Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA726262 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14363059_1.fastq.gz | Fastqsanger.gz | |||
| SRR14363059_2.fastq.gz | Fastqsanger.gz | |||
| SRR14363060_1.fastq.gz | Fastqsanger.gz | |||
| SRR14363060_2.fastq.gz | Fastqsanger.gz | |||
| SRR14363061_1.fastq.gz | Fastqsanger.gz |
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Project description:Succinate functions both as a classical TCA cycle metabolite and as an extracellular metabolic stress signal sensed by the mainly Gi-coupled succinate receptor, SUCNR1. In the present study, we characterize and compare effects and signaling pathways activated by succinate and both classes of non-metabolite SUCNR1 agonists. By use of specific receptor and pathway inhibitors, rescue in G protein depleted cells and monitoring of receptor G protein activation by BRET we surprisingly identify Gq rather than Gi signaling, to be responsible for SUCNR1-mediated effects on basic transcriptional regulation. Importantly, in primary human M2 macrophages, where SUCNR1 is highly expressed, we demonstrate that physiological concentrations of extracellular succinate act through SUCNR1 activated Gq signaling to efficiently regulate transcription of immune function genes in a manner that hyperpolarizes their M2 versus M1 phenotype. Thus, sensing of stress-induced extracellular succinate by SUCNR1 is an important transcriptional regulator in human M2 macrophages through Gq signaling.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide and is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signaling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic utility of brown and beige adipocytes, and UCP1, extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
2022-02-17 | PXD024717 | Pride
Project description:The concept of “signaling metabolites” in the control of metabolic homeostasis is gaining traction. The Krebs cycle substrate succinate, a pleiotropic metabolite that acts akin to hormones and cytokines through succinate receptor 1 (SUCNR1, also known as GPR91), is one example of this new class of metabolites. SUCNR1 has a broad expression and is highly abundant in white adipose tissue. It was a general assumption that SUCNR1 is functionally inactive in healthy tissues, and for many years, SUCNR1 was explored from an immune perspective, mainly in inflammatory-related conditions, particularly those associated with chronic hypersuccinemia. Recent studies, however, indicate that extracellular levels of succinate transiently increase in response to physiological changes such as exercise, cold exposure, or food ingestion. Succinate thus emerges as a reporter of both tissue stress and metabolism, raising the possibility of its involvement in additional metabolic functions as a hormone-like metabolite. Indeed, it is conceivable that "succinate sensing" by SUCNR1 may be part of the metabolite-sensing machinery that governs energy homeostasis. To better understand the effect of the adipocyte Sucnr1 deletion on adipose tissue, we selectively inactivated Sucnr1 in murine adipocytes and profiled the transcription state of epididymal white adipose tissue from adipocyte cell-specific Sucnr1 knockout mice (Ad-Sucnr1 KO) and control Sucnr1fl/fl mice.
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Project description:Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1 -/- and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1 -/- mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1 -/- mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (-59%; p < 0.05). Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes.
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