Publication Date:
2013-02-08
Description:
Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism. MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr(db/db) mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kornfeld, Jan-Wilhelm -- Baitzel, Catherina -- Konner, A Christine -- Nicholls, Hayley T -- Vogt, Merly C -- Herrmanns, Karolin -- Scheja, Ludger -- Haumaitre, Cecile -- Wolf, Anna M -- Knippschild, Uwe -- Seibler, Jost -- Cereghini, Silvia -- Heeren, Joerg -- Stoffel, Markus -- Bruning, Jens C -- England -- Nature. 2013 Feb 7;494(7435):111-5. doi: 10.1038/nature11793.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck-Institute for Neurological Research, Gleueler Strasse 50a, 50931 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23389544" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Gene Expression Regulation
;
*Gene Silencing
;
Gluconeogenesis
;
Glucose/biosynthesis/*metabolism
;
Glucose Intolerance/genetics/metabolism
;
Hepatocyte Nuclear Factor 1-beta/*deficiency/genetics/metabolism
;
Humans
;
Insulin/metabolism
;
Insulin Resistance/genetics
;
Liver/metabolism
;
Mice
;
MicroRNAs/biosynthesis/*genetics
;
Obesity/*genetics
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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