SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes.

Pancreatic ß-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in ß-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human ß-cells. Mice with ß-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

A specific gut microbiota signature is associated with an enhanced GLP-1 and GLP-2 secretion and improved metabolic control in patients with type 2 diabetes after metabolic Roux-en-Y gastric bypass.

Objective: To determine changes in incretins, systemic inflammation, intestinal permeability and microbiome modifications 12 months after metabolic RYGB (mRYGB) in patients with type 2 diabetes (T2D) and their relationship with metabolic improvement. Materials and methods: Prospective single-center non-randomized controlled study, including patients with class II-III obesity and T2D undergoing mRYGB. At baseline and one year after surgery we performed body composition measurements, biochemical analysis, a meal tolerance test (MTT) and lipid test (LT) with determination of the area under the curve (AUC) for insulin, C-peptide, GLP-1, GLP-2, and fasting determinations of succinate, zonulin, IL-6 and study of gut microbiota. Results: Thirteen patients aged 52.6 ± 6.5 years, BMI 39.3 ± 1.4 kg/m2, HbA1c 7.62 ± 1.5% were evaluated. After mRYGB, zonulin decreased and an increase in AUC after MTT was observed for GLP-1 (pre 9371 ± 5973 vs post 15788 ± 8021 pM, P<0.05), GLP-2 (pre 732 ± 182 vs post 1190 ± 447 ng/ml, P<0.001) and C- peptide, as well as after LT. Species belonging to Streptococaceae, Akkermansiacea, Rickenellaceae, Sutterellaceae, Enterobacteriaceae, Oscillospiraceae, Veillonellaceae, Enterobacterales_uc, and Fusobacteriaceae families increased after intervention and correlated positively with AUC of GLP-1 and GLP-2, and negatively with glucose, HbA1c, triglycerides and adiposity markers. Clostridium perfringens and Roseburia sp. 40_7 behaved similarly. In contrast, some species belonging to Lachnospiraceae, Erysipelotricaceae, and Rumnicocaceae families decreased and showed opposite correlations. Higher initial C-peptide was the only predictor for T2D remission, which was achieved in 69% of patients. Conclusions: Patients with obesity and T2D submitted to mRYGB show an enhanced incretin response, a reduced gut permeability and a metabolic improvement, associated with a specific microbiota signature.

Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.

OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression.

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.

Orally administered Odoribacter laneus improves glucose control and inflammatory profile in obese mice by depleting circulating succinate.

BACKGROUND: Succinate is produced by both human cells and by gut bacteria and couples metabolism to inflammation as an extracellular signaling transducer. Circulating succinate is elevated in patients with obesity and type 2 diabetes and is linked to numerous complications, yet no studies have specifically addressed the contribution of gut microbiota to systemic succinate or explored the consequences of reducing intestinal succinate levels in this setting. RESULTS: Using germ-free and microbiota-depleted mouse models, we show that the gut microbiota is a significant source of circulating succinate, which is elevated in obesity. We also show in vivo that therapeutic treatments with selected bacteria diminish the levels of circulating succinate in obese mice. Specifically, we demonstrate that Odoribacter laneus is a promising probiotic based on its ability to deplete succinate and improve glucose tolerance and the inflammatory profile in two independent models of obesity (db/db mice and diet-induced obese mice). Mechanistically, this is partly mediated by the succinate receptor 1. Supporting these preclinical findings, we demonstrate an inverse correlation between plasma and fecal levels of succinate in a cohort of patients with severe obesity. We also show that plasma succinate, which is associated with several components of metabolic syndrome including waist circumference, triglycerides, and uric acid, among others, is a primary determinant of insulin sensitivity evaluated by the euglycemic-hyperinsulinemic clamp. CONCLUSIONS: Overall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation. Video Abstract.