Phenotypic and genetic variation in leptin as determinants of weight regain

Abstract

Aims: Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention. Subjects and methods: In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the 'weight loss phase' (0-6 months) and the 'weight maintenance/regain phase' (7-24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP). Results: Mean weight reduction was À5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7-24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0-to 6-month weight loss (b ¼ À0.222, P-value ¼ 0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (b ¼ 0.505, P-valueo0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (b ¼ À0.131, P-valueo0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin ( þ 3.4% (95% confidence interval 2.1-4.8)) as compared with those in the lowest combined tertiles ( þ 0.2% (95% confidence interval À1.1 to 1.4)); P-valueo0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P ¼ 0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%. Conclusion: Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.

Human Biology of Weight Maintenance after Weight Loss

“…The fact that higher baseline plasma levels seemed to predict weight regain had been reported before [13]. Further, in a study with a weight loss phase of 6 months and a follow-up of 7–24 months, Erez et al [49 ]showed that weight regain was predicted by a relatively strong decrease in weight together with a decrease in leptin. On the other hand, conflicting findings have been reported as well.…”

Baseline characteristics associated with different BMI trajectories in weight loss trials: a case for better targeting of interventions

“…Strong hormonal influences drive weight regain after weight loss 26 , and the individual variation in this process has yet to be characterised. However associations between success of initial weight loss and baseline leptin levels have been demonstrated 27 . Many genes may be involved in causing and/or promoting obesity and so it is not unexpected that the phenotypic presentation and response to treatments may vary substantially 28 .…”

Effects of a 2-y dietary weight-loss intervention on cholesterol metabolism