Circulating MicroRNA-128-1 And Changes In Energy Metabolism And Insulin Sensitivity In Response To Weight Loss Diet Interventions: The Pounds Lost Trial

Background: MicroRNA (miRNAs) are short non-coding RNAs that play important roles in regulating gene expression. Recently, miR-128-1 was identified as a potential thrifty miRNA that controls energy expenditure, contributing to obesity and metabolic diseases. miR-128-1 is located at the locus harboring the lactase ( LCT ) gene, a hallmark gene of the positive selection and evolutionary adaptation to famine by promoting energy storage. Hypothesis: We investigated whether circulating thrifty miR-128-1 was associated with insulin resistance, adiposity, and energy expenditure among adults with overweight and obesity and tested whether miR-128-1 was associated with changes in these metabolic conditions after low-calorie weight-loss diet interventions. Methods: We included 495 participants from the POUNDS Lost trial with available data on circulating miR-128-1-5p measured at baseline and 6 months after the intervention. The LCT genotype rs4988235, which is responsible for lactase persistence in Europeans, was assessed to analyze the relationship between miR-128-1 and the positive selection at this locus. Outcome measurements included adiposity (weight, waist circumference [WC], and body composition), insulin resistance (HOMA-IR), and energy metabolism. Habitual physical activity was assessed by the Baecke questionnaires; total, leisure time, sport, work index were calculated. Results: The LCT rs4988235 (A) allele was associated with higher levels of miR-128-1 ( p =0.04). Pre-intervention miR-128-1 was significantly and positively associated with HOMA-IR ( p =0.009), insulin ( p =0.008), BMI ( p =0.0002), WC ( p =0.036), and whole-body total % fat mass ( p =0.013), and energy metabolism (resting energy expenditure, oxygen consumption, and carbon dioxide production; p <0.05 for all). Also, we found that higher miR-128-1 was related to lower total physical activity index ( p =0.001) and subscales (leisure index ( p =0.007) and sport index ( p =0.02)). We found significant interactions between miR-128-1 and physical activity on changes in adiposity and insulin resistance at 6 months after the interventions ( P interaction =0.03 for weight; P interaction =0.004 for WC; and P interaction =0.01 for HOMA-IR). Participants with lower levels of physical activity and higher miR-128-1 at baseline responded better to the intervention to improve HOMA-IR at 6 months. There were also significant interactions between changes in miR-128-1 and changes in physical activity on changes in HOMA-IR and energy expenditure. Conclusions: Elevated levels of circulating miR-128-1 were associated with greater adiposity and insulin resistance in adults with overweight and obesity. The thrifty miR-128-1 interacted with physical activity on changes in energy metabolism and insulin sensitivity in response to weight-loss diet interventions.