Goliath induces inflammation in obese mice by linking fatty acid β‐oxidation to glycolysis

Article2 March 2023 Source DataTransparent process Goliath induces inflammation in obese mice by linking fatty acid β-oxidation to glycolysis Shumeng Hao Shumeng Hao orcid.org/0000-0002-9114-0759 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Sulin Zhang Sulin Zhang Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Jialin Ye Jialin Ye orcid.org/0000-0002-6520-8844 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Lifan Chen Lifan Chen Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yan Wang Yan Wang CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Siyu Pei Siyu Pei CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Qingchen Zhu Qingchen Zhu CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Jing Xu Jing Xu CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yongzhen Tao Yongzhen Tao CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Neng Zhou Neng Zhou Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Huiyong Yin Huiyong Yin orcid.org/0000-0001-7049-1560 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Cai-Wen Duan Cai-Wen Duan Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Chaoming Mao Chaoming Mao orcid.org/0000-0002-2915-0921 Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China Search for more papers by this author Mingyue Zheng Corresponding Author Mingyue Zheng [email protected] Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yichuan Xiao Corresponding Author Yichuan Xiao [email protected] orcid.org/0000-0001-7804-6971 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Shumeng Hao Shumeng Hao orcid.org/0000-0002-9114-0759 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Sulin Zhang Sulin Zhang Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Jialin Ye Jialin Ye orcid.org/0000-0002-6520-8844 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Lifan Chen Lifan Chen Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yan Wang Yan Wang CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Siyu Pei Siyu Pei CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Qingchen Zhu Qingchen Zhu CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Jing Xu Jing Xu CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yongzhen Tao Yongzhen Tao CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Neng Zhou Neng Zhou Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Huiyong Yin Huiyong Yin orcid.org/0000-0001-7049-1560 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Cai-Wen Duan Cai-Wen Duan Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Chaoming Mao Chaoming Mao orcid.org/0000-0002-2915-0921 Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China Search for more papers by this author Mingyue Zheng Corresponding Author Mingyue Zheng [email protected] Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Yichuan Xiao Corresponding Author Yichuan Xiao [email protected] orcid.org/0000-0001-7804-6971 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China Search for more papers by this author Author Information Shumeng Hao1,†, Sulin Zhang2,†, Jialin Ye1,†, Lifan Chen2, Yan Wang1, Siyu Pei1,3, Qingchen Zhu1, Jing Xu1, Yongzhen Tao1, Neng Zhou4, Huiyong Yin1, Cai-Wen Duan4, Chaoming Mao5, Mingyue Zheng *,2 and Yichuan Xiao *,1 1CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China 2Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China 3Department of Thoracic Surgical Oncology, Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 4Key Laboratory of Pediatric Hematology and Oncology Ministry of Health and Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China 5Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, China † These authors contributed equally to this work *Corresponding author. Tel: +86 21 50806600; E-mail: [email protected] *Corresponding author. Tel: +86 21 54923276; E-mail: [email protected] EMBO Reports (2023)24:e56932https://doi.org/10.15252/embr.202356932 Full textView the full text of the articlePDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract Obesity is associated with metabolic disorders and chronic inflammation. However, the obesity-associated metabolic contribution to inflammatory induction remains elusive. Here, we show that, compared with lean mice, CD4+ T cells from obese mice exhibit elevated basal levels of fatty acid β-oxidation (FAO), which promote T cell glycolysis and thus hyperactivation, leading to enhanced induction of inflammation. Mechanistically, the FAO rate-limiting enzyme carnitine palmitoyltransferase 1a (Cpt1a) stabilizes the mitochondrial E3 ubiquitin ligase Goliath, which mediates deubiquitination of calcineurin and thus enhances activation of NF-AT signaling, thereby promoting glycolysis and hyperactivation of CD4+ T cells in obesity. We also report the specific GOLIATH inhibitor DC-Gonib32, which blocks this FAO-glycolysis metabolic axis in CD4+ T cells of obese mice and reduces the induction of inflammation. Overall, these findings establish a role of a Goliath-bridged FAO-glycolysis axis in mediating CD4+ T cell hyperactivation and thus inflammation in obese mice. Synopsis The mitochondrial E3 ubiquitin ligase Goliath links fatty acid β-oxidation (FAO) to glycolysis and mediates CD4+ T cell hyperactivation and inflammation in obese mice. A FAO-glycolysis metabolic axis in CD4+ T cells promotes inflammation in obese mice. The FAO rate-limiting enzyme Cpt1a stabilizes Goliath in mitochondria. Obesity-upregulated Goliath links levels of FAO to the glycolytic rate in CD4+ T cells. A GOLIATH inhibitor curtails obesity-related inflammation by blocking the FAO-glycolysis axis. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 24,Issue 4,05 April 2023This month's cover highlights the article Ubiquitylation of BBSome is required for ciliary assembly and signaling by Francesco Chiuso, Rossella Delle Donne, Ivan Conte, Antonio Feliciello and colleagues. The images show the expression of the BBSome component BBS1 (green), wt (left panels) and an ubiquitylation‐defective BBS1 mutant (right panels), namely BBS1K143R, in differentiating rods (immunostained for Rhodopsin, red). DAPI staining is shown in blue. Expression of the mutant impairs ciliogenesis and photoreceptor morphogenesis, thus recapitulating Bardet Biedl Syndrome (BBS) phenotypes in a medaka fish model.(Scientific image by Giuliana Giamundo and Daniela Intartaglia, University of Naples Federico II.) Volume 24Issue 45 April 2023In this issue ReferencesRelatedDetailsLoading ...