The role of the transcription factor ETV5 in insulin exocytosis.
AIMS/HYPOTHESIS:Genome-wide association studies have revealed an association of the transcription factor ETS variant gene 5 (ETV5) with human obesity. However, its role in glucose homeostasis and energy balance is unknown. METHODS:Etv5 knockout (KO) mice were monitored weekly for body weight (BW) and food intake. Body composition was measured at 8 and 16 weeks of age. Glucose metabolism was studied, and glucose-stimulated insulin secretion was measured in vivo and in vitro. RESULTS:Etv5 KO mice are smaller and leaner, and have a reduced BW and lower fat mass than their wild-type controls on a chow diet. When exposed to a high-fat diet, KO mice are resistant to diet-induced BW gain. Despite a greater insulin sensitivity, KO mice have profoundly impaired glucose tolerance associated with impaired insulin secretion. Morphometric analysis revealed smaller islets and a reduced beta cell size in the pancreatic islets of Etv5 KO mice. Knockdown of ETV5 in an insulin-secreting cell line or beta cells from human donors revealed intact mitochondrial and Ca(2+) channel activity, but reduced insulin exocytosis. CONCLUSION/INTERPRETATION:This work reveals a critical role for ETV5 in specifically regulating insulin secretion both in vitro and in vivo.
Gutierrez-Aguilar, R; Kim, D-H; Casimir, M; Dai, X-Q; Pfluger, PT; Park, J; Haller, A; Donelan, E; Park, J; D'Alessio, D; Woods, SC; MacDonald, PE; Seeley, RJ
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