Loss of Transcriptional Repression by BCL6 Confers Insulin Sensitivity in the Setting of Obesity

Senagolage, Madhavi D.; Sommars, Meredith A; Ramachandran, Krithika; Futtner, Christopher R.; Omura, Yasuhiro; Allred, Amanda L.; Wang, Jianing; Yang, Cynthia; Procissi, Daniele; Evans, Ronald M.; Han, Xianlin; Bederman, Ilya; Barish, Grant D.

doi:10.1016/j.celrep.2018.11.074

Cited by 37 publications

(30 citation statements)

References 74 publications

(85 reference statements)

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“…The phosphorylation of IRS1 at Ser307 site has been shown to impair insulin signaling (12,13), which was reported as one of the major postreceptor factors involved in IR in skin fibroblasts and skeletal muscle cells from patients with PCOS (3,9,32). The phosphorylation of IR-b Tyr1150/115, the phosphorylation of IRS1/2 Tyr612, and the phosphorylation of Akt Ser473 were important insulin signaling molecules (33)(34)(35)(36)(37). Here, we found that the insulin-induced Ser307 19).…”

Section: Discussionmentioning

confidence: 58%

Elevated chemerin induces insulin resistance in human granulosa‐lutein cells from polycystic ovary syndrome patients

Zhu

Wang

et al. 2019

FASEB j.

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The insulin resistance (IR) of ovarian granulosa cells from polycystic ovary syndrome (PCOS) aggravates the abnormalities in steroidogenesis and anovulation, and chemerin is an adipokine involved in regulating adipogenesis and glucose homeostasis. The role and underlying mechanism of chemerin in developing IR of the granulosa cells from PCOS remain unclear. Plasma, follicular fluid, and human granulosa‐lutein cells (hGLs) were collected from non‐PCOS and patients with PCOS with or without IR. The chemerin levels were elevated in both follicular fluid and hGL samples from patients with PCOS with IR, and the hGLs from patients with PCOS with IR showed decreased insulin sensitivity and impaired glucose uptake capacity. Moreover, treatment of chemerin attenuated insulin‐stimulated glucose uptake by decreasing phosphorylation of insulin receptor substrate (IRS)1/2 Tyr612, phosphorylation of protein kinase B Ser473, and membrane translocation of glucose transporter type 4 through increasing Ser307 phosphorylation of IRS1 in cultured hGLs. These effects could be abolished by small interfering RNA‐mediated knockdown of chemokine‐like receptor 1. Furthermore, insulin induced the expression of chemerin in hGLs. Our findings demonstrate a novel role of chemerin in the metabolic dysfunction of PCOS, which suggested that chemerin and its receptor can be further implicated as potential therapeutic targets in the future treatment of PCOS.—Li, X., Zhu, Q., Wang, W., Qi, J., He, Y., Wang, Y., Lu, Y., Wu, H., Ding, Y., Sun, Y. Elevated chemerin induces insulin resistance in human granulosa‐lutein cells from polycystic ovary syndrome patients. FASEB J. 33, 11303–11313 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 58%

Elevated chemerin induces insulin resistance in human granulosa‐lutein cells from polycystic ovary syndrome patients

Zhu

Wang

et al. 2019

FASEB j.

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“…While this is likely the result of AGS adaptations in numerous proteins, the importance of the ATP5G1 variant is highlighted by our experimental evidence demonstrating improvement in spare respiratory capacity in mouse NPCs over-expressing AGS ATP5G1 variants and decreased spare respiratory capacity in AGS NPCs with ATP5G1 L32P knock-in. A critical role for ATP5G1 in cellular energetics is also supported by recent work uncovering ATP5G1 as one of the major effectors of the transcription factor, BCL6, in regulating adipose tissue energetics as well as maintaining thermogenesis in response to hypothermia (43, 44).…”

