Cell Reports
Volume 36, Issue 12, 21 September 2021, 109748
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Article
A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism

https://doi.org/10.1016/j.celrep.2021.109748Get rights and content
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Highlights

  • Myeloid A20 deficiency creates a pro-inflammatory environment in metabolic tissues

  • Myeloid A20 deficiency protects mice from diet-induced obesity and insulin resistance

  • Myeloid A20 deficiency promotes the expansion of inflammatory CD206+ ATMs

  • A20-deficient macrophages metabolize more palmitate in vitro and in vivo

Summary

Obesity-induced inflammation is a major driving force in the development of insulin resistance, type 2 diabetes (T2D), and related metabolic disorders. During obesity, macrophages accumulate in the visceral adipose tissue, creating a low-grade inflammatory environment. Nuclear factor κB (NF-κB) signaling is a central coordinator of inflammatory responses and is tightly regulated by the anti-inflammatory protein A20. Here, we find that myeloid-specific A20-deficient mice are protected from diet-induced obesity and insulin resistance despite an inflammatory environment in their metabolic tissues. Macrophages lacking A20 show impaired mitochondrial respiratory function and metabolize more palmitate both in vitro and in vivo. We hypothesize that A20-deficient macrophages rely more on palmitate oxidation and metabolize the fat present in the diet, resulting in a lean phenotype and protection from metabolic disease. These findings reveal a role for A20 in regulating macrophage immunometabolism.

Data and code availability

  • All data and code supporting the findings of this study are available within the paper or are available from the lead contact upon request.

  • RNA-seq data have been deposited at Gene Expression Omnibus (GEO) and are publicly available with accession number GEO: GSE182155.

  • Any additional information required to reanalyze the data reported in this work paper is available from the Lead Contact upon request.

Cited by (0)

8

These authors contributed equally

9

Senior author

10

Lead contact