Cholesterol 25-hydroxylase (CH25H) as a promoter of adipose tissue inflammation in obesity and diabetes

• Published in: Molecular metabolism (Germany) Vol. 39; p. 100983
• Main Authors: Russo, Lucia, Muir, Lindsey, Geletka, Lynn, Delproposto, Jennifer, Baker, Nicki, Flesher, Carmen, O'Rourke, Robert, Lumeng, Carey N.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.09.2020; Elsevier
• Subjects: 3T3-L1 Cells; Adipose tissue; Adipose Tissue - metabolism; Adult; Animals; Biomarkers; CH25H; Cytokines - metabolism; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Disease Susceptibility; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin Resistance - genetics; Macrophage; Macrophages - immunology; Macrophages - metabolism; Male; Metabolome; Mice; Mice, Knockout; Middle Aged; Obesity; Obesity - complications; Obesity - diagnosis; Obesity - metabolism; Original; Oxysterol; Panniculitis - etiology; Panniculitis - metabolism; Panniculitis - pathology; Sequence Analysis, RNA; Signal Transduction; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Obesity; T2DM; SVF; Adipose tissue; KO; IR; DM; eWAT; CH25H; AT; NDM; Oxysterol; ATM; Diabetes; 25-HC; WT; Macrophage
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2020.100983

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. 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. 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 7α25diHC, 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. 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. •CH25H upregulation in visceral adipose tissue is associated with diabetes in humans.•ATMs are the primary site of CH25H expression in humans and mice.•DIO in mice activates Ch25h expression and 25-HC production in visceral adipose tissue.•Obese Ch25h KO mice have improved insulin sensitivity due to attenuated adipose tissue inflammation.•In response to inflammatory stimuli, Ch25h/25-HC potentiates myeloid activation.