Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs

Robert J A Frost, Eric N. Olson

Research output: Contribution to journalArticle

269 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)21075-21080
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number52
DOIs
StatePublished - Dec 27 2011

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Keywords

  • Insulin receptor
  • Insulin receptor substrate 2
  • Metabolic syndrome
  • β-cell

ASJC Scopus subject areas

  • General

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