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Heterozygous rho kinase2 deficinecy increases whole body insulin sensitivity in mice

University of British Columbia

The incidence of obesity and type 2 diabetes is increasing worldwide. Impaired insulin sensitivity in peripheral tissues has been considered one of the major causes of whole body insulin resistance. Previous in vitro and in vivo studies have shown that the RhoA/ROCK pathway regulates the insulin signaling pathway. Two isoforms of Rho kinase (ROCK) have been identified, known as ROCK1 and ROCK2. It has recently been shown that in-vivo deletion of ROCK1 causes insulin resistance, whereas whether ROCK2 has a role in regulation of insulin sensitivity is unknown. In the current study, we investigated the physiological role of ROCK2 in the regulation of whole body insulin sensitivity in mice with heterozygous ROCK2 deficiency (ROCK2 +/-). ROCK2 +/- mice showed increased glucose tolerance and whole body insulin sensitivity compared to their wild-type littermates. Increased whole body insulin sensitivity in ROCK2 +/- mice was associated with increased activation of the insulin signaling in skeletal muscles and adipose tissues. To explore the mechanism of increased peripheral insulin sensitivity in ROCK2 +/- mice, we studied PPARγ and adiponectin signaling. We found selective upregulation of PPARγ and adiponectin signaling in skeletal muscles, whereas PPAR gamma levels were downregulated in adipose tissues of ROCK2 +/- mice. These findings suggest that partial ROCK2 deficiency increases insulin sensitivity in vivo through upregulation of PPARγ selectively in skeletal muscles. This suggests that ROCK2 is a potential therapeutic target in the development of new drugs for type 2 diabetes.

Text

2013-04-03

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44092

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/