Section: Discussionmentioning

confidence: 84%

Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels

Singhal

Bai

Lee

et al. 2020

Preprint

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1Many organisms, from anaerobic bacteria to hibernating ground squirrels, have evolved 2 mechanisms to tolerate severe hypoxia or ischemia. In particular, the arctic ground squirrel 3 (AGS) has been shown to be highly resilient to ischemic and reperfusion injuries, 4demonstrating an ability to withstand metabolic stress under hibernation conditions. Although 5 physiological adaptations are critical to ischemic tolerance in AGS, little is known about cellular 6 mechanisms underlying intrinsic AGS cell tolerance to metabolic stressors. Through cell 7 survival-based cDNA expression screens and comparative genomics, we have discovered that 8 in AGS, a cytoprotective variant of ATP5G1 helps confer improved mitochondrial metabolism 9and cell resilience to metabolic stress. ATP5G1 encodes a proton-transporting subunit of the 10 mitochondrial ATP synthase complex. Ectopic expression in mouse cells and CRISPR/Cas9 11 base editing of the endogenous AGS locus revealed causal roles of one AGS-specific amino 12 acid substitution (leucine-32) in mediating the cytoprotective effects of AGS ATP5G1. We 13 provide evidence that AGS ATP5G1 promotes cell resilience to stress by modulating 14 mitochondrial morphological change and metabolic functions. Thus, our results identify a 15 naturally occurring variant of ATP5G1 from a mammalian hibernator that causally contributes 16 to intrinsic cytoprotection against metabolic stresses. 17 18 Proteomic and transcriptomic investigations have comprehensively catalogued the 17 impact of season, torpor, and hibernation on cellular and metabolic pathways in several 18 different tissues of hibernating ground squirrels, including brain (6,(10)(11)(12)(13)(14)(15)(16). Although the 19 mechanisms underlying hibernating ground squirrel ischemia and hypothermia tolerance in the 20 brain are not fully elucidated, studies suggest that post-translational modifications, regulation of 21 cytoskeletal proteins, and upregulation of antioxidants play a prominent role (17)(18)(19). Recent 22 studies employing unbiased next-generation sequencing and bioinformatics approaches have 23 also highlighted the cytoprotective contributions of mitochondrial and lysosomal pathways in to determine functional importance of amino acid substitutions uniquely evolved in AGS, and 15 identified AGS ATP5G1 L32 as a mediator of key cytoprotective metabolic functions, suggesting 16 potential for targeting this component of ATP synthase for neuroprotective treatments. 17 18 Results 19 20 AGS neural cells exhibit marked resistance to metabolic stressors associated with 21 improvements in mitochondrial function and morphology 22When growing under identical cell culture conditions, AGS and mouse NPCs exhibit 23 similar morphology, growth rates and expression of Nestin and Ki67, markers for proliferating

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“…By RNA sequencing and promoter analysis, BCL6 was found to enhance the promoter activity of signal transducer and activator of transcription 1, and was identified as an upregulator of Zfp423, early B cell factor 1 (Ebf1), and PPAR . [32] However, in vivo model of conditional knockout of BCL6 in adipose tissues showed that BCL6 deletion would lead to WAT expansion, [33] implying that BCL6 possibly plays different roles in regulating early adipogenesis and late lipogenesis. From some RNA-seq data used to identify BCL6, we have also identified a novel transcription factor Zfp217 that regulates early adipogenesis of C3H10T1/2 cell line [25,34] (Figure 2), implying that the transcriptional atlas of commitment can be further improved.…”

Section: Transcription Factors Regulating Commitmentmentioning

confidence: 99%

Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6‐Methyladenosine‐Mediated Post‐Transcriptional Regulation

et al. 2020

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Obesity is a critical risk factor causing the development of metabolic diseases and cancers. Its increasing prevalence worldwide has aroused great concerns of the researchers on adipose development and metabolic function. During adipose expansion, adipogenesis is a way to store lipids as well as to avoid lipotoxicity in other tissues, and may be an approach to offset the negative metabolic effects of obesity. In this Review, the transcriptional regulation of adipogenesis is outlined to characterize numerous biological processes in research on the determination of adipocyte fate and regulation of adipogenic differentiation. Notably, one of the post‐transcriptional modifications of mRNA, namely, N 6 ‐methyladenosine (m 6 A), has been recently found to play a role in adipogenesis. Here, the roles of m 6 A‐related enzymes and proteins in adipogenesis, with a particular focus on how these m 6 A‐related proteins function at different stages of adipogenesis, are mainly discussed. The Review also highlights the coordination role of the transcriptional and post‐transcriptional (RNA m 6 A methylation) regulation in adipogenesis and related biological processes. In this context, a better understanding of adipogenesis at both the transcriptional and post‐transcriptional levels may facilitate the development of novel strategies to improve metabolic health in obesity.

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Loss of Transcriptional Repression by BCL6 Confers Insulin Sensitivity in the Setting of Obesity

Cited by 37 publications

References 74 publications

Elevated chemerin induces insulin resistance in human granulosa‐lutein cells from polycystic ovary syndrome patients

Elevated chemerin induces insulin resistance in human granulosa‐lutein cells from polycystic ovary syndrome patients

Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels

Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6‐Methyladenosine‐Mediated Post‐Transcriptional Regulation

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