Elevated Serum Uric Acid Is a Facilitating Mechanism for Insulin Resistance Mediated Accumulation of Visceral Adipose Tissue

Background: Serum uric acid (SUA) is related to cardiometabolic conditions such as insulin resistance (IR) and visceral adipose tissue (VAT) accumulation, which have a thoroughly explored bidirectional relationship. Here, we aimed to clarify the nature of the role uric acid plays inside this relationship, alongside the underlying causality mechanism. Methods: We conducted a population-based cross-sectional study comprising 8,504 subjects from a joint cohort composed from both NHANES 2003–2004 and 2011–2012 cycles and ENSANUT Medio Camino 2016. We performed mixed effects linear regression models using HOMA2-IR, adipoIR, and METS-VF as indicators of both peripheral and adipose tissue IR and VAT accumulation, indicating the subject’s cohort of origin as a random effect. Furthermore, we performed multiple mediation analyses to assess a potential causal mechanism and ROC curves to establish cut-off points for identification of IR and visceral obesity using SUA. Finally, with an additional dataset comprised of 226 subjects with both euglycemic hyperinsulinemic clamp (EHC) and dual X-ray absorptiometry (DXA) measurements for IR and VAT accumulation, we performed a network of confirmatory mediation analyses including adiponectin measurements. Results: We found that SUA has a mediating role inside the bidirectional relationship between IR and visceral obesity, and it is part of an underlying causality mechanism which includes adiponectin. The proportion of the mechanism mediated by SUA is greater when stated that IR (in either peripheral or adipose tissue) leads to VAT accumulation (14.90%[13.20%-17.00%] and 15.54%[13.61%-18.00%]) instead of the opposite direction (4.88%[3.06%-7.00%] and 8.13%[5.91%-10.00%]). This result was strengthened by a mediation analysis network using the gold-standard measurements where we observed that the joint effect of SUA and adiponectin mediated 16.32% [8.84%-26.00%] for the effect of IR and VAT accumulation and 12.52% [3.23%-23.00%] in the opposite direction. Cut-off points for SUA to predict peripheral IR were 6.1 mg/dL and 4.8 mg/dL, for males and females respectively. For visceral obesity, cut-offs were 6.4 mg/dL and 4.8 mg/dL for males and females. SUA had a high negative predictive value for all assessments. Conclusions: Elevated SUA acts as mediator inside the bidirectional relationship between IR and VAT accumulation. Its role appears to be larger when considering adipose tissue IR as the promoter for VAT accumulation.