Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure
Wei Zou, … , Nada A. Abumrad, Steven L. Teitelbaum
Wei Zou, … , Nada A. Abumrad, Steven L. Teitelbaum
Published April 20, 2020
Citation Information: J Clin Invest. 2020;130(5):2644-2656. https://doi.org/10.1172/JCI128687.
View: Text | PDF
Research Article Metabolism

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure

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 (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.

Authors

Wei Zou, Nidhi Rohatgi, Jonathan R. Brestoff, John R. Moley, Yongjia Li, Jesse W. Williams, Yael Alippe, Hua Pan, Terri A. Pietka, Gabriel Mbalaviele, Elizabeth P. Newberry, Nicholas O. Davidson, Anwesha Dey, Kooresh I. Shoghi, Richard D. Head, Samuel A. Wickline, Gwendalyn J. Randolph, Nada A. Abumrad, Steven L. Teitelbaum

×

Figure 5

ASXL2 expression in myeloid cells is required for macrophage accumulation in WAT and BAT in obesity.

Options: View larger image (or click on image) Download as PowerPoint
ASXL2 expression in myeloid cells is required for macrophage accumulatio...
Asxl2fl/fl and Asxl2ΔLysM mice were fed either a chow diet or HFD. (A) Frequencies and (B) numbers of F4/80+CD64+ macrophages in gonadal WAT: pregated on singlet, live, CD45+ cells. (C) Frequencies and (D) numbers of F4/80+CD64+ macrophages in BAT: pregated on singlet, live, CD45+ cells. (E) Inflammatory cytokine and chemokine mRNA expression in stromal vascular fraction of BAT of Asxl2fl/fl or Asxl2ΔLysM mice after 8 weeks fed with chow diet or HFD. (F) Macrophage marker mRNA expression in stromal vascular fraction of BAT of Asxl2fl/fl or ASXL2ΔLysM mice after 8 weeks fed with chow diet or HFD. (G) Body weight and brown or gonadal fat pad weight of Asxl2fl/fl and Asxl2ΔLysM mice after 4 weeks of HFD. (H) Adgre1 (F4/80) and inflammatory cytokine mRNA expression in stromal vascular fraction of BAT of Asxl2fl/fl or Asxl2ΔLysM mice after 4 weeks on HFD. (I) IL-1β and TNF-α secretion by bone marrow–derived macrophages of Asxl2fl/fl or Asxl2ΔLysM mice stimulated with 100 ng/mL LPS for 3 hours, followed by 15 μM nigericin for 1 hour. (J–L) Histological sections of WAT of HFD-fed control or Asxl2ΔLysM mice stained to identify (J) fibrosis (hematoxylin and eosin), (K) hypoxic adipocytes, and (L) crown-like structures (F4/80). Scale bars: 1 mm (J), 400 μm (K), and 200 μm (L). (M) ECM gene mRNA expression in gonadal WAT stromal vascular fraction of chow- or HFD-fed Asxl2fl/fl or Asxl2ΔLysM mice. Data are presented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; as determined by unpaired t test (H and I) or 2-way ANOVA with Holm-Sidak post hoc analysis for multiple comparisons (B, D–F, and M).