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There is now a wealth of evidence showing that communication between microbiota and the host is critical to sustain the vital functions of the healthy host, and disruptions of this homeostatic coexistence are known to be associated with a range of diseases including obesity and type 2 diabetes. Microbiota-derived metabolites act both as nutrients and as messenger molecules and can signal to distant organs in the body to shape host pathophysiology. In this review, we provide a new perspective on succinate as a gut microbiota-derived metabolite with a key role governing intestinal homeostasis and energy metabolism. Thus, succinate is not merely a major intermediary of the TCA traditionally considered as an extracellular danger signal in the host, but also a by-product of some bacteria and a primary cross-feeding metabolite between gut resident microbes. In addition to maintain a healthy microbiome, specific functions of microbiota-derived succinate in peripheral tissues regulating host nutrient metabolism should not be rule out. Indeed, recent research point to some probiotic interventions directed to modulate succinate levels in the intestinal lumen, as a new microbiota-based therapies to treat obesity and related co-morbidities. While further research is essential, a large body of evidence point to succinate as a new strategic mediator in the microbiota-host cross-talk, which might provide the basis for new therapeutically approaches in a near future.

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe-microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk.

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. Succinate is a signaling metabolite sensed extracellularly by SUNCR1. Fernandez-Veledo and colleagues show that activation of SUCNR1 promotes an anti-inflammatory phenotype in adipose-tissue macrophages in lean mice and people.

Maintaining metabolic balance relies on accumulating nutrients during feeding periods and their subsequent release during fasting. In obesity and metabolic disorders, strategies aimed at reducing food intake while simulating fasting have garnered significant attention for weight loss. Caloric restriction (CR) diets and intermittent fasting (IF) interventions have emerged as effective approaches to improving cardiometabolic health. Although the comparative metabolic benefits of CR IF remain inconclusive, this review focuses on various forms of IF, particularly time-restricted eating (TRE). This study employs a narrative review methodology, systematically collecting, synthesizing, and interpreting the existing literature on TRE and its metabolic effects. A comprehensive and unbiased search of relevant databases was conducted to identify pertinent studies, including pre-clinical animal studies and clinical trials in humans. Keywords such as \"Obesity,\" \"Intermittent Fasting,\" \"Time-restricted eating,\" \"Chronotype,\" and \"Circadian rhythms\" guided the search. The selected studies were critically appraised based on predefined inclusion and exclusion criteria, allowing for a thorough exploration and synthesis of current knowledge. This article synthesizes pre-clinical and clinical studies on TRE and its metabolic effects, providing a comprehensive overview of the current knowledge and identifying gaps for future research. It explores the metabolic outcomes of recent clinical trials employing different TRE protocols in individuals with overweight, obesity, or type II diabetes, emphasizing the significance of individual chronotype, which is often overlooked in practice. In contrast to human studies, animal models underscore the role of the circadian clock in mitigating metabolic disturbances induced by obesity through time-restricted feeding (TRF) interventions. Consequently, we examine pre-clinical evidence supporting the interplay between the circadian clock and TRF interventions. Additionally, we provide insights into the role of the microbiota, which TRE can modulate and its influence on circadian rhythms.

The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically “healthy” from “unhealthy” obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.

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. 3xBZTCGcPCuPE54e-xtBbB Video Abstract

In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.

This paper proposes a quantum-inspired evolutionary algorithm (QiEA) to solve an optimal service-matching task-assignment problem. Our proposed algorithm comes with the advantage of generating always feasible population individuals and, thus, eliminating the necessity for a repair step. That is, with respect to other quantum-inspired evolutionary algorithms, our proposed QiEA algorithm presents a new way of collapsing the quantum state that integrates the problem constraints in order to avoid later adjusting operations of the system to make it feasible. This results in lower computations and also faster convergence. We compare our proposed QiEA algorithm with three commonly used benchmark methods: the greedy algorithm, Hungarian method and Simplex, in five different case studies. The results show that the quantum approach presents better scalability and interesting properties that can be used in a wider class of assignment problems where the matching is not perfect.

Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β cells. Mice with β cell-specific Sucnr1 deficiency exhibited 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 showed an enhanced nutrition-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.

Background Our aim was to determine the predictive value of gut hormone changes for the improvement of type 2 diabetes (T2D) following metabolic Roux-en-Y gastric bypass (mRYGB), sleeve gastrectomy (SG), and greater curvature plication (GCP) in a randomized controlled trial. Summary Background Data Contradictory results have been obtained regarding the role of gastrointestinal hormones (in particular GLP-1) in beneficial metabolic bariatric surgery outcomes. Methods Forty-five patients with T2D (mean BMI 39.4 ± 1.9 kg/m 2 ) were randomly assigned to mRYGB, SG, or GCP. Anthropometric and biochemical parameters, fasting concentrations of PYY, ghrelin, glucagon, and area under the curve (AUC) of GLP-1 after a standard meal test were determined prior to and at months 1 and 12 after surgery. Results Twelve months after surgery, total weight loss percentage was higher and HbA1c lower in the mRYGB group than in the SG and GCP groups (−35.2 ± 8.1 and 5.1 ± 0.6% vs. −27.8 ± 5.4 and 6.2 ± 0.8% vs. −20.5 ± 6.8 and 6.6 ± 1.3%; p  = 0.007 and p  < 0.001, respectively). Moreover, GLP-1 AUC at months 1 and 12 was greater and T2D remission was higher in mRYGB (80 vs. 53.3 vs. 20%, p  < 0.001). Insulin treatment (odds ratio (OR) 0.025, p  = 0.018) and the increase in GLP-1 AUC from baseline to month 1 (OR 1.021, p  = 0.013) were associated with T2D remission. Conclusions mRYGB achieves a superior rate of weight loss and T2D remission at month 12. Enhanced GLP-1 secretion 1 month after surgery was a determinant of glucose metabolism improvement. Registration number ( http://www.clinicaltrials.gov ): NCT14104758.