1,25-Dihydroxyvitamin D regulates lipid metabolism and glucose utilization in differentiated 3T3-L1 adipocytes

It is well established that adipose tissue can both store and metabolize vitamin D. The active form of vitamin D, 1,25 dihydroxyvitamin D [1,25(OH)₂D], regulates adipocyte differentiation and inflammation, highlighting the multifaceted role that vitamin D plays in adipose tissue physiology. However, there is limited evidence regarding vitamin D regulation of mature adipocyte lipid metabolism. We hypothesize that 1,25(OH)₂D alters lipid and glucose metabolism in differentiated 3T3-L1 adipocytes to reduce triacylglycerol (TAG) accumulation. In this study, 1,25(OH)₂D (10 nmol/L) stimulated a 21% reduction in TAG accumulation in differentiated 3T3-L1 adipocytes after 4 days (P = .01) despite a significant increase in fatty acid uptake (P < .01). Additionally, 1,25(OH)₂D stimulated a 2.5-fold increase in ¹⁴CO₂ production from [1-¹⁴C] palmitic acid (P < .01), indicative of an elevated rate of fatty acid β-oxidation, while stimulating a 9% reduction in de novo fatty acid synthesis (P = .03). Interestingly, d-[U-¹³C]glucose incorporation into fatty acids was reduced by 30% in response to 1,25(OH)₂D (P < .01), indicating a reduced contribution of glucose as a substrate for de novo lipogenesis. Consistent with these findings, mRNA expression of the anaplerotic enzyme pyruvate carboxylase was reduced by 41% (P < .01). In summary, 1,25(OH)₂D stimulated fatty acid oxidation and reduced TAG accumulation in differentiated adipocytes. Furthermore, 1,25(OH)₂D reduced glucose utilization as a substrate for fatty acid synthesis potentially by downregulating pyruvate carboxylase and stimulating glucose disposal as glycerol. Collectively, these 1,25(OH)₂D-induced changes in lipid metabolism and glucose utilization may contribute to the reduction in TAG accumulation and be protective against excessive fat mass accumulation and associated metabolic disorders.