Journal
CELL METABOLISM
Volume 16, Issue 6, Pages 723-737Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2012.10.019
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Funding
- JDRF
- Canadian Diabetes Association (CDA)
- Canadian Institutes for Health Research (CIHR),
- Michael Smith Foundation for Health Research (MSFHR)
- Heart and Stroke Foundation of BC
- Natural Sciences and Engineering Research Council of Canada.
- Heart and Stroke Foundation of Yukon
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Hyperinsulinemia is associated with obesity and pancreatic islet hyperplasia, but whether insulin causes these phenomena or is a compensatory response has remained unsettled for decades. We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain. Age-dependent increases in fasting insulin and beta cell mass were absent in Ins1(+/-):Ins2(-/-) mice fed a high-fat diet when compared to Ins1(+/+):Ins2(-/-) littermate controls. Remarkably, Ins1(+/-):Ins2(-1-) mice were completely protected from diet-induced obesity. Genetic prevention of chronic hyperinsulinemia in this model reprogrammed white adipose tissue to express uncoupling protein 1 and increase energy expenditure. Normalization of adipocyte size and activation of energy expenditure genes in white adipose tissue was associated with reduced inflammation, reduced fatty acid spillover, and reduced hepatic steatosis. Thus, we provide genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications.
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