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 (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM 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 Asxl2ΔLysM 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.
Bibliographical noteFunding Information:
This study was supported by the following grants from the NIH: K99 HL1388163 (to JWW), AR064755 (to GM), AR068972 (to GM), AR070975 (to GM), HL38180 (to NOD), DK56260 (to NOD), P30 DK52574 (to NOD), P41 EB025815 (to KIS), HL073646 (to SAW), DK102691 (to SAW), AI019653 (to GJR), DK109668 (to GJR), DK056341 (to NAA), AR046523 (to SLT), DK111389 (to SLT), and P30 AR074992 (to SLT and GM). JRB is supported by the Physician-Scientist Training Program at Washington University School of Medicine and the Children’s Discovery Institute. We thank the Cyclotron and the Preclinical PET/CT Imaging facilities at Mallinckrodt Institute of Radiology (MIR) for production of radiopharmaceuticals and imaging studies.
Copyright: © 2020, American Society for Clinical Investigation.