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

Abstract

Background: MicroRNAs (miRNAs) are short noncoding RNAs and important posttranscriptional 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.

Methods: This study included adults with abdominal obesity from an 18-mo diet and physical activity intervention trial. Circulating miR-99a-5p, miR-99b-5p, and miR-100-5p were measured at baseline and 18 mo; changes in these miRNAs in response to the interventions were evaluated. The primary outcomes were changes in abdominal adipose tissue [visceral (VAT), deep subcutaneous (DSAT), and 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 ± SE per 1-SD decrease: -9.63 ± 3.13 cm2; P = 0.0025), DSAT (β ± SE: -5.48 ± 2.36 cm2; P = 0.0218), SSAT (β ± SE: -4.64 ± 1.68 cm2; P = 0.0067), and intrahepatic fat percentage (β ± SE: -1.54% ± 0.49%; P = 0.0023) after the interventions. Similarly, participants with greater decrease in miR-99a-5p had larger 18-mo reductions of VAT (β ± SE: -10.12 ± 3.31 cm2 per 1-SD decrease; P = 0.0027) and intrahepatic fat percentage (β ± SE: -1.28% ± 0.52%; P = 0.015). Further, decreases in circulating miR-99b-5p (β ± SE: per 1-SD decrease: -0.44% ± 0.21%; P = 0.038) and miR-100-5p (β ± SE: -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 mo.

Conclusions: Decreases in circulating miR-99-5p/100-5p expression 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.This trial was registered at clinicaltrials.gov as NCT01530724.

Keywords: body fat distribution; ectopic fat; insulin sensitivity; lifestyle interventions; microRNAs.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1

Associations of changes in circulating miR-99/100 after a diet/lifestyle intervention with 18-mo changes in intrahepatic fat (A) and pancreatic fat (B). Data are β ± SE per 1-SD decrease in each miRNA change (% change from baseline to 18 mo after the intervention) for changes in (A) intrahepatic fat (n = 141) or (B) pancreatic fat (n = 143) after adjusting for age, sex, intervention group, the respective miRNA at baseline, and the respective outcome trait at baseline using general linear models. The definition of 1 SD decrease: −9.18% for miR-100-5p; −6.29% for miR-99a-5p; −5.97% for miR-99b-5p. miRNA, microRNA; miR-99/100, microRNA-99/100.

FIGURE 2

Trajectories of changes in VAT and intrahepatic fat over 18 mo according to the tertile categories of miR-100-5p changes (A, B) or miR-99a-5p changes (C, D). Total number of participants: n = 87 at 6 mo; n = 144 at 18 mo. For the tertiles of miR-100-5p changes (% change from baseline to 18 mo after the intervention), median (IQR) values were as follows: T1 (dashed): −5.0% (−9.8%, −2.7%); T2 (gray): 2.5% (1.4%, 5.1%); and T3 (black): 12.4% (8.1%, 16.4%). For the tertiles of changes in miR-99a-5p (% change from baseline to 18 mo after the intervention), median (IQR) values were as follows: T1 (dashed): −4.6% (−6.8%, −2.7%); T2 (gray): 1.6% (0.4%, 2.6%); and T3 (black): 7.1% (5.4%, 10.4%). Ptime × miRNA interactions by the linear mixed models: (A) Ptime × miR-100-interaction = 0.033; (B) Ptime × miR-100-interaction < 0.001; (C) Ptime × miR-99a-interaction = 0.014; (D) Ptime × miR-99a-interaction = 0.005. miR-99/100, microRNA-99/100; T, tertile; VAT, visceral adipose tissue.