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UBC Theses and Dissertations

Characterization of the effects of a high fat-high sucrose diet in wild-type and ROCK2 heterozygous mice Jia, Yanzhi

Abstract

Obesity is associated with systemic insulin resistance, impaired insulin signaling, and increased inflammation, as well as with the development of cardiomyopathy. Heterozygous deletion of ROCK2 has been demonstrated to protect CD-1 mice from cardiac contractile dysfunction and insulin resistance induced by a high fat diet. A high fat-high sucrose diet (HFHS) more closely resembles the human “Western diet” than a high fat diet, but it is unclear whether ROCK2 contributes to the obesity-related complications caused by this diet. The purpose of the work described here was to characterize the effects of a HFHS diet on cardiac function and insulin tolerance in wild-type (WT) and ROCK2+/- CD-1 mice. In Chapter 2, the effect of a HFHS diet containing 45% kcal from fat and 17% kcal from sucrose on cardiac function and systemic insulin sensitivity of WT and ROCK2+/- CD-1 mice was assessed. Despite the development of severe obesity and systemic insulin intolerance, WT + HFHS animals did not develop cardiac contractile dysfunction, while no increase in ROCK2 expression and or impaired insulin signaling was detected in these hearts. Furthermore, HFHS diet-fed ROCK2+/- mice were not protected from systemic insulin intolerance. In Chapter 3, the mechanisms underlying whole-body insulin intolerance at the level of insulin signaling in the liver and adipose tissue from WT and ROCK2+/- mice were evaluated. Although no over-expression of ROCK2 or activation of ROCK could be detected in the liver or adipose tissue of HFHS diet-fed mice, both WT and ROCK2+/- animals had significantly elevated levels of liver triglycerides and impaired insulin signaling in the liver and adipose tissue. In addition, elevated levels of inflammatory factors were found in adipose tissue from both WT + HFHS and ROCK2+/- + HFHS mice. Overall, feeding CD-1 mice a HFHS diet failed to induce cardiac dysfunction, despite producing obesity and systemic insulin resistance that were resistant to heterozygous deletion of ROCK2. These data suggest that ROCK2 does not appear to contribute to the complications of obesity induced by a HFHS diet. However, the liver and adipose tissue may be potential tissue targets for improving disrupted insulin signaling and inflammation induced by this diet.

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