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The role of the transcription factor ETV5 in insulin exocytosis.

ABSTRACT: 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.

SUBMITTER: Gutierrez-Aguilar R

PROVIDER: S-EPMC3947344 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The role of the transcription factor ETV5 in insulin exocytosis.

Gutierrez-Aguilar Ruth R Kim Dong-Hoon DH Casimir Marina M Dai Xiao-Qing XQ Pfluger Paul T PT Park Jongsun J Haller April A Donelan Elizabeth E Park Jisoo J D'Alessio David D Woods Stephen C SC MacDonald Patrick E PE Seeley Randy J RJ

Diabetologia 20131105 2

<h4>Aims/hypothesis</h4>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.<h4>Methods</h4>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.<h4>Res ...[more]

PMID: 24190582

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Project description:PurposeInsulin resistant muscle is resistant to gene expression changes induced by acute exercise. This study was undertaken to identify transcription factors that differentially respond to exercise in insulin resistance. Candidate transcription factors were identified from analysis of 5'-untranslated regions (5'-UTRs) of exercise responsive genes and from analysis of the 5'-UTRs of genes coding for proteins that differ in abundance in insulin resistance.Research design and methodsTwenty participants took part in this study. Insulin sensitivity was assessed by an euglycemic clamp. Participants were matched for aerobic capacity and performed a single 48 min bout of exercise with sets at 70 and 90% of maximum heart rate. Muscle biopsies were obtained at resting conditions, 30 min and 24 h after exercise. Global proteomics analysis identified differentially abundant proteins in muscle. The 5'-UTRs of genes coding for significant proteins were subjected to transcription factor enrichment analysis to identify candidate transcription factors. Q-rt-PCR to determine expression of candidate transcription factors was performed on RNA from resting and post-exercise muscle biopsies; immunoblots quantified protein abundance.ResultsProteins involved in mitochondrial function, protein targeting and translation, and metabolism were among those significantly different between lean and obese groups. Transcription factor enrichment analysis of genes coding for these proteins revealed new candidate transcription factors to be evaluated along the previously identified factors. Q-rt-PCR analysis of RNA and immunoblot analysis from pre- and post-exercise muscle biopsies revealed several transcription and growth factors that had altered responses to exercise in insulin resistant participants. A significant increase (EGR3 and CTGF) and decrease (RELA and ATF2) in the mRNA expression of transcription and growth factors was found after exercise in the lean group, but not in the obese participants.ConclusionsThese results confirm findings of an association between insulin sensitivity and transcription factor mRNA response to exercise and show that obesity also may be a sufficient prerequisite for exercise resistance. Analysis of the muscle proteome together with determination of effects of exercise on expression of transcription factors suggests that abnormal responses of transcription factors to exercise may be responsible for differences in protein abundances in insulin resistant muscle.

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The role of the transcription factor ETV5 in insulin exocytosis.

Publications

The role of the transcription factor ETV5 in insulin exocytosis.

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