Cardiovascular disease (CVD), encompassing heart and blood vessel disorders, remains the leading cause of death worldwide. In developed nations, CVD often manifests as coronary artery disease, atherosclerosis, and hypertension, with central obesity emerging as a significant risk factor. While research has traditionally focused on reactive oxygen species in CVD progression, attention is now shifting to the human metabolome, particularly the tricarboxylic acid (TCA) intermediate, succinate, as a potential biomarker and therapeutic target.
Succinate, concentrated in body fluids during hypoxia and inflammation, acts as a metabolic signal of local stress and immunologic danger. Elevated circulating succinate levels are observed in high-risk CVD states like hypertension, ischemic heart disease, and type 2 diabetes mellitus (T2DM). In these scenarios, extracellular succinate signals through its receptor SUCNR1/GPR91, potentially contributing to hypertrophic cardiomyopathy, obesity-related metabolic disturbances, renin-induced hypertension, and diabetic retinopathy.
The Gut Microbiota-Succinate Connection
The origin of circulating succinate remains debated. While damaged tissues likely contribute, the gut microbiota may also play a role, aligning with the bacterial origin of mitochondria. Succinate, traditionally linked to microbial propionate synthesis, is a natural metabolic end product in some bacteria. Studies show that colonization of germ-free mice with the succinate producer Prevotella copri increases cecal succinate, improving glycemic control via intestinal gluconeogenesis activation.
Dysbiosis of the gut microbiota is associated with CVD and its risk factors like T2DM, insulin resistance, and obesity. Bacterial metabolism products can have both health benefits and detrimental effects. Short-chain fatty acids (SCFAs), produced by colonic microbiota fermentation of non-digestible carbohydrates, enter systemic circulation and activate receptors, improving body composition and glucose and lipid homeostasis. Conversely, metabolites like trimethylamine and trimethylamine N-oxide (TMAO) are proatherogenic and predict cardiovascular events. Similarly, succinate released by gut commensal bacteria into circulation, especially during increased intestinal permeability ("leaky gut") in conditions like obesity, might have implications for weight management.
Succinate and Obesity: Clinical Studies
Several clinical substudies have been conducted to analyze circulating succinate levels in lean, obese, and diabetic subjects; examine the relationship between gut microbiota and succinate; and establish a link between circulating succinate and gut microbiota, including a dietetic intervention study and a follow-up study.
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Cross-Sectional Studies
In a cross-sectional study involving lean, obese, and T2DM subjects, researchers analyzed circulating succinate levels. Another study included lean and obese female subjects to examine the relationship between gut microbiota and succinate. A confirmatory study further investigated this relationship in lean and obese subjects.
Dietary Intervention and Follow-Up Studies
A dietary intervention study involved obese women undergoing a hypocaloric Mediterranean Diet and physical exercise program. A follow-up study monitored patients for two years to assess the spontaneous evolution of their microbiota.
Inclusion and Exclusion Criteria
Subjects were included based on being Caucasian men and women with a BMI range from lean to obese, absence of underlying pathology (except those associated with excess weight or diabetes), and signed informed consent. Exclusion criteria included serious systemic diseases, liver or kidney disease, pregnancy, specific dietary habits (vegetarian, irregular diet), eating disorders, recent infections, anti-inflammatory treatments, prior antibiotic use, psychiatric antecedents, and uncontrolled alcoholism or drug abuse.
Succinate Supplementation: Effects on Obesity in Mice
To directly assess the impact of succinate on obesity, researchers supplemented mice with obesity induced by a high-fat diet with succinate (1.5% m/v in drinking water) for 11 weeks without changing the diet. Succinate supplementation significantly decreased subcutaneous adipose tissue, triglyceride contents, and non-esterified fatty acids (NEFA) in adipose tissue. Adipocyte sizes also significantly decreased in both subcutaneous and visceral adipose tissue. Succinate enhanced lipolysis in adipose tissue and stimulated the expression of Ucp1 and Cidea, which are related to brown adipose tissue activation.
Experimental Design
Mice were fed a high-fat diet for 21 weeks, then divided into two groups: HFD only (HFD group) and HFD combined with sodium succinate (HFD-SA group) for 11 weeks. Weight gain, food intake, and water intake were recorded weekly. At the end of treatment, various tissues were collected for analysis.
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Impact on Glucose Intolerance and Energy Expenditure
Succinate supplementation did not significantly improve glucose intolerance induced by HFD, although circulating insulin levels slightly increased. VO2, VCO2, and energy expenditure of obese mice also slightly increased.
Effects on Lipolysis and Liver Lipid Deposition
Succinate supplementation increased mRNA expression of lipolysis-related genes in adipose tissue. Oil Red O staining revealed decreased lipid deposition in the liver with succinate supplementation.
Activation of Brown Adipose Tissue Thermogenesis
Thermographic imaging showed a significant increase in interscapular temperature in mice supplemented with succinate after cold exposure, suggesting enhanced activation of brown adipose tissue.
Succinic Acid and Adipose Tissue Metabolism
Succinic acid, a crucial intermediate in the TCA cycle, has shown promise in regulating fat metabolism. Studies aimed to investigate its effects on adipose tissue metabolism and insulin sensitivity in high-fat diet (HFD)-induced obese mice.
Experimental Setup
Mice were divided into groups receiving a high-fat diet (HFD) or a normal chow diet (NCD), with some groups receiving succinic acid supplementation at different concentrations in their drinking water.
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Results
Succinic acid supplementation inhibited the hypertrophy of inguinal white adipose tissue (iWAT) in HFD-induced mice and enhanced insulin sensitivity. It also improved lipid metabolism, decreasing serum levels of TG, TC, LDL-C, and increasing HDL-C. Furthermore, succinic acid increased the expression of browning markers and mitochondria-related genes in iWAT.
Mechanism of Action
Succinic acid promotes the browning of iWAT by activating the PI3K-AKT/MAPK signaling pathway.Succinic acid may activate the P38 and AKT signaling pathways through the cell surface receptor SUCNR1, promoting the browning of white adipose, and improving the lipid metabolism of obese mice.
Succinate: A Novel Approach to Weight Management?
Research indicates that succinate offers a novel method of activating heat generation in brown fat cells. Succinate is produced within mitochondria during the tricarboxylic acid cycle, the reaction that produces chemical energy for cells.
Succinate and Thermogenesis
Brown fat cells have an abundance of succinate, especially in cold temperatures, and can gather additional succinate molecules from the bloodstream. The cells can then metabolize succinate and create reactive oxygen species (ROS), which are key in making this reaction happen.
Animal Studies
Mice fed high-fat diets and given drinking water containing sodium succinate experienced a "robust concentration-dependent suppression and reversal of weight gain induced by high-fat feeding over four weeks" and succinate "had remarkable effects on fat mass loss and protection against parameters of obesity and diabetes."
Potential Anti-Inflammatory Effects
Succinate encourages inflammation, acting as a chemical signal that helps the body deal with potentially harmful stimuli. Brown fat tissue's ability to gather succinate may help combat conditions like asthma, Crohnâs disease and ulcerative colitis, tuberculosis and rheumatoid arthritis, by acting as sinks for circulating succinate and preventing them from exacerbating the immune systemâs response.
Caveats
The mice needed to have brown fat in the first place for the succinate to have an effect.