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UBC Theses and Dissertations

Effects of insulin gene dosage on body weight and glucose homeostasis Mehran, Arya E.


Obesity is one of the biggest health concerns around the world and is closely associated with insulin hypersecretion. However, the causality relationship between these conditions remains enigmatic. We tested the hypothesis that fasting hyperinsulinemia is necessary for diet-induced obesity by varying the pancreatic-specific Ins1 gene dosage in Ins2-/- mice. Male Ins1+/-:Ins2-/- mice did not exhibit high fat diet-induced fasting hyperinsulinemia, when compared with their Ins1+/+:Ins2-/- littermate controls. This genetic inability to become hyperinsulinemic prevented the expected increase in pancreatic β-cell number, confirming a role for insulin in high fat diet-induced β-cell expansion. Male Ins1+/-:Ins2-/- mice were also protected from diet-induced obesity and hepatic steatosis when compared to high fat fed Ins1+/+:Ins2-/- littermate controls in the absence of sustained changes in glucose homeostasis. Genetic prevention of hyperinsulinemia increased energy expenditure while reducing adipose inflammation and fatty acid spillover. Female control Ins1+/+:Ins2-/- mice did not exhibit hyperinsulinemia or weight gain on the high fat diet we employed, so it was not possible to test the same hypothesis in the female mice. The effects of reducing Ins2 gene dosage on the Ins1 null background were also assessed. Male Ins1-/-:Ins2+/- mice had a phenotype that differed strongly between cohorts. In one cohort of the male mice, Ins2 haploinsufficiency was associated with increased food intake of the high fat diet, relative to Ins1-/-:Ins2+/- mice fed the same diet, but no changes in circulating insulin levels. On the other hand, female Ins1-/-:Ins2+/- mice were partially protected from high fat diet-induced obesity relative to their littermate controls. The differences in the consequences of Ins1 versus Ins2 loss prompted analysis of the tissue expression of both insulin genes, focusing on the central nervous system. We demonstrated that, unlike Ins1, Ins2 is expressed in the brain. High fat feeding reduced Ins2 expression in the brain in a region- and sex-specific manner. Collectively, our data provide genetic evidence that circulating hyperinsulinemia can drive obesity in mammals. These findings may be important for understanding the causes of obesity and eventually the development of approaches to prevent or treat it.

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