Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure
- 30 April 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (5), 2644-2656
- https://doi.org/10.1172/JCI128687
Abstract
We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2(Delta LysM)) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2(Delta LysM) mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2(Delta LysM) mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2(Delta LysM) mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells' inflammatory phenotype may impact obesity and its complications.Funding Information
- National Institutes of Health (K99 HL1388163)
- National Institutes of Health (HL38180)
- National Institutes of Health (DK56260)
- National Institutes of Health (P30 DK52574)
- National Institutes of Health (P41 EB025815)
- National Institutes of Health (HL073646)
- National Institutes of Health (DK102691)
- National Institutes of Health (AI019653)
- National Institutes of Health (DK109668)
- National Institutes of Health (DK056341)
- National Institutes of Health (AR046523)
- National Institutes of Health (DK111389)
- Shriners Hospitals for Children (85400)
- National Institutes of Health (P30 AR074992)
This publication has 56 references indexed in Scilit:
- Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repairBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013
- Recruited brown adipose tissue as an antiobesity agent in humansJCI Insight, 2013
- Muscle lipogenesis balances insulin sensitivity and strength through calcium signalingJCI Insight, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat DietCell Metabolism, 2012
- Adipose tissue remodeling and obesityJCI Insight, 2011
- Eosinophils Sustain Adipose Alternatively Activated Macrophages Associated with Glucose HomeostasisScience, 2011
- Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activationAmerican Journal of Physiology-Endocrinology and Metabolism, 2010
- Ablation of CD11c-Positive Cells Normalizes Insulin Sensitivity in Obese Insulin Resistant AnimalsCell Metabolism, 2008
- Alternative activation of macrophagesNature Reviews Immunology, 2003