PMID- 37487068 OWN - NLM STAT- MEDLINE DCOM- 20230726 LR - 20240125 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 120 IP - 31 DP - 2023 Aug TI - NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis. PG - e2308750120 LID - 10.1073/pnas.2308750120 [doi] LID - e2308750120 AB - Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARgamma. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation. FAU - Hiraike, Yuta AU - Hiraike Y AUID- ORCID: 0000-0001-9799-7975 AD - Division for Health Service Promotion, The University of Tokyo, Tokyo 113-0033, Japan. AD - The University of Tokyo Excellent Young Researcher Program, The University of Tokyo, Tokyo 113-8654, Japan. FAU - Saito, Kaede AU - Saito K AD - Division for Health Service Promotion, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Oguchi, Misato AU - Oguchi M AD - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. FAU - Wada, Takahito AU - Wada T AD - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. FAU - Toda, Gotaro AU - Toda G AD - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. FAU - Tsutsumi, Shuichi AU - Tsutsumi S AD - Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan. FAU - Bando, Kana AU - Bando K AD - Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe 650-0047, Japan. FAU - Sagawa, Junji AU - Sagawa J AD - Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan. FAU - Nagano, Gaku AU - Nagano G AUID- ORCID: 0000-0003-0291-4669 AD - Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan. FAU - Ohno, Haruya AU - Ohno H AD - Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan. FAU - Kubota, Naoto AU - Kubota N AD - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. AD - Department of Clinical Nutrition Therapy, The University of Tokyo Hospital, Tokyo 113-8655, Japan. FAU - Kubota, Tetsuya AU - Kubota T AD - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. AD - Division of Diabetes and Metabolism, The Institute of Medical Science, Asahi Life Foundation, Tokyo 103-0002, Japan. AD - National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo 162-8636, Japan. FAU - Aburatani, Hiroyuki AU - Aburatani H AD - Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan. FAU - Kadowaki, Takashi AU - Kadowaki T AD - Toranomon Hospital, Tokyo 105-8470, Japan. FAU - Waki, Hironori AU - Waki H AD - Department of Diabetes and Endocrinology, Akita University Graduate School of Medicine, Akita 010-8543, Japan. FAU - Yanagimoto, Shintaro AU - Yanagimoto S AD - Division for Health Service Promotion, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Yamauchi, Toshimasa AU - Yamauchi T AD - Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230724 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (NFI Transcription Factors) RN - 0 (Cytokines) RN - 0 (NFIA protein, human) SB - IM MH - Humans MH - Animals MH - Mice MH - *NFI Transcription Factors MH - *Diabetes Mellitus, Type 2 MH - Adipocytes MH - Homeostasis MH - Inflammation MH - Adipose Tissue, Brown MH - Cytokines PMC - PMC10401007 OTO - NOTNLM OT - adipocytes OT - diabetes OT - inflammation OT - transcription factor COIS- Y.H., H.W., and T.Y. are inventors on a filed patent application related to this work. All other authors declare that they do not have a competing financial interest related to this work. EDAT- 2023/07/24 19:09 MHDA- 2023/07/26 06:43 PMCR- 2024/01/24 CRDT- 2023/07/24 15:13 PHST- 2023/07/26 06:43 [medline] PHST- 2023/07/24 19:09 [pubmed] PHST- 2023/07/24 15:13 [entrez] PHST- 2024/01/24 00:00 [pmc-release] AID - 202308750 [pii] AID - 10.1073/pnas.2308750120 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2023 Aug;120(31):e2308750120. doi: 10.1073/pnas.2308750120. Epub 2023 Jul 24.