Adenoviral shRNA-based knockdown of hepatic Hnf1b (Ad-shHnf1b)

ABSTRACT: Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus (T2D) and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism 1,2,3. MicroRNA (miR)-dependent posttranscriptional gene silencing has recently been recognized to control gene expression in disease development and progression including that of insulin-resistant T2D. MiRs, whose deregulation alters hepatic insulin sensitivity include miR-143, miR-181 and miR-103/107. Here we report that expression of miR-802 is increased in liver of two obese mouse models and of obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, while reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b as a target of miR-802-dependent silencing and shRNA-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signaling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in db/db mice. Thus, the present study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism via targeting Hnf1b and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.

ORGANISM(S): Mus musculus

PROVIDER: GSE42188 | GEO | 2012/11/10

SECONDARY ACCESSION(S): PRJNA179265

REPOSITORIES: GEO