Insulin-induced serine 22 phosphorylation of retinoid X receptor alpha is dispensable for adipogenesis in brown adipocytes

Ardenkjær-Larsen, Jacob; Rupar, Kaja; Sinkevičiūtė, Goda; Petersen, Patricia S S; Villarroel, Julia; Lundh, Morten; Barrès, Romain; Rabiee, Atefeh; Emanuelli, Brice

doi:10.1080/21623945.2020.1747352

Cited by 8 publications

(8 citation statements)

References 33 publications

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“…The Agencourt RNAClean XP (Beckman Coulter, CA, USA) was used to purify the rRNA-depleted samples. Libraries were then prepared as described previously 27 , with the TruSeq Stranded Total Sample Prep Kit (Illumina, CA, USA). The quality of the libraries were controlled with a Bioanalyzer instrument (Agilent Technologies) and then subjected to 100-bp single-end sequencing on a NextSeq 500 system (Illumina).…”

Section: Methodsmentioning

confidence: 99%

Cold-induction of afadin in brown fat supports its thermogenic capacity

Lundh

Altıntaş

Tozzi

et al. 2021

Sci Rep

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The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β3-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.

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Section: Methodsmentioning

confidence: 99%

Cold-induction of afadin in brown fat supports its thermogenic capacity

Lundh

Altıntaş

Tozzi

et al. 2021

Sci Rep

Self Cite

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“…The phosphorylation of Ser 22 of RXRα was shown to reduce the proliferation rate of mouse F9 testicular cells in the presence of RA [120]. In 9-11 week old male C57BL/6 J mice fasted overnight, the retro-orbital injection of 1 unit insulin for 5 min resulted in the elevation of phosphorylation of RXRα at serine 22 in brown adipose tissue [121]. However, the phosphorylation state was not changed after the mice were refed for 2 h or 6 h but was reduced in mice fed a high-fat diet (HFD) for 8 weeks [121].…”

Section: Rxr Phosphorylationmentioning

confidence: 99%

“…In 9-11 week old male C57BL/6 J mice fasted overnight, the retro-orbital injection of 1 unit insulin for 5 min resulted in the elevation of phosphorylation of RXRα at serine 22 in brown adipose tissue [121]. However, the phosphorylation state was not changed after the mice were refed for 2 h or 6 h but was reduced in mice fed a high-fat diet (HFD) for 8 weeks [121]. Interesting, re-expressing wild type RXRα or a RXRαS22A mutant results in similar transcriptomic profiles, indicating that RXRα S22 phosphorylation is dispensable for adipogenesis in brown fat [121].…”

Section: Rxr Phosphorylationmentioning

confidence: 99%

“…However, the phosphorylation state was not changed after the mice were refed for 2 h or 6 h but was reduced in mice fed a high-fat diet (HFD) for 8 weeks [121]. Interesting, re-expressing wild type RXRα or a RXRαS22A mutant results in similar transcriptomic profiles, indicating that RXRα S22 phosphorylation is dispensable for adipogenesis in brown fat [121].…”

Section: Rxr Phosphorylationmentioning

confidence: 99%

“…It appears that RXRα can be phosphorylated by multiple kinases and at multiple sites in different domains, as shown in Table 2. The phosphorylation of Ser 22 is linked to IRS-1 and IRS-2 [118], and its phosphorylation appears to mediate RA action [119][120][121]. GSK3β phosphorylates Ser 49, Ser 78, and Thr 82 of RARα in order to regulate it activity [122,123] In addition, MAPK seems to be responsible for the Ser 260 phosphorylation, which reduces the interaction of RARα and VDRβ or RARβ [126][127][128][129].…”

Section: Rxr Phosphorylationmentioning

confidence: 99%

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The Interactions of Insulin and Vitamin A Signaling Systems for the Regulation of Hepatic Glucose and Lipid Metabolism

Chen

2021

Cells

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The pandemics of obesity and type 2 diabetes have become a concern of public health. Nutrition plays a key role in these concerns. Insulin as an anabolic hormonal was discovered exactly 100 years ago due to its activity in controlling blood glucose level. Vitamin A (VA), a lipophilic micronutrient, has been shown to regulate glucose and fat metabolism. VA’s physiological roles are mainly mediated by its metabolite, retinoic acid (RA), which activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are two transcription factors. The VA status and activations of RARs and RXRs by RA and synthetic agonists have shown to affect the glucose and lipid metabolism in animal models. Both insulin and RA signaling systems regulate the expression levels of genes involved in the regulation of hepatic glucose and lipid metabolism. Interactions of insulin and RA signaling systems have been observed. This review is aimed at summarizing the history of diabetes, insulin and VA signaling systems; the effects of VA status and activation of RARs and RXRs on metabolism and RAR and RXR phosphorylation; and possible interactions of insulin and RA in the regulation of hepatic genes for glucose and lipid metabolism. In addition, some future research perspectives for understanding of nutrient and hormone interactions are provided.

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Integrative analyses of genetic mechanisms responsible for bone–fat imbalance in osteoporosis

Zhang,

Tao,

Zhang

et al. 2024

The Journal of Gene Medicine

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Osteoporosis manifests through adipocyte accrual and osteoblast diminution within bone marrow. However, the precise mechanisms driving the shift from osteogenesis to adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remain largely undefined. In this study, we harnessed the power of bioinformatic tools to analyze gene expression patterns of BMSCs during adipogenic differentiation and osteoporosis using the data from Gene Expression Omnibus (GEO) repositories (GSE113253 and GSE35956), complemented by in vitro and in vivo experiments to validate the findings. Five distinct expression profiles of differentially expressed genes across the adipogenic timeline were identified. The initial phase is marked by ribosome biogenesis and rRNA processing, which is followed by the metabolism of organic acids and processing of inorganic ions. In contrast, the terminal phase is characterized by lipid transport, accumulation, and metabolism, alongside inorganic cation metabolism, thereby underscoring unique transcriptional signatures during the early and late stages of adipogenic differentiation. In BMSCs derived from osteoporotic samples, there is a notable decline in cellular proliferation and a diminished osteogenic capacity. Critically, the genes common to both adipogenesis and osteoporosis in BMSCs are predominantly involved in the negative regulation of Wnt signaling and cellular proliferation. Key genes including SOCS1, MYC, CEBPB, FYN, AXIN2, and RXRA are identified and show downregulation in BMSCs from aged mice. Subsequent in vitro experiments have validated the regulatory influence of RXRA on both adipogenic and osteogenic differentiations of BMSCs, highlighting its crucial role as a central modulator in bone formation and the pathophysiology of osteoporosis.

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Insulin-induced serine 22 phosphorylation of retinoid X receptor alpha is dispensable for adipogenesis in brown adipocytes

Cited by 8 publications

References 33 publications

Cold-induction of afadin in brown fat supports its thermogenic capacity

Cold-induction of afadin in brown fat supports its thermogenic capacity

The Interactions of Insulin and Vitamin A Signaling Systems for the Regulation of Hepatic Glucose and Lipid Metabolism

Integrative analyses of genetic mechanisms responsible for bone–fat imbalance in osteoporosis

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