Metabolites that activate the inflammasome in nascent metabolic syndrome.

Abstract

Metabolic Syndrome (MetS) is a cardio-metabolic cluster that increases the risk of type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). Whilst it affects 35% of the American adult population, its pathogenesis remains to be elucidated. Both insulin resistance and increased inflammation appear to be pivotal mechanisms. The NOD-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome, an intracellular multi-protein complex, is crucial in the activation of Caspase 1, resulting in an increase in both IL-1and IL-18. In this preliminary report we examined the relationship between metabolites from our exploratory metabolomics studies with the NLRP3 inflammasome activity in the adipose tissue of patients with nascent MetS. This study comprised patients with nascent MetS matched with controls. All patients in this study had normal renal and hepatic function. Metabolites were analyzed from frozen early morning urine samples and correlated with adipose tissue Caspase 1, interleukin-1, and interleukin-18 density. Caspase 1, a marker of NLRP3 inflammasome activity, was significantly elevated in patients with nascent MetS compared to controls. Isoleucine, GABA, Carnitine and PC34: 2 were also significantly increased in patients with MetS. Caspase1 correlated positively with Isoleucine, GABA, Carnitine, and PC34:2. We make the novel observation that the NLRP3 inflammasome activity is correlated with certain metabolites (Isoleucine, GABA, Carnitine and PC34:2) and hypothesize that they could trigger increased NLRP3 Inflammasome activity in MetS. However, these preliminary ,hypothesis generating novel findings need confirmation in larger studies of the metabolome and inflammasome.