Attenuation of obesity-induced insulin resistance in mice with heterozygous deletion of ROCK2.

BACKGROUND/OBJECTIVES: Obesity-associated insulin resistance is a major risk factor for the development of type 2 diabetes, cardiovascular disease and non-alcoholic liver disease. Over-activation of the RhoA-Rho kinase (ROCK) pathway has been implicated in the development of obesity-induced insulin resistance, but the relative contribution of ROCK2 has not been elucidated. This was investigated in the present study. METHODS: Male ROCK2+/- mice and their wild-type (WT) littermate controls were fed normal chow or a high fat diet (HFD) for 18 weeks. Glucose and insulin tolerance tests were conducted 8 and 16 weeks after the start of feeding. At termination, isoform-specific ROCK activity and insulin signaling were evaluated in epididymal adipose tissue. Adipocyte size was assessed morphometrically, while adipose tissue production of PPARγ was determined by western blotting, and inflammatory cytokines were evaluated by RT-PCR and immunofluorescence. RESULTS: The decrease in systemic insulin sensitivity and glucose tolerance produced by high fat feeding was attenuated in ROCK2+/- mice. There was no reduction in food intake, body weight or epididymal fat pad weight in HFD-ROCK2+/- mice. However, the increase in adipocyte size detected in HFD-WT mice was attenuated in HFD-ROCK2+/- mice. The increase in adipose tissue ROCK2 activity produced by high fat feeding in WT mice was also prevented in ROCK2+/- mice, and this was accompanied by improved insulin-induced phosphorylation of Akt. The expression of both isoforms of PPARγ was increased in adipose tissue from HFD-ROCK2+/- mice, while adipocyte hypertrophy and production of inflammatory cytokines were reduced compared with HFD-WT mice. CONCLUSIONS: These data suggest that activation of ROCK2 in adipose tissue contributes to obesity-induced insulin resistance. This may result in part from suppression of PPARγ expression, leading to adipocyte hypertrophy and an increase in inflammatory cytokine production. ROCK2 may be a suitable target to improve insulin sensitivity in obesity.