Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure

Dalle, H.; Garcia, M.; Antoine, B; Boehm, Vanessa; Huong, Thi Thu; Buyse, Marion; Ledent, Tatiana; Lamazière, Antonin; Magnan, Christophe; Postic, Catherine; Denis, Raphaël; Luquet, Serge; Fève, Bruno; Moldes, Marthe

doi:10.2337/db17-1577

Cited by 41 publications

(21 citation statements)

References 49 publications

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“…Our model of chronic corticosterone treatment supports and extends the results of other elegant studies using similar approaches but giving greater doses of corticosterone (1, 28–30), indicating that this is a reliable approach for addressing the different potential mechanisms underlying glucocorticoid-induced metabolic abnormalities. Mice given corticosterone, when glucocorticoid receptor is knocked down in adipose tissue, have improved glucose tolerance and insulin sensitivity (29). Other studies, in which mice had been given corticosterone when Hsd11b1 (the enzyme responsible for the regeneration of corticosterone) had been deleted, had identified glucocorticoid regeneration in adipose tissue as a key factor in corticosterone-induced hepatic steatosis and fatty acid excess (28).…”

Section: Discussionmentioning

confidence: 99%

“…Whether these changes had resulted from glucocorticoids acting centrally or peripherally is unknown. Deletion of glucocorticoid receptor in adipose tissue in adult mice has highlighted its importance in glucocorticoid-induced systemic insulin resistance (29). However, central mechanisms have also been proposed to cause peripheral insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice

et al. 2019

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Glucocorticoids are potent and widely used medicines but often cause metabolic side effects. A murine model of corticosterone treatment resulted in increased hypothalamic expression of the melanocortin antagonist AgRP in parallel with obesity and hyperglycemia. We investigated how these adverse effects develop over time, with particular emphasis on hypothalamic involvement. Wild-type and Agrp −/− male mice were treated with corticosterone for 3 weeks. Phenotypic, biochemical, protein, and mRNA analyses were undertaken on central and peripheral tissues, including white and brown adipose tissue, liver, and muscle, to determine the metabolic consequences. Corticosterone treatment induced hyperphagia within 1 day in wild-type mice, which persisted for 3 weeks. Despite this early increase in food intake, the body weight only started to increase after 10 days. Hyperinsulinemia occurred at day 1. Also, although after 2 days, alterations were present in the genes often associated with insulin resistance in several peripheral tissues, hyperglycemia only developed at 3 weeks. Throughout, sustained elevation in hypothalamic Agrp expression was present. Mice with Agrp deleted [using clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9, Agrp −/− ] were partially protected against corticosterone-induced hyperphagia. However, Agrp −/− mice still had corticosterone-induced increases in body weight and adiposity similar to those of the Agrp +/+ mice. Loss of Agrp did not diminish corticosterone-induced hyperinsulinemia or correct changes in hepatic gluconeogenic genes. Chronic glucocorticoid treatment in mice mimics many of the metabolic side effects seen in patients and leads to a robust increase in Agrp . However, AgRP does not appear to be responsible for most of the glucocorticoid-induced adverse metabolic effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice

et al. 2019

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“…Multicenter prospective studies are needed to further establish the association of plasma 17-OHP levels and incidence of T2DM. Second, recent studies have shown the GR in adipocytes also exerts important roles in the development of metabolic disorders (66,67). Understanding whether overproduction of hepatic 17-OHP could activate the adipocyte GR and subsequently affect glucose and lipid metabolism requires further in-depth analysis.…”

Section: Methodsmentioning

confidence: 99%

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor

Lu¹,

Wang²,

Chen³

et al. 2020

Journal of Clinical Investigation

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“…In obese patients, MR activation seems to be involved in inflammation and insulin resistance (59) and plays a major role in adipogenesis (60). In another study, Lee et al demonstrated the importance of GR in promoting adipogenesis but not of the MR (61), while white-adiposetissue-specific GR-knockout mice displayed a healthier metabolic profile (62), except one report (63). GR blockade of adipogenesis seems to protect against the development of metabolic alterations.…”

Section: Hirsutismmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome

Vitellius

Lombès

2020

European Journal of Endocrinology

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Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11βHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier metabolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resistant patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients.

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Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure

Cited by 41 publications

References 49 publications

Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice

Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor

GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome

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