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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; cm(2)] (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 cm(2); P = 0.0025), DSAT (β ± SE: −5.48 ± 2.36 cm(2); P = 0.0218), SSAT (β ± SE: −4.64 ± 1.68 cm(2); 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 cm(2) 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.

Purpose Little is known about the relations between changes in circulating microRNA-122 (miR-122) and liver fat in response to weight-loss interventions. We aimed to investigate the association between miR-122 and changes of hepatic fat content during 18-month diet and physical activity interventions. Methods The CENTRAL trial is an 18-month randomized, controlled trial among adults with abdominal obesity or dyslipidemia. Subjects were randomly assigned to a low-fat diet or a Mediterranean/low-carbohydrate diet. After 6 months of dietary intervention, each diet group was further randomized into added physical activity groups or no added physical activity groups for the following 12 months of intervention. The current study included 220 participants at baseline and 134 participants with repeated measurements on serum miR-122 and hepatic fat content over 18 months. Results Serum miR-122 significantly increased from baseline to 18 months, while no difference was observed across the 4 intervention groups. We found a significant association between miR-122 and hepatic fat content at baseline, as per unit increment in log-transformed miR-122 was associated with 3.79 higher hepatic fat content (P Conclusions Our data indicate that participants with higher elevation in serum miR-122 may benefit less in reduction of hepatic fat content in response to diet and physical activity interventions.

OBJECTIVE To investigate whether changes in circulating levels of pancreatic islet–related miRNA-375 (miR-375) are related to improved visceral and intrahepatic fat accumulation. RESEARCH DESIGN AND METHODS This study included adults with abdominal obesity from an 18-month weight loss lifestyle intervention trial. Circulating miR-375-3p was measured at baseline and 18 months. MRI was performed (n = 139) to assess 18-month changes in abdominal and intrahepatic fat depots. RESULTS Circulating miR-375-3p was related to fasting insulin and insulin resistance in participants with prediabetes. After the interventions, there was a significant increase of miR-375-3p (P < 0.001). Greater increase in miR-375-3p was associated with greater reductions of visceral (P = 0.024) and deep subcutaneous (P < 0.001) adipose tissues and intrahepatic fat content (P = 0.012). CONCLUSIONS Increases in circulating miR-375-3p were associated with visceral and intrahepatic fat reduction. Changes in circulating pancreatic islet–related miR-375-3p may be linked to improved diabetogenic fat depots during weight loss lifestyle interventions.

Introduction: MicroRNA (miRNAs) are short non-coding RNAs that regulate gene expression at the translational level. Circulating exosomal miRNAs have emerged as novel biomarkers of obesity, insulin resistance, and related metabolic abnormalities. miR-375 has been identified as a regulator of insulin secretion, and miR-375 may also be involved in regulating visceral adiposity and ectopic fat accumulation in the liver. Hypothesis: We aimed to investigate whether changes in circulating miR-375 induced by lifestyle interventions were related to improved visceral adiposity and hepatic fat depot among individuals with abdominal obesity. Methods: This study included adults with abdominal obesity from an 18-month diet and physical activity intervention study (the CENTRAL trial) and with available data on circulating miR-375-3p at baseline (n=222) and 18 months (n=152). Magnetic resonance imaging (MRI) was performed to assess body fat distribution and ectopic fat depots. Outcome measurements included 18-month changes in abdominal (total [TAT], visceral [VAT], deep subcutaneous [DSAT], superficial subcutaneous [SSAT]) adipose tissue area and intrahepatic fat content. Results: At baseline, higher levels of miR-375 were related to lower degrees of BMI ( p =0.0006), waist circumference ( p =0.0008), as well as abdominal adipose tissue area (TAT [ p =0.0024], VAT [ p =0.059], DSAT [ p =0.011], and SSAT [ p =0.0027]). There was a significant increase in circulating miR-375 levels after the 18-month lifestyle interventions ( P by paired t-test < 0.0001). When we analyzed effects (β) of per 1 SD increase in miR-375 changes on the outcomes after adjusting for covariates including baseline levels of miR-375 and BMI, we found that greater increase in miR-375 was associated with larger reductions of VAT (β -8.09 [3.09] cm 2 , p =0.01), as well as DSAT (β -7.87 [2.21] cm 2 , p =0.001) and intrahepatic fat content (β -1.38% [0.5%], p =0.006) at 18 months. Conclusions: Circulating miR-375 levels significantly increased after the long-term lifestyle interventions, and greater increases in miR-375 were related to significant improvements in visceral adiposity and liver fat content that are closely related to insulin resistance in adults with abdominal obesity.

MicroRNAs (miRNAs) are small non-coding RNAs, and adipose tissue is a major source of circulating miRNAs that may regulate body fat distribution. We investigated whether changes in circulating adipose-derived miRNAs (miR-99a-5p, miR-99b-5p, and miR-100-5p) were related to improvements in visceral and ectopic fat depots in abdominal obese adults who participated in the CENTRAL diet-and-lifestyle intervention trial. We further tested whether changes in these miRNAs were related to improved glucose metabolism and insulin sensitivity after the intervention. Plasma levels of miRNAs were measured both at baseline (n=227) and 18 months (n=157) after the intervention; changes in miRNAs from baseline to 18 months were calculated. Magnetic resonance imaging (MRI) was performed to assess visceral adipose tissue (VAT), intrahepatic fat %, and pancreatic fat %. At baseline, higher levels of miR-99a-5p and miR-100-5p were associated with greater intrahepatic fat (p Disclosure Y. Heianza: None. P. Kovacs: None. I. Shai: None. L. Qi: None. K. K. Krohn: None. M. Wang: None. A. Yaskolka meir: None. Q. Xue: None. S. Ziesche: None. U. Ceglarek: Research Support; Self; Roche Diagnostics Germany. M. Blüher: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH, Speaker’s Bureau; Self; Daiichi Sankyo, Novartis AG. M. Keller: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK091718, DK100383, DK115679)