[HTML][HTML] Hyperinsulinemia drives diet-induced obesity independently of brain insulin production

AE Mehran, NM Templeman, GS Brigidi, GE Lim… - Cell metabolism, 2012 - cell.com
AE Mehran, NM Templeman, GS Brigidi, GE Lim, KY Chu, X Hu, JD Botezelli, A Asadi
Cell metabolism, 2012cell.com
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 β cell mass
were absent in Ins1+/−: Ins2−/− mice fed a high-fat diet when compared to Ins1+/+: Ins2 …
Summary
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 β cell mass were absent in Ins1+/−:Ins2−/− mice fed a high-fat diet when compared to Ins1+/+:Ins2−/− littermate controls. Remarkably, Ins1+/−:Ins2−/− 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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