1UT Southwestern Medical Center at Dallas, Department of Molecular Biology, Dallas, USA;
Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression and have been implicated in many biological processes, including metabolism and cardiovascular disease. The Let-7 family of microRNAs is a group of 9 microRNAs with similar sequence and strong expression in most tissues. We generated Cre-inducible transgenic mice to study over-expression of Let-7a, Let-7d, and Let-7f in vivo. We found that global and pancreas-specific over-expression of Let-7 resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Let-7 over-expressing mice also displayed decreased fat mass and body weight, as well as reduced body size. To study loss-of Let-7 function in vivo, we developed an LNA-DNA antimiR that strongly diminished expression of all Let-7 family members as assessed by Northern blot analysis. Global knockdown of the Let-7 family with the antimiR was sufficient to prevent and treat impaired glucose tolerance in C57BL/6 mice with diet-induced obesity. AntimiR treatment blunted high fat diet-induced downregulation of insulin receptor, a predicted Let-7 target, in liver and muscle suggesting an improved insulin sensitivity. Furthermore, antimiR treatment of mice on high fat diet resulted in increased lean and muscle mass, but not 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 to study tissue-specific aspects of type 2 diabetes.
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6