Macrophage immunometabolism in inflammatory bowel diseases: From pathogenesis to therapy

Pharmacology & Therapeutics, Год журнала: 2022, Номер 238, С. 108176 - 108176

Опубликована: Март 26, 2022

Язык: Английский

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

Microbiome, Год журнала: 2022, Номер 10(1)

Опубликована: Авг. 25, 2022

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

Язык: Английский

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

Cell Metabolism, Год журнала: 2023, Номер 35(4), С. 601 - 619.e10

Опубликована: Март 27, 2023

Язык: Английский

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Cellular succinate metabolism and signaling in inflammation: implications for therapeutic intervention

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июнь 11, 2024

Succinate, traditionally viewed as a mere intermediate of the tricarboxylic acid (TCA) cycle, has emerged critical mediator in inflammation. Disruptions within TCA cycle lead to an accumulation succinate mitochondrial matrix. This excess subsequently diffuses into cytosol and is released extracellular space. Elevated cytosolic levels stabilize hypoxia-inducible factor-1α by inhibiting prolyl hydroxylases, which enhances inflammatory responses. Notably, also acts extracellularly signaling molecule engaging receptor 1 on immune cells, thus modulating their pro-inflammatory or anti-inflammatory activities. Alterations have been associated with various disorders, including rheumatoid arthritis, bowel disease, obesity, atherosclerosis. These associations are primarily due exaggerated cell Given its central role inflammation, targeting pathways offers promising therapeutic avenues for these diseases. paper provides extensive review succinate's involvement processes highlights potential targets future research possibilities development.

Язык: Английский

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Type 2 diabetes and succinate: unmasking an age-old molecule

Diabetologia, Год журнала: 2024, Номер 67(3), С. 430 - 442

Опубликована: Янв. 5, 2024

Beyond their conventional roles in intracellular energy production, some traditional metabolites also function as extracellular messengers that activate cell-surface G-protein-coupled receptors (GPCRs) akin to hormones and neurotransmitters. These signalling metabolites, often derived from nutrients, the gut microbiota or host's intermediary metabolism, are now acknowledged key regulators of various metabolic immune responses. This review delves into multi-dimensional aspects succinate, a dual metabolite with roots both mitochondria microbiome. It connects dots between succinate's role Krebs cycle, mitochondrial respiration, its double-edge transmitter within outside cell. We aim provide an overview succinate-succinate receptor 1 (SUCNR1) axis diabetes, discussing potential use succinate biomarker novel prospect targeting SUCNR1 manage complications associated diabetes. further propose strategies manipulate succinate-SUCNR1 for better diabetes management; this includes pharmacological modulation innovative approaches concentrations, such administration indirect strategies, like modulation. The nature terms origins roles, offers rich landscape understanding intricate connections diseases, indicates promising pathways developing new therapeutic strategies.

Язык: Английский

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Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91

Molecular Cell, Год журнала: 2024, Номер 84(5), С. 955 - 966.e4

Опубликована: Фев. 6, 2024

SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) mutagenesis across human, mouse, rat SUCNR1, we characterize how a five-arginine motif around extracellular pole TM-VI determines initial capture succinate in vestibule (ECV) to either stay or move down orthosteric site. Metadynamics demonstrate low-energy binding both sites, with energy barrier corresponding intermediate stage during which succinate, associated water cluster, unlocks hydrogen-bond-stabilized conformationally constrained loop (ECL)-2b. Importantly, simultaneous two molecules through "sequential" "bypassing" mode frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters between TM-I -II does not unlock ECL-2b. It proposed that occupancy high-affinity sites required for selective activation by high local concentrations.

Язык: Английский

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

Metabolism, Год журнала: 2023, Номер 145, С. 155630 - 155630

Опубликована: Июнь 13, 2023

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

Язык: Английский

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Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction

Pharmacological Research, Год журнала: 2023, Номер 194, С. 106865 - 106865

Опубликована: Июль 22, 2023

Succinate is a vital signaling metabolite produced by the host and gut microbiota. has been shown to regulate metabolic homeostasis inhibit obesity-associated inflammation in macrophages engaging its cognate receptor, SUCNR1. However, contribution of succinate-SUCNR1 axis intestinal barrier dysfunction obesity remains unclear. In present study, we explored effects on high-fat diet (HFD)-induced dysfunction. Using SUCNR1-deficient mouse model under HFD feeding conditions, identified impairment. Our results showed that administration decreased goblet cell numbers mucus production, promoted pro-inflammatory responses, induced microbiota composition imbalance, increased permeability, caused mucosal Dietary succinate supplementation was sufficient activate type 2 immune response, trigger differentiation barrier-promoting cells, suppress inflammation, restore HFD-induced impairment dysbiosis, eventually exert anti-obesity effects. SUNNR1-deficient mice failed improve function phenotype mice. data indicate protective role

Язык: Английский

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

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(12)

Опубликована: Май 7, 2024

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

Язык: Английский

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Succinate-SUCNR1 induces renal tubular cell apoptosis

AJP Cell Physiology, Год журнала: 2023, Номер 324(2), С. C467 - C476

Опубликована: Янв. 9, 2023

Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. is widely expressed throughout body, especially kidney. Abnormally elevated succinate associated with many diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, and ischemia injury, but it not whether can cause kidney damage. This study showed that induced apparent renal injury after treatment 12 wk, characterized by reduction 24 h urine significant detachment brush border proximal tubular epithelial cells, dilation, cast formation, vacuolar degeneration cells succinate-treated mice. Besides, caused cell apoptosis kidneys HK-2 cells. Mechanistically, triggered via activation. In addition, upregulated ERK binding SUCNR1, inhibition using PD98059 abolished proapoptotic effects summary, our provides first evidence acts risk factor contributes further research required discern pathological on functions.

Язык: Английский

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