PMID- 32229247 OWN - NLM STAT- MEDLINE DCOM- 20210708 LR - 20230603 IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 39 DP - 2020 Sep TI - Cholesterol 25-hydroxylase (CH25H) as a promoter of adipose tissue inflammation in obesity and diabetes. PG - 100983 LID - S2212-8778(20)30057-0 [pii] LID - 10.1016/j.molmet.2020.100983 [doi] LID - 100983 AB - OBJECTIVE: Expansion of visceral adipose tissue (VAT) and metabolic inflammation are consequences of obesity and associated with type 2 diabetes (T2DM). Metabolically activated adipose tissue macrophages (ATMs) undergo qualitative and quantitative changes that influence their inflammatory responses. How these cells contribute to insulin resistance (IR) in humans is not well understood. Cholesterol 25-Hydroxylase (CH25H) converts cholesterol into 25-Hydroxycholesterol (25-HC), an oxysterol that modulates immune responses. Using human and murine models, we investigated the role of CH25H in metabolic inflammation. METHODS: We performed transcriptomic (RNASeq) analysis on the human whole AT biopsies and sorted ATMs from obese non-diabetic (NDM) and obese diabetic (DM) subjects to inquire if CH25H was increased in DM. We challenged mice lacking Ch25h with a high-fat diet (HFD) to characterize their metabolic and immunologic profiling. Ch25h KO mice and human adipose tissue biopsies from NDM and DM subjects were analyzed. LC-MS was conducted to measure 25-HC level in AT. In vitro analysis permitted us to investigate the effect of 25-HC on cytokine expression. RESULTS: In our RNASeq analysis of human visceral and subcutaneous biopsies, gene pathways related to inflammation were increased in obese DM vs. non-DM subjects that included CH25H. CH25H was enriched in the stromal vascular fraction of human adipose tissue and highly expressed in CD206(+) human ATMs by flow cytometry analysis. We measured the levels of the oxysterols, 25-HC and 7alpha25diHC, in human visceral adipose tissue samples and showed a correlation between BMI and 25-HC. Using mouse models of diet-induced obesity (DIO), we found that HFD-induced Ch25h expression in eWAT and increased levels of 25-HC in AT. On HFD, Ch25h KO mice became obese but exhibited reduced plasma insulin levels, improved insulin action, and decreased ectopic lipid deposit. Improved insulin sensitivity in Ch25h KO mice was due to attenuation of CD11c(+) adipose tissue macrophage infiltration in eWAT. Finally, by testing AT explants, bone marrow-derived macrophages (BMDMs) and SVF cells from Ch25h deficient mice, we observed that 25-HC is required for the expression of pro-inflammatory genes. 25-HC was also able to induce inflammatory genes in preadipocytes. CONCLUSIONS: Our data suggest a critical role for CH25H/25-HC in the progression of meta-inflammation and insulin resistance in obese humans and mouse models of obesity. In response to obesogenic stimuli, CH25H/25-HC could exert a pro-inflammatory role. CI - Copyright (c) 2020 The Authors. Published by Elsevier GmbH.. All rights reserved. FAU - Russo, Lucia AU - Russo L AD - Department of Pediatrics, Division of Pulmonary Medicine, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - Muir, Lindsey AU - Muir L AD - Department of Pediatrics, Division of Pulmonary Medicine, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - Geletka, Lynn AU - Geletka L AD - Department of Pediatrics, Division of Pulmonary Medicine, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - Delproposto, Jennifer AU - Delproposto J AD - Department of Pediatrics, Division of Pulmonary Medicine, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - Baker, Nicki AU - Baker N AD - Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - Flesher, Carmen AU - Flesher C AD - Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - O'Rourke, Robert AU - O'Rourke R AD - Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, United States. FAU - Lumeng, Carey N AU - Lumeng CN AD - Department of Pediatrics, Division of Pulmonary Medicine, University of Michigan Medical School, Ann Arbor, MI, United States; Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States. Electronic address: clumeng@umich.edu. LA - eng GR - R01 DK115190/DK/NIDDK NIH HHS/United States GR - F32 DK105676/DK/NIDDK NIH HHS/United States GR - I01 CX001811/CX/CSRD VA/United States GR - R01 DK090262/DK/NIDDK NIH HHS/United States GR - P30 DK020572/DK/NIDDK NIH HHS/United States GR - K01 DK116928/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200327 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - EC 1.14.- (Steroid Hydroxylases) RN - EC 1.14.99.38 (cholesterol 25-hydroxylase) SB - IM MH - 3T3-L1 Cells MH - Adipose Tissue/*metabolism MH - Adult MH - Animals MH - Biomarkers MH - Cytokines/metabolism MH - Diabetes Mellitus, Type 2/*complications/diagnosis/*metabolism MH - Disease Models, Animal MH - Disease Susceptibility MH - Female MH - Gene Expression Profiling MH - Gene Expression Regulation MH - Humans MH - Insulin Resistance/genetics MH - Macrophages/immunology/metabolism MH - Male MH - Metabolome MH - Mice MH - Mice, Knockout MH - Middle Aged MH - Obesity/*complications/diagnosis/*metabolism MH - Panniculitis/*etiology/metabolism/pathology MH - Sequence Analysis, RNA MH - Signal Transduction MH - Steroid Hydroxylases/genetics/*metabolism PMC - PMC7267735 OTO - NOTNLM OT - Adipose tissue OT - CH25H OT - Diabetes OT - Macrophage OT - Obesity OT - Oxysterol EDAT- 2020/04/02 06:00 MHDA- 2021/07/09 06:00 PMCR- 2020/03/27 CRDT- 2020/04/02 06:00 PHST- 2020/01/20 00:00 [received] PHST- 2020/03/09 00:00 [revised] PHST- 2020/03/20 00:00 [accepted] PHST- 2020/04/02 06:00 [pubmed] PHST- 2021/07/09 06:00 [medline] PHST- 2020/04/02 06:00 [entrez] PHST- 2020/03/27 00:00 [pmc-release] AID - S2212-8778(20)30057-0 [pii] AID - 100983 [pii] AID - 10.1016/j.molmet.2020.100983 [doi] PST - ppublish SO - Mol Metab. 2020 Sep;39:100983. doi: 10.1016/j.molmet.2020.100983. Epub 2020 Mar 27.