A20 deficiency in myeloid cells protects mice from diet-induced obesity and insulin resistance due to increased fatty acid metabolism.

Leen Catrysse,Bart Van De Sluis,Bart Ghesquière,Geert Van Loo,Anneleen Remmerie,Hanna Vikkula,Karolina Slowicka,Sophie Janssens,Charlotte L Scott,Christian Maueröder,Anna Bujko,Arne Martens,Esther Hoste,Bastiaan Maes,Liesbet Martens,Mozes Sze,Kodi Ravichandran,Parul Mehrotra,Yvan Saeys

doi:10.1016/j.celrep.2021.109748

Leen Catrysse, Bart Van De Sluis + Show 17 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109748

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Abstract

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 invitro and invivo. 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.

Highlights

The prevalence of obesity is steadily rising and has more than doubled since 1980
Myeloid A20 deficiency in mice creates a proinflammatory environment in metabolic tissues A20myel-KO mice develop a systemic inflammatory pathology caused by hyperactive macrophages that uncontrollably produce inflammatory cytokines due to a prolonged Nuclear factor kB (NF-kB) response (Matmati et al, 2011; Vande Walle et al, 2014)
As previously shown (Matmati et al, 2011), A20myel-KO mice already show high serum levels of inflammatory cytokines in unchallenged conditions compared to wild-type control mice, and these levels remain high after the high-fat diet (HFD) (Figure 1A)

Summary

Introduction

The prevalence of obesity is steadily rising and has more than doubled since 1980. Obesity is closely associated with multiple metabolic disorders including insulin resistance and type 2 diabetes (T2D), non-alcoholic fatty liver disease, cardiovascular disease, and obesity-related cancers. Research over the past decade has established that obesity causes a condition of chronic low-grade inflammation, which is considered to lie at the origin of metabolic disease development (Gregor and Hotamisligil, 2011; Odegaard and Chawla, 2013). The adipose tissue becomes infiltrated with large numbers of CD11c+ macrophages that adopt a pro-inflammatory phenotype, leading to the secretion of pro-inflammatory cytokines including tumor necrosis factor (TNF) and interleukin (IL)-1b (Osborn and Olefsky, 2012). This phenotypic switch in macrophage activity is believed to be a main driving force in the development of the low-grade inflammatory state associated with obesity

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