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

doi:10.1172/JCI128687

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

Physiology

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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^ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2^ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2^ΔLysM 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^ΔLysM 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.

Original language	English (US)
Pages (from-to)	2644-2656
Number of pages	13
Journal	Journal of Clinical Investigation
Volume	130
Issue number	5
DOIs	https://doi.org/10.1172/JCI128687
State	Published - May 1 2020

Bibliographical note

Funding 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.

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

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Zou, W., Rohatgi, N., Brestoff, J. R., Moley, J. R., Li, Y., Williams, J. W., Alippe, Y., Pan, H., Pietka, T. A., Mbalaviele, G., Newberry, E. P., Davidson, N. O., Dey, A., Shoghi, K. I., Head, R. D., Wickline, S. A., Randolph, G. J., Abumrad, N. A., & Teitelbaum, S. L. (2020). Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure. Journal of Clinical Investigation, 130(5), 2644-2656. https://doi.org/10.1172/JCI128687

Zou, W, Rohatgi, N, Brestoff, JR, Moley, JR, Li, Y, Williams, JW, Alippe, Y, Pan, H, Pietka, TA, Mbalaviele, G, Newberry, EP, Davidson, NO, Dey, A, Shoghi, KI, Head, RD, Wickline, SA, Randolph, GJ, Abumrad, NA & Teitelbaum, SL 2020, 'Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure', Journal of Clinical Investigation, vol. 130, no. 5, pp. 2644-2656. https://doi.org/10.1172/JCI128687

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title = "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{\textquoteright} inflammatory phenotype may impact obesity and its complications.",

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

note = "Funding 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{\textquoteright}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. Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

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AU - Rohatgi, Nidhi

AU - Brestoff, Jonathan R.

AU - Moley, John R.

AU - Li, Yongjia

AU - Williams, Jesse W.

AU - Alippe, Yael

AU - Pan, Hua

AU - Pietka, Terri A.

AU - Mbalaviele, Gabriel

AU - Newberry, Elizabeth P.

AU - Davidson, Nicholas O.

AU - Dey, Anwesha

AU - Shoghi, Kooresh I.

AU - Head, Richard D.

AU - Wickline, Samuel A.

AU - Randolph, Gwendalyn J.

AU - Abumrad, Nada A.

AU - Teitelbaum, Steven L.

N1 - Funding 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. Publisher Copyright: Copyright: © 2020, American Society for Clinical Investigation.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

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

Abstract

Bibliographical note

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