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

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Figure 6

siRNA-mediated Asxl2 suppression in macrophages prevents diet-induced obesity.

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siRNA-mediated Asxl2 suppression in macrophages prevents diet-induced ob...
(A) Body weight, (B) glucose tolerance test, and (C) insulin tolerance test of Bap1fl/fl and Bap1ΔLysM mice fed HFD for 6 weeks. (D) WT BMMs were incubated with GFP-siRNA– or Asxl2-siRNA–associated nanoparticles. Asxl2 mRNA was measured by qPCR and compared to that of Asxl2ΔLysM BMMs. Colocalization of macrophages (F4/80) and Asxl2-siRNA–associated nanoparticles in (E) spleen and (F) gonadal WAT of HFD-fed WT mice. Scale bars: 100 μm (E) and 30 μm (F). (G) Body weight of WT HFD-fed mice administered GFP-siRNA– or Asxl2-siRNA–associated nanoparticles. Data are presented as mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; as determined by 1-way ANOVA with Holm-Sidak post hoc analysis for multiple comparisons (A–C and G).