The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids

Abstract

The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis.

Obesity‐related genetic polymorphisms are associated with the risk of early puberty in Han Chinese girls

“…Also, ETV5, the encoded protein, regulates insulin secretion both in vitro and in vivo 29 . A corollary study revealed that ETV5 has a directly effect on hypothalamic–pituitary–adrenocortical axis and diminish circulating glucocorticoids 30 . Taken together with the clear role that EVT5 plays and the close relationship between obesity and early puberty, we hypothesized that EVT5 variation can affect early‐onset puberty.…”

Expression and prognosis analyses of PEA3 subfamily in head and neck squamous cell carcinoma via integrated bioinformatics

“…ETV5 was a target gene of the Src family kinase, and it promoted female germline stem cells [33] . Besides, ETV5 has been thought to be an obesity-related gene that was important for regulating energy balance and metabolism, including insulin secretion and glucocorticoid circulation [34,35] . Another study has also found that ETV5 acted as a transcription factor related to papillary thyroid cancer cell growth by targeting Twist1 to trigger the EMT process [17,36] .…”

Expression and prognosis analyses of PEA3 subfamily in head and neck squamous cell carcinoma via integrated bioinformatics

“…ETV5 was a target gene of the Src family kinase, and it promoted female germline stem cells [33] . Besides, ETV5 has been thought to be an obesity-related gene that was important for regulating energy balance and metabolism, including insulin secretion and glucocorticoid circulation [34,35] . Another study has also found that ETV5 acted as a transcription factor related to papillary thyroid cancer cell growth by targeting Twist1 to trigger the EMT process [17,36] .…”