Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity

Jiyoung, Y.; Kim, Hyo Jung; Yu, Jung Hwan; Xu, Jin; Kim, Daham; Paul, Bindu D.; Choi, Hong-Seok; Kim, Se-Yun; Lee, Yoo Jeong; Ho, Gary P.H.; Rao, Feng; Snyder, Solomon H.; Kim, Jae Woo

doi:10.1073/pnas.1320454110

Cited by 42 publications

(46 citation statements)

References 28 publications

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“…Given the established role of GCs in promoting the differentiation of preadipocytes into adipocytes (7,8), we then investigated the role of Foxa3 in facilitating GR signaling during the adipogenic process. We treated primary iWAT stromal vascular fraction (SVF) cells obtained from WT and Foxa3 KO mice or undifferentiated 10T1/2 cells expressing control or Foxa3 knockdown with DMSO or Dex and analyzed the expressions of 73 genes known to be involved in adipogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…For example, GC treatment has been shown to increase hepatic gluconeogenesis and lipogenesis and to cause muscle atrophy (1,6). Specifically, in adipose tissues GCs have been shown to increase adiposity in human and rodents by promoting fat differentiation (7,8) and inhibiting energy expenditure by decreasing brown adipose tissue (BAT) thermogenesis (9,10) and by suppressing the browning of subcutaneous fat (11). Furthermore, depending on the length of treatment and the intracellular concentrations, GCs have been shown to increase lipogenesis and lipolysis (12).…”

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confidence: 99%

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Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Mueller

2016

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Mueller

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the biological relevance of Group I and II AGS in the kidney requires further investigation in genetically modified animal models. At present, mouse models that are genetically deficient for AGS1 (Cha, Kim 2013, Chen, Khan 2013, Cheng, Obrietan 2004), AGS3 (Regner, Nozu 2011, Blumer, Lord 2008), AGS4 (Giguere, Billard 2013, Giguere, Gall 2014), AGS5 (Konno, Shioi 2008) and AGS6 (Yang, Li 2013) are available, so there is opportunity exists to determine whether changes in the AGS gene expression can play a crucial role during various pathologies in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Localization and expression profile of Group I and II Activators of G-protein Signaling in the kidney

et al. 2014

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Activators of G-protein Signaling (AGS) are a family of accessory proteins that were discovered as modulators of heterotrimeric G-protein subunits. The primary aim of the present study was to localize Group I and II AGS proteins and determine the renal expression profile using immunohistochemistry and quantitative RT-PCR, respectively, during normal and injured states of the kidney. Group I AGS1 was found to be predominantly localized to the proximal tubule, Group II AGS3 and AGS5 were exclusively localized to the distal tubular segments, and Group II AGS6 was ubiquitously expressed in every nephron segment of the rodent kidney. In rat kidneys following ischemia-reperfusion injury (IRI), Group I AGS1 mRNA was dramatically increased after 24 hours by 5-fold (P<0.05), whereas Group II AGS3 and AGS4 mRNA was significantly decreased at the same time point (P<0.05). No significant change in the transcript levels were detected at other time points for any of the AGS genes between control and IRI groups. In polycystic diseased kidneys, mRNA levels for AGS3, AGS4 and AGS6 was significantly increased (P<0.05) by 75–80% in PCK rat kidneys. The identification of Group I and II AGS mRNA and protein in the kidney may provide insight into the potential mechanism of action during normal and varying states of renal disease or injury.

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“…In addition, although DEX treatment has been described to boost adipocyte differentiation, GR is not essential for adipogenesis in mouse models [15]. However, the transcription factors DEXRAS1 and KLF15 have been described as direct targets of GR, affecting adipocyte differentiation [33,34]. In the case of KLF15, in addition of being activated by GR its expression also depends on the expression of CEBPb and CEBPd [34].…”

Section: Discussionmentioning

confidence: 99%

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

Giroud

Tsokanos

Caratti

et al. 2020

Preprint

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Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart-and neural crest derivatives-expressed protein 2 (HAND2) is an obesitylinked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT)HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

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Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity

Cited by 42 publications

References 28 publications

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Localization and expression profile of Group I and II Activators of G-protein Signaling in the kidney

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

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