Elevated plasma succinate levels are linked to higher cardiovascular disease risk factors in young adults

Abstract

Background Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic disorders in middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown. Methods Cross-sectional study in 100 (65% women) individuals aged 18–25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory fitness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample. Results Individuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+ 42.5%), triglycerides (+ 63.9%), C-reactive protein (+ 124.2%), diastolic blood pressure (+ 5.5%), and pro-inflammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity. Conclusions Plasma succinate levels are linked to a specific pro-inflammatory omega-6 signature pattern and higher VAT levels, and seem to reflect the cardiovascular status of young adults.

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

“…While this might seem contradictory, these findings fit well with our results if a distinction is made between normal physiological and aberrantly high succinate levels. Indeed, in our perspective, succinate pleiotropy is well explained by the amount of succinate available: low, physiological levels of succinate have beneficial and homeostatic effects in a healthy setting, as for example improving glycemic control through activation of intestinal gluconeogenesis [9], whereas an excess of succinate is generated in different pathological scenarios where it plays a damaging pro-inflammatory role, not only in the context of obesity-related disorders and its complications [4,[67][68][69] but also in other diseases such as IBD [8]. Similarly, this dichotomy has also been reported for some SCFAs such as propionic acid, which although defined as an anti-inflammatory factor, is significantly increased in patients with type 2 diabetes and is linked to gut barrier disruption [54].…”

Metabolic Syndrome and Overactive Bladder Syndrome May Share Common Pathophysiologies

“…Succinate is an essential intermediate of the tricarboxylic acid cycle that exerts pleiotropic roles through GPR91 (a G protein-coupled receptor), including worse hypertension, metabolic signaling, and impaired glucose intolerance [ 64 , 65 ]. Researchers reported that plasma succinate levels are linked to proinflammation and more visceral adipose tissue in young adults [ 66 ]. Mossa et al reported that urothelial cells and detrusor muscle can express GPR91 [ 67 ].…”

Cardio-onco-metabolism: metabolic remodelling in cardiovascular disease and cancer

“…However, whether succinate drives tumorigenesis and acts as a metabolic signal during malignancy remains to be determined. Increased plasma succinate levels are associated with CVDs and increased inflammation, as well as ischaemiareperfusion injury 129,130 . Preclinical studies suggest that succinate release from cancer cells activates an immune response and cellular signalling via succinate receptor 1 (reFs 131,132 ).…”