title: 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.
authors: Department of Internal Medicine, University of Cincinnati, United States; Laboratorio de Enfermedades Metabólicas Obesidad y Diabetes, Hospital Infantil de México Federico Gómez, Mexico. Electronic address: ruthgutierrezhimfg@gmail.com.
authors: Ruth
authors: R
authors: Gutierrez-Aguilar
authors: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, OH 45237, United States.
authors: Abigail
authors: A
authors: Thompson
authors: UMR8161 CNRS, Université de Lille, Institut Pasteur de Lille, Institut de Biologie de Lille, 1 Rue Calmette, 59021 Lille CEDEX, France.
authors: Nathalie
authors: N
authors: Marchand
authors: UMR8161 CNRS, Université de Lille, Institut Pasteur de Lille, Institut de Biologie de Lille, 1 Rue Calmette, 59021 Lille CEDEX, France.
authors: Patrick
authors: P
authors: Dumont
authors: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, OH 45237, United States.
authors: Stephen C
authors: SC
authors: Woods
authors: UMR8161 CNRS, Université de Lille, Institut Pasteur de Lille, Institut de Biologie de Lille, 1 Rue Calmette, 59021 Lille CEDEX, France.
authors: Yvan
authors: Y
authors: de Launoit
authors: Department of Internal Medicine, University of Cincinnati, United States.
authors: Randy J
authors: RJ
authors: Seeley
authors: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, OH 45237, United States.
authors: Yvonne M
authors: YM
authors: Ulrich-Lai
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D005938:Glucocorticoids / Q000008:administration & dosage / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000473:pathology*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D004268:DNA-Binding Proteins; C513242:Etv5 protein, mouse; D005938:Glucocorticoids; D007328:Insulin; C575863:NR3C1 protein, mouse; C000598932:Nr3c2 protein, mouse; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D017483:Receptors, Vasopressin; D014157:Transcription Factors; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone
keywords: ETV5; Glucocorticoids; Hypothalamic–pituitary–adrenocortical (HPA) axis; Metabolism; Stress