Gastric bypass surgery with exercise alters plasma microRNAs that predict improvements in cardiometabolic risk

Abstract

Background/objectives: Roux-en-Y gastric bypass (RYGB) surgery improves insulin sensitivity (S_I) and β-cell function in obese non-diabetic subjects. Exercise also improves S_I and may be an effective adjunct therapy to RYGB surgery. However, the mechanisms by which exercise or weight loss improve peripheral S_I after RYGB surgery are unclear. We hypothesized that microRNAs (miRNAs) mediate at least some of the regulatory processes driving such mechanisms. Consequently, this work aimed at profiling plasma miRNAs in participants of the Physical Activity Following Surgery Induced Weight Loss study (clinicaltrials.gov identifier: NCT00692367), to assess whether miRNA levels track with improvements in S_I and cardiometabolic risk factors.

Subjects/methods: Ninety-four miRNAs implicated in metabolism were profiled in plasma samples from 22 severely obese subjects who were recruited 1-3 months after RYGB surgery and followed for 6 months of RYGB surgery-induced weight loss, with (exercise program (EX), N=11) or without (CON, N=11) an exercise training intervention. The subjects were selected, considering a priori sample size calculations, among the participants in the parent study. Mixed-effect modeling for repeated measures and partial correlation analysis was implemented in the R environment for statistical analysis.

Results: Mirroring results in the parent trial, both groups experienced significant weight loss and improvements in cardiometabolic risk. In the CON group, weight loss significantly altered the pattern of circulating miR-7, miR-15a, miR-34a, miR-106a, miR-122 and miR-221. In the EX group, a distinct miRNA signature was altered: miR-15a, miR-34a, miR-122, miR-135b, miR-144, miR-149 and miR-206. Several miRNAs were significantly associated with improvements in acute insulin response, S_I, and other cardiometabolic risk factors.

Conclusions: These findings present novel insights into the RYGB surgery-induced molecular changes and the effects of mild exercise to facilitate and/or maintain the benefits of a 'comprehensive' weight-loss intervention with concomitant improvements in cardiometabolic functions. Notably, we show a predictive value for miR-7, miR-15a, miR-106b and miR-135b.

Figure 1

Schematic representation of the study design and sample collection.

Figure 2

Dual boxplot/dotplot for miRNAs that significantly changed in the exercise (EX) and/or the control (CON) groups. (a–c), Pattern A miRNAs; (d–f), Pattern B miRNAs; (g–j), Pattern C miRNAs. Data presented are quantile-normalized log fold changes respective to spiked-in cel-miR-39. Dual plots include (pre–post) connected dotplots for each group (CON and EX), where connected dots represent corresponding pre-intervention–post-intervention measurements for each individual participant (n = 11 per group). Boxplots (boxes delineating first and third quartile; whiskers delineating the smallest and largest values inside a 1.5 box-length (IQR) from the end of the box) summarize the data presented in the corresponding (side-by-side) dotplot. Red dots represent potential outliers located at greater that 1.5 IQR from the end of the box. Blue filling for CON group and orange filling for EX group. IQR, interquartile range.

Figure 3

Correlations between the changes in cardiometabolic risk factors and differentially abundant circulating miRNAs. (a–e) Relevant correlations with changes in patterns A and B miRNAs in the CON group; (f–j) relevant correlations with changes in patterns A and C miRNAs in the EX group; (k–n): relevant correlations with baseline miRNA levels in the complete cohort (miRNAs with predictive potential). Blue and orange dots represent individual data points for CON and EX group, respectively. Reported are partial correlations adjusted for age and time from bariatric surgery to pre-treatment. Data points ploted are unadjusted quantile-normalized log fold changes (x axis) respective to spiked-in cel-miR-39 levels. For visualization purposes, a fitted line on the unadjusted data with 95% confidence band is also drawn. A full color version of this figure is available at the International Journal of Obesity journal online.