GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation

Drareni, Karima; Ballaire, Raphaëlle; Barilla, Serena; Mathew, Mano Joseph; Toubal, Amine; Fan, Rongrong; Liang, Ning; Chollet, Catherine; Huang, Zhiqiang; Kondili, Maria; Foufelle, Fabienne; Soprani, Antoine; Roussel, Ronan; Gautier, Jean‐François; Alzaïd, Fawaz; Treuter, Eckardt; Venteclef, Nicolas

doi:10.1016/j.celrep.2018.08.032

Cited by 46 publications

(46 citation statements)

References 52 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Clinical and anthropometric data are detailed in Supplementary Table 1 . This study was conducted in accordance with the Helsinki Declaration as previously described [ 32 , 36 ]. The Ethics Committee of CPP Ile-de-France approved the clinical investigations, and written informed consent was obtained from all of the individuals.…”

Section: Methodsmentioning

confidence: 99%

“…GPS2 may also play a cytoplasmic role by regulating insulin signaling via AKT ubiquitination [ 35 ]. Our recent work discovered that GPS2 controls adipocyte hypertrophy in mice by repressing transcription factor HIF1α [ 36 ]. We found that dysregulation of the GPS2-HIF1α axis disrupts mitochondrial activity and predisposes to adipose tissue expansion and a pro-diabetic status.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1

Barilla

Liang

Mileti

et al. 2020

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

Objective Adipogenesis is critical for adipose tissue remodeling during the development of obesity. While the role of transcription factors in the orchestration of adipogenic pathways is already established, the involvement of coregulators that transduce regulatory signals into epigenome alterations and transcriptional responses remains poorly understood. The aim of our study was to investigate which pathways are controlled by G protein pathway suppressor 2 (GPS2) during the differentiation of human adipocytes. Methods We generated a unique loss-of-function model by RNAi depletion of GPS2 in human multipotent adipose-derived stem (hMADS) cells. We thoroughly characterized the coregulator depletion-dependent pathway alterations during adipocyte differentiation at the level of transcriptome (RNA-seq), epigenome (ChIP-seq H3K27ac), cistrome (ChIP-seq GPS2), and lipidome. We validated the in vivo relevance of the identified pathways in non-diabetic and diabetic obese patients. Results The loss of GPS2 triggers the reprogramming of cellular processes related to adipocyte differentiation by increasing the responses to the adipogenic cocktail. In particular, GPS2 depletion increases the expression of BMP4 , an important trigger for the commitment of fibroblast-like progenitors toward the adipogenic lineage and increases the expression of inflammatory and metabolic genes. GPS2-depleted human adipocytes are characterized by hypertrophy, triglyceride and phospholipid accumulation, and sphingomyelin depletion. These changes are likely a consequence of the increased expression of ATP-binding cassette subfamily G member 1 ( ABCG1 ) that mediates sphingomyelin efflux from adipocytes and modulates lipoprotein lipase (LPL) activity. We identify ABCG1 as a direct transcriptional target, as GPS2 depletion leads to coordinated changes of transcription and H3K27 acetylation at promoters and enhancers that are occupied by GPS2 in wild-type adipocytes. We find that in omental adipose tissue of obese humans, GPS2 levels correlate with ABCG1 levels, type 2 diabetic status, and lipid metabolic status, supporting the in vivo relevance of the hMADS cell-derived in vitro data. Conclusion Our study reveals a dual regulatory role of GPS2 in epigenetically modulating the chromatin landscape and gene expression during human adipocyte differentiation and identifies a hitherto unknown GPS2-ABCG1 pathway potentially linked to adipocyte hypertrophy in humans.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1

Barilla

Liang

Mileti

et al. 2020

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is exemplified by GPS2 actions in others cell types. In fact, the anti-inflammatory action of GPS2 is conserved in adipocytes by repressing CCL2 and IL6 (198,199). While the main action of GPS2 in hepatocytes is to repress the metabolic nuclear receptor PPAR-α action (200).…”

Section: Epigenetic Control Of Macrophage Polarizationmentioning

confidence: 99%

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

et al. 2020

Self Cite

View full text Add to dashboard Cite

Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.

show abstract

“…This epigenome-sensitive response could be controlled by abnormal activation of enhancers region leading to uncontrolled inflammation and a pro-diabetic status as we recently proposed [ 79 ]. In collaboration with Eckardt Treuter's group, we discovered that G protein pathway suppressor 2 (GPS2), a HDAC3 corepressor complex subunit, controls enhancer activity and consequently the activation of macrophages [ [79] , [80] , [81] , [82] ]. Macrophage GPS2-KO mice display a pro-inflammatory phenotype, leading to increased adipose tissue inflammation and macrophage infiltration and development of systemic insulin resistance under diet-induced obesity conditions.…”

Section: Epigenomic Regulation Of Inflammation: Importance Of Enhancementioning

confidence: 99%

Regulation of inflammation in diabetes: From genetics to epigenomics evidence

Diedisheim

Carcarino

Vandiedonck

et al. 2020

Molecular Metabolism

Self Cite

View full text Add to dashboard Cite

Background Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes. Scope of review Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease. Major conclusions In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.

show abstract

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation

Cited by 46 publications

References 52 publications

Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1

Loss of G protein pathway suppressor 2 in human adipocytes triggers lipid remodeling by upregulating ATP binding cassette subfamily G member 1

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

Regulation of inflammation in diabetes: From genetics to epigenomics evidence

Contact Info

Product

Resources

About