Changes in circulating MicroRNAs-99/100 and reductions of visceral and ectopic fat depots in response to lifestyle interventions: The CENTRAL trial.

BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNAs and important post-transcriptional regulators of gene expression. Adipose tissue is a major source of circulating miRNAs; adipose-related circulating miRNAs may regulate body fat distribution and glucose metabolism. OBJECTIVES: We investigated how changes in adipose-related circulating microRNAs-99/100 (miR-99/100) in response to lifestyle interventions were associated with improved body fat distribution and reductions of diabetogenic ectopic fat depots among adults with abdominal obesity. DESIGN: This study included adults with abdominal obesity from an 18-month diet and physical activity intervention trial. Circulating levels of miR-99a-5p, miR-99b-5p, and miR-100-5p were measured at baseline and 18 months; changes in these miRNAs in response to the interventions were evaluated. The primary outcomes were changes in abdominal (visceral [VAT], deep subcutaneous [DSAT], superficial subcutaneous [SSAT]) adipose tissue (cm2) (n = 144). The secondary outcomes were changes in ectopic fat accumulation in the liver (n = 141) and pancreas (n = 143). RESULTS: Greater decreases in miR-100-5p were associated with more reductions of VAT (β per 1 SD decrease: -9.63 [SE 3.13]; P = 0.0025], DSAT (β -5.48 [2.36]; P = 0.0218), SSAT (β -4.64 [1.68]; P = 0.0067), and intrahepatic fat percentage (β -1.54 [0.49]; P = 0.0023) after the interventions. Similarly, participants with greater decrease in miR-99a-5p had larger 18-month reductions of VAT (β -10.12 [3.31] per 1 SD decrease; P = 0.0027) and intrahepatic fat percentage (β -1.28 [0.52]; P = 0.015). Further, decreases in circulating miR-99b-5p (β per 1 SD decrease: -0.44 [0.21]; P = 0.038) and miR-100-5p (β -0.50 [0.23]; P = 0.033) were associated with a decrease in pancreatic fat percentage, as well as improved glucose metabolism and insulin secretion at 18 months. CONCLUSIONS: Decreases in circulating miR-99-5p/100-5p levels induced by lifestyle interventions were related to improved body fat distribution and ectopic fat accumulation. Our study suggests that changes in circulating adipose-related miR-99-5p/100-5p may be linked to reducing diabetogenic fat depots in patients with abdominal obesity