Nicotinuric acid acts as a pro-diabetic tryptophan metabolite in human and rodent obesity

Background: Obesity and Type 2 diabetes are linked to an imbalance in nicotinic acid (NA) metabolism. While NA has lipid-modulating and anti-inflammatory properties, only little is known about its degradation product, nicotinuric acid (NUA). This study aims to investigate the role of NUA in the pathophysiology of metabolic diseases through an exploratory analysis using cross-sectional cohort data followed by an obesity mouse model and cell culture experiments.

Methods: An exploratory analysis was conducted with data from the FoCus cohort (N=1767). NUA serum levels were measured using FT-ICR-MS and analyzed in relation to metabolic phenotypes using age- and sex-adjusted Tobit-regression models designed for left-censored data. A mouse model, comprising wildtype and HCA2-knockout (KO) mice, was used to validate previously identified associations. 126 mice were fed a high-fat diet for 6 weeks inducing obesity, followed by an 8-week supplementation with either NA, NUA or water as control. Weight was regularly monitored, and insulin resistance was assessed by glucose tolerance test (GTT) at the end of intervention. Cell culture experiments (HepG2, INS-1, THP-1, neutrophils, monocytes) examined NUA effects on hepatic lipogenesis, insulin sensitivity, inflammation, and intracellular signaling, respectively.

Results: NUA was detected in 34.97% of participants. Higher NUA levels were associated with obesity, Type 2 diabetes, hypertension (p<0.001), and cardiovascular disease (p<0.05). NUA also correlated with inflammation and metabolic biomarkers (p<0.001: CRP, p<0.01: HOMA-IR, triglycerides, lipoprotein(a), p<0.05: sDPP-4). In mice, NA and NUA supplementation resulted in smaller weight gain independent of HCA2-KO towards the end of intervention (p<0.05). Contrary, only in the KO-model, GTT revealed stronger impairment of glucose regulation by NA and NUA compared to water controls with significantly higher serum glucose after 120 minutes (NA vs. controls: p<0.05, NUA vs. controls: p<0.001, NA vs. NUA: p<0.05). In HepG2 cells, NUA mildly increased SREBP-1 expression (p<0.05), proposing effects on lipogenesis. No effects were observed on insulin secretion (INS-1) or NF-κB p50 expression (THP-1). NUA induced Ca²⁺ flux and reduced NF-κB p65 expression in neutrophils (p<0.05). In monocytes, NUA decreased MAPK activation and protein kinase activity (p<0.05), while both cell types showed reduced cAMP levels (p<0.01 neutrophils; p<0.05 monocytes).

Conclusion: Our findings suggest that NUA is elevated in metabolic disease states and may influence metabolic regulation, inflammation, and intracellular signaling contrary to its precursor NA. NUA appears to impact glucose homeostasis in obese mice even with smaller overall weight gain, yet its role in metabolic disease progression remains complex and requires further investigation. Ongoing tissue-specific studies will provide deeper insights into its metabolic impact.