Discussion
obesity, adiposity, obesity-induced hepatic dysfunction, cardiometabolic dysfunction, diabetes
OBESITY, PARATHYROID, ADIPOSITY, DIABETES
Our analysis of older US adults from the randomized VITAL presents novel hypothesis-generating evidence that adiposity blunts the response to vitamin D supplementation. Consistent with prior cross-sectional evidence, higher overall and central obesity were associated with significantly lower serum total 25-OHD levels in our large sample size of 16 515 participants at baseline, controlling for numerous variables used to estimate vitamin D levels. Furthermore, treatment with vitamin DSeveral authors of the present study previously explored factors associated with changes in serum 25-OHD levels from baseline to 1-year follow-up in VITAL and identified minoritized race and ethnicity, baseline 25-OHD levels, and nonrandomized supplementation as factors related to the magnitude of change.There are conflicting hypotheses as to why higher BMI might be associated with lower 25-OHD circulating levels or activity. One theory proposes that, as a fat-soluble vitamin, there is a greater removal of vitamin D from circulation due to increased storage capacity across higher adiposity volumes.Another hypothesis posits obesity-induced hepatic dysfunction contributes to impaired vitamin D metabolism. Oral vitamin D enters circulation and is activated enzymatically in the liver to 25-OHD by cytochrome P450 (CYP) enzymes. Interference in metabolism by obesity and related cardiometabolic dysfunction would result in a dampened response to vitamin D supplementation on the amount of circulating 25-OHD and its downstream activity. Animal models demonstrated downregulation of CYP2R1 in obesity and diabetes.Parathyroid hormone levels correspond inversely to serum 25-OHD, with insufficient vitamin D leading to elevated PTH levels and normalization of PTH levels in response to supplementation.