Editors' ChoiceObesity

Targeting ASXL2 in macrophages: An antidote to adiposity?

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Science Translational Medicine  20 May 2020:
Vol. 12, Issue 544, eabb7099
DOI: 10.1126/scitranslmed.abb7099

Abstract

Myeloid-specific Asxl2 deletion renders mice resistant to high-fat diet–induced obesity and related complications by regulating brown adipose tissue.

Preventing the complications of a high-fat diet (HFD) is now a public health imperative. As HFD-induced obesity develops, macrophages infiltrate adipose tissue and generate proinflammatory cytokines. The ensuing inflammation leads to pathologic remodeling that inhibits the ability of adipose tissue to store energy and regulate metabolism normally. In mice, global deletion of a transcriptional regulator called Asxl2 was previously found to block HFD-induced obesity for unknown reasons. Now, Zou and colleagues have discovered that myeloid cells are central to this phenomenon.

In their recent work, Zou et al. reveal that mice lacking Asxl2 only in myeloid cells (termed Asxl2ΔLysM) show complete resistance to HFD-induced obesity that cannot be explained by changes in diet or exercise. The mechanism, they determined, likely involves augmentation of basal metabolism by catecholamines in brown adipose tissue, a metabolically active type of fat. In wild-type mice fed a HFD, catecholamines are degraded by abundant fat-infiltrating proinflammatory macrophages. In Asxl2ΔLysM mice, however, brown adipose tissue is protected against macrophage infiltration. Thus, catecholamines accumulate and prevent obesity by increasing basal energy expenditure. Mice injected with Asxl2-siRNA–laden nanoparticles targeted to macrophages demonstrated the same resistance to HFD-induced obesity as genetically deficient Asxl2ΔLysM mice, identifying macrophages as the myeloid cells critical for obesity prevention.

Once thought to be lost after infancy, brown adipose tissue is now recognized as an important regulator of metabolic homeostasis in adult humans, raising the possibility of therapeutic targeting of ASXL2 to combat the obesity pandemic. However, it is not clear how beneficial such targeting would be in individuals who are already suffering from HFD-induced obesity and related complications. Inhibition of ASXL2 may not reprogram proinflammatory macrophages that have already infiltrated the fat, and once pathologic remodeling has occurred, brown adipose tissue may be too dysfunctional to respond even if metabolism-boosting catecholamine concentrations rise. Furthermore, although Asxl2ΔLysM mice appear healthy, ASXL2 mutations in humans are associated with hematopoietic malignancy and other abnormalities that warrant consideration. Nonetheless, with worldwide obesity nearly tripling in the past 50 years, the intriguing therapeutic potential of these findings merits further investigation.

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