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 Ca2+ 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.

The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids

“…ETV5 was recently linked with obesity (Thorleifsson et al 2009), and it plays an important role in regulating energy balance and glucose metabolism (Gutierrez-Aguilar et al 2014). The present work addressed the hypothesis that ETV5 also contributes to HPA axis regulation.…”

“…In a previous study (Gutierrez-Aguilar et al 2014), a glucose tolerance test (GTT) was performed in ETV5 KO and WT mice at 12 weeks of age. Mice were briefly fasted (06:00–10:00 h), and at 10:00 h, tail blood samples were quickly collected immediately prior to (0 min) and at 15 and 30 min after intraperitoneal (i.p.)…”

“…More recently, ETV5 has been functionally-linked with obesity. ETV5-deficient (knockout; KO) mice have reduced body weight and adiposity compared to wildtype (WT) littermates (Gutierrez-Aguilar et al 2014; Schlesser et al 2008). Furthermore, they are resistant to high fat diet-induced obesity, suggesting that ETV5 normally promotes body fat and body weight gain (Gutierrez-Aguilar et al 2014).…”

“…ETV5-deficient (knockout; KO) mice have reduced body weight and adiposity compared to wildtype (WT) littermates (Gutierrez-Aguilar et al 2014; Schlesser et al 2008). Furthermore, they are resistant to high fat diet-induced obesity, suggesting that ETV5 normally promotes body fat and body weight gain (Gutierrez-Aguilar et al 2014). ETV5 KO mice are also glucose intolerant (despite reduced adiposity), due at least in part to impaired insulin secretion, suggesting that ETV5 also plays an important role in glucose metabolism (Gutierrez-Aguilar et al 2014).…”

“…Furthermore, they are resistant to high fat diet-induced obesity, suggesting that ETV5 normally promotes body fat and body weight gain (Gutierrez-Aguilar et al 2014). ETV5 KO mice are also glucose intolerant (despite reduced adiposity), due at least in part to impaired insulin secretion, suggesting that ETV5 also plays an important role in glucose metabolism (Gutierrez-Aguilar et al 2014). Importantly, ETV5 mRNA is expressed in brain regions that are critical for the regulation of energy balance (e.g., arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei) and this expression varies with nutritional state, suggesting that ETV5 may contribute to metabolic regulation, at least in part, via its role in the brain (Boender, van Rozen, and Adan 2012; Schmid et al 2012; Gutierrez-Aguilar et al 2012).…”