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Gene expression analysis in hepatocytes in response to hepatocyte-specific Succinate Receptor 1 (SUCNR1) deletion

ABSTRACT: The liver plays a crucial role in metabolic adaptations in response to nutrients, a function that is critically dependent on its zonated structure. Succinate, a key intermediate of the tricarboxylic acid cycle, has emerged as a postprandial signaling metabolite that regulates metabolic adaptations to food intake in adipose tissue and pancreatic beta cells through its receptor SUCNR1. Considering that SUCNR1 is also expressed in hepatocytes, we hypothesized a role for the succinate-SUCNR1 axis in liver metabolic homeostasis. To better understand the role of Sucnr1in hepatocytes, we generated a mouse model specifically lacking Sucnr1 in hepatocytes (Hep-Sucnr1 KO mice) and performed an RNA-seq of isolated hepatocytes from controls (Sucnr1 fl/fl mice) and Hep-Sucnr1 KO mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE301098 | GEO | 2026/04/28

REPOSITORIES: GEO

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Effect of depletion of succinate receptor 1 (SUCNR1) on the gene expression of mouse adipose tissue

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Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

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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SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

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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SUCNR1 signaling controls macrophage alternative activation

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Gene expression analysis in hepatocytes in response to hepatocyte-specific Succinate Receptor 1 (SUCNR1) deletion

Project description:Gene expression analysis in hepatocytes in response to hepatocyte-specific Succinate Receptor 1 (SUCNR1) deletion

| PRJNA1283257 | ENA

Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

Project description:Extracellular Succinate Hyperpolarizes M2 Macrophages through SUCNR1/GPR91-Mediated Gq Signaling

| PRJNA726262 | ENA

UCP1-dependent depletion of liver extracellular succinate antagonizes inflammatory pathogenesis

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