SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity

Abstract

Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.

Gut microbiota-derived succinate: Friend or foe in human metabolic diseases?

“…Similarly, a recent study from our laboratory has uncovered a hitherto unrecognized mechanism whereby SUCNR1 signaling in macrophages is key for the active resolution of acute inflammation in the context of obesitya physiological circuit broken in human obesity [28]. Interestingly, obesity is associated with higher circulating levels of succinate [29] but impaired SUCNR1-signaling, which we have termed a succinate-resistant state [28]. Remarkably, succinate-SUCNR1 signaling has been described as a major driver of helminth-triggered type 2 immunity in the intestine [30], although the source of succinate (microbiota, diet or dying epithelial cells) remains to be determined.…”

“…Conversely, antiinflammatory functions have also recently been ascribed to SUCNR1 through its activation in neural stem cells [27]. Similarly, a recent study from our laboratory has uncovered a hitherto unrecognized mechanism whereby SUCNR1 signaling in macrophages is key for the active resolution of acute inflammation in the context of obesitya physiological circuit broken in human obesity [28]. Interestingly, obesity is associated with higher circulating levels of succinate [29] but impaired SUCNR1-signaling, which we have termed a succinate-resistant state [28].…”

“…Remarkably, succinate-SUCNR1 signaling has been described as a major driver of helminth-triggered type 2 immunity in the intestine [30], although the source of succinate (microbiota, diet or dying epithelial cells) remains to be determined. While the available evidence supporting succinate as a harmful or a beneficial signal is inconclusive, it would seem fairly evident that the succinate/SUCNR1 axis might serve as a link between metabolic stress and immune function [28,31,32].…”

“…Recent research has shed new light on the TCA cycle intermediate succinate, which is now recognized both as a fuel and as a signaling metabolite with unexpected pleiotropic functions, such as a positive regulator of intestinal gluconeogenesis [18] and thermogenesis [21], as well as a key mediator in the resolution of inflammation associated with obesity [28]. Intriguingly, unlike other intermediary metabolites, succinate holds the unique distinction of being at the interface of host-gut microbiota metabolic interactions.…”

Metabolic determinants of lupus pathogenesis

“…SUCNR1 signaling was already known to induce pro-inflammatory phenotypes in innate immune cells, including RA 226 and MetS. 227 This novel study 225 now suggests that succinate sensing plays an essential role in the activation of autoreactive B cells in lupus.…”