Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity

Acı́n-Pérez, Rebeca; Iborra, Salvador; Martí-Mateos, Yolanda; Cook, Emma C. L.; Conde-Garrosa, Ruth; Petcherski, Anton; Muñoz, Ma Del Mar; Mena, Raquel Martínez de; Krishnan, Karthickeyan Chella; Jiménez, Concepción; Bolaños, Juan P.; Laakso, Markku; Lusis, AJ; Shirihai, Orian S.; Sancho, David; Enríquez, José Antonio

doi:10.1038/s42255-020-00273-8

Cited by 50 publications

(28 citation statements)

References 49 publications

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“…A dipose tissue dysfunction, characterized by increased inflammation and cellular senescence and reduced adipogenesis, is an important contributor to obesityassociated metabolic disturbances, including insulin resistance (10,33,44). Increased oxidative stress and reactive oxygen species (ROS) levels in adipose tissue have been extensively demonstrated in obesity in association to insulin resistance and adipocyte dysfunction (1,2,13,24,62). The attenuation of adipose tissue oxidative stress might be an important therapeutic approach to prevent adipose tissue dysfunction and improve obesity-associated metabolic disturbances (50).…”

Section: Introductionmentioning

confidence: 99%

Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

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et al. 2021

Antioxidants & Redox Signaling

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Aims: To investigate the impact of exogenous hydrogen sulfide (H 2 S) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance. Results: Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H 2 S or the activation of endogenous H 2 S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARc transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating H 2 S (CTH, CBS, MPST) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of H 2 S-synthesising enzymes was significantly reduced in morbidly obese subjects in association with attenuated adipogenesis and increased markers of adipose tissue inflammation and senescence. Interestingly, weight-loss interventions (including bariatric surgery or diet/exercise) improved the expression of H 2 S biosynthesis-related genes. In human preadipocytes, the expression of CTH, CBS, and MPST genes and H 2 S production were dramatically increased during adipocyte differentiation. More importantly, the adipocyte proteome exhibiting persulfidation was characterized, disclosing that different proteins involved in fatty acid and lipid metabolism, the citrate cycle, insulin signaling, several adipokines, and PPAR, experienced the most dramatic persulfidation (85-98%). Innovation: No previous studies investigated the impact of H 2 S on human adipose tissue. This study suggests that the potentiation of adipose tissue H 2 S biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance. Conclusion: Altogether, these data supported the relevance of H 2 S biosynthesis in the modulation of human adipocyte physiology. Antioxid. Redox Signal. 00, 000-000.

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Section: Introductionmentioning

confidence: 99%

Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Comas

Latorre

Ortega

et al. 2021

Antioxidants & Redox Signaling

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“…A previous study showed that MAPK signaling related genes interacted with dietary factors involved in inflammation and oxidative stress ( Slattery et al, 2013 ). Inflammation of fat adipose tissue could induce insulin resistance and metabolic disease ( Acin-Perez et al, 2020 ), which suggested that activated MAPK might help to improve the understanding of the epigenetic effects of HFD on obesity and metabolic disease.…”

Section: Discussionmentioning

confidence: 99%

Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues

et al. 2021

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BackgroundThe number of diet induced obese population is increasing every year, and the incidence of type 2 diabetes is also on the rise. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes.ObjectiveIn this study, we aimed to explore gene activation or repression and related biological processes by histone modification across the whole genome on a high-fat diet (HFD) condition. We also aimed to elucidate the correlation of these genes that modulated by histone modification with energy metabolism and inflammation under both short-term and long-term HFD conditions.MethodWe performed ChIP-seq analysis of H3K9me2 and H3K9me3 in brown and white adipose tissues (WATs; subcutaneous adipose tissue) from mice fed with a standard chow diet (SCD) or HFD and a composite analysis of the histone modification of H3K9me2, H3K9me3, H3K4me1 and H3K27ac throughout the whole genome. We also employed and integrated two bulk RNA-seq and a single-nuclei RNA sequencing dataset and performed western blotting (WB) to confirm the gene expression levels in adipose tissue of the SCD and HFD groups.ResultsThe ChIP-seq and transcriptome analysis of mouse adipose tissues demonstrated that a series of genes were activated by the histone modification of H3K9me2, H3K9me3, H3K4me1, and H3K27ac in response to HFD condition. These genes were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in lipogenesis, energy metabolism and inflammation. Several genes in the activated mitogen-activated protein kinase (MAPK) pathway might be related to both inflammation and energy metabolism in mice, rats and humans fed with HFD for a short or long term, as showed by bulk RNA-seq and single nuclei RNA-seq datasets. Western blot analyses further confirmed the increased expression of MET, VEGFA and the enhanced phosphorylation ratio of p44/42 MAPK upon HFD treatment.ConclusionThis study expanded our understanding of the influence of eating behavior on obesity and could assist the identification of putative therapeutic targets for the prevention and treatment of metabolic disorders in the future.

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“…The increase in succinate oxidation causes ROS production by CI-RET and favors inflammation [12]. Very interestingly, blocking CII phosphorylation by Fgr tyrosine kinase or overexpression of catalase in macrophage mitochondrial matrix prevent high fat diet-induced inflammation and obesity [9]. These works highlight the importance of metabolic rewiring of mitochondria in macrophages, from ATP-forming to ROS-producing, to promote a pro-inflammatory state.…”

Section: Mitochondrial Ros Production In (Patho)physiologymentioning

confidence: 97%

“…Subsequent one-electron reduction of H 2 O 2 yields hydroxyl radical ( • OH), which is an extremely harmful ROS that is notoriously involved in toxic reactions, such as the Fenton reaction. Mitochondrial ROS are involved in numerous physiological processes [9][10][11][12][13][14][15] and also link the progression from tissue homeostasis to disease [16][17][18][19]. Very surprisingly, the mechanisms of ROS production in live cells and tissues are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Generation of Reactive Oxygen Species by Mitochondria

2021

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Reactive oxygen species (ROS) are series of chemical products originated from one or several electron reductions of oxygen. ROS are involved in physiology and disease and can also be both cause and consequence of many biological scenarios. Mitochondria are the main source of ROS in the cell and, particularly, the enzymes in the electron transport chain are the major contributors to this phenomenon. Here, we comprehensively review the modes by which ROS are produced by mitochondria at a molecular level of detail, discuss recent advances in the field involving signalling and disease, and the involvement of supercomplexes in these mechanisms. Given the importance of mitochondrial ROS, we also provide a schematic guide aimed to help in deciphering the mechanisms involved in their production in a variety of physiological and pathological settings.

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Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity

Cited by 50 publications

References 49 publications

Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues

Generation of Reactive Oxygen Species by Mitochondria

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Fgr kinase is required for proinflammatory macrophage activation during diet-induced obesity

Cited by 50 publications

References 49 publications

Activation of Endogenous H2S Biosynthesis or Supplementation with Exogenous H2S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Activation of Endogenous H2S Biosynthesis or Supplementation with Exogenous H2S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues

Generation of Reactive Oxygen Species by Mitochondria

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Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans

Activation of Endogenous H₂S Biosynthesis or Supplementation with Exogenous H₂S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans