Evelyn M S Litwinoff1, Merav Y Gold1, Karan Singh1, Jiyuan Hu2, Huilin Li2, Ken Cadwell3, Ann Marie Schmidt4. 1. Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NYU Langone Health, New York, NY 10016, USA. 2. Departments of Population Health (Biostatistics) and Environmental Medicine, NYU Langone Health, New York, NY 10016, USA. 3. Kimmel Center for Biology and Medicine at the Skirball Institute, and the Department of Microbiology, NYU Langone Health, New York, NY 10016, USA. 4. Kimmel Center for Biology and Medicine at the Skirball Institute, and the Department of Microbiology, NYU Langone Health, New York, NY 10016, USA. Electronic address: Annmarie.Schmidt@nyumc.org.
Abstract
BACKGROUND: An influx of lipid-loaded macrophages characterizes visceral adipose tissue (VAT) inflammation, which is an important factor in the development of insulin resistance (IR) in obesity. Depletion of macrophage lipids accompanies increased whole body insulin sensitivity, but the underlying mechanism is unknown. Deficiency of autophagy protein ATG16L1 is associated with increases in inflammatory diseases and lipid metabolism, but the connection between ATG16L1, IR, and obesity remains elusive. We hypothesize that myeloid ATG16L1 contributes to lipid loading in macrophages and to IR. METHODS: Wild-type (WT) bone marrow derived macrophages (BMDMs) were treated with fatty acids and assessed for markers of autophagy. Myeloid-deficient Atg16l1 and littermate control male mice were fed high fat diet (HFD) or low fat diet (LFD) for 3 months starting at 8 weeks of age. Mice were assessed for body mass, fat and lean mass, glucose and insulin sensitivity, food consumption and adipose inflammation. Fluorescence-activated cell sorted VAT macrophages were assessed for lipid content and expression of autophagy related genes. RESULTS: VAT and VAT macrophages from HFD-fed WT mice did not show differences in autophagy protein and gene expression compared to tissue from LFD-fed mice. Fatty acid-treated BMDMs increased neutral lipid content but did not change autophagy protein expression. HFD-fed Atg16l1 myeloid-deficient and littermate mice demonstrated no differences in body mass, glucose or insulin sensitivity, food consumption, fat or lean mass, macrophage lipid content, or adipose tissue inflammation. CONCLUSION: ATG16L1 does not contribute to obesity, IR, adipose tissue inflammation or lipid loading in macrophages in mice fed HFD.
BACKGROUND: An influx of lipid-loaded macrophages characterizes visceral adipose tissue (VAT) inflammation, which is an important factor in the development of insulin resistance (IR) in obesity. Depletion of macrophage lipids accompanies increased whole body insulin sensitivity, but the underlying mechanism is unknown. Deficiency of autophagy protein ATG16L1 is associated with increases in inflammatory diseases and lipid metabolism, but the connection between ATG16L1, IR, and obesity remains elusive. We hypothesize that myeloid ATG16L1 contributes to lipid loading in macrophages and to IR. METHODS: Wild-type (WT) bone marrow derived macrophages (BMDMs) were treated with fatty acids and assessed for markers of autophagy. Myeloid-deficient Atg16l1 and littermate control male mice were fed high fat diet (HFD) or low fat diet (LFD) for 3 months starting at 8 weeks of age. Mice were assessed for body mass, fat and lean mass, glucose and insulin sensitivity, food consumption and adipose inflammation. Fluorescence-activated cell sorted VAT macrophages were assessed for lipid content and expression of autophagy related genes. RESULTS: VAT and VAT macrophages from HFD-fed WT mice did not show differences in autophagy protein and gene expression compared to tissue from LFD-fed mice. Fatty acid-treated BMDMs increased neutral lipid content but did not change autophagy protein expression. HFD-fed Atg16l1myeloid-deficient and littermate mice demonstrated no differences in body mass, glucose or insulin sensitivity, food consumption, fat or lean mass, macrophage lipid content, or adipose tissue inflammation. CONCLUSION:ATG16L1 does not contribute to obesity, IR, adipose tissue inflammation or lipid loading in macrophages in mice fed HFD.
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