Elevated serum uric acid is a facilitating mechanism for insulin resistance mediated accumulation of visceral adipose tissue

ABSTRACT OBJECTIVE Serum uric acid (SUA) has been associated to cardiometabolic conditions such as insulin resistance (IR) and visceral adipose tissue (VAT) accumulation. Here, we aimed to clarify a unifying mechanism linking elevated SUA to IR and VAT. METHODS We conducted analyses in 226 subjects from the UIEM cohort with both euglycemic hyperinsulinemic clamp (EHC) and dual X-ray absorptiometry (DXA) measurements for IR and VAT accumulation, and explored the role of SUA and adiponectin by developing a network of causal mediation analyses to assess their impact on IR and VAT. These models were then translated to two population-based cohorts comprising 6,337 subjects from NHANES 2003-2004 and 2011-2012 cycles in the US and ENSANUT Medio Camino 2016 in Mexico, using HOMA2IR and adipoIR as indicators of peripheral and adipose tissue IR, and METS-VF as a surrogate for VAT accumulation. Results SUA has a mediating role inside a bidirectional relationship between IR and visceral obesity, which was similar using either gold standard measurements or surrogate measures for IR and VAT. Furthermore, adiponectin acts as a linking mediator between elevated SUA and both peripheral IR and VAT accumulation. The proportion of the mechanism for IR-mediated (in either peripheral or adipose tissue) VAT accumulation was greater, compared to VAT-mediated IR accumulation (10.53%[9.23%-12.00%] to 5.44%[3.78%-7.00%]). Normal-range SUA levels can be used to rule-out underlying cardio-metabolic abnormalities in both men and women. CONCLUSIONS Elevated SUA acts as mediator inside the bidirectional relationship between IR and VAT accumulation and these observations could be applicable at a phenotype scale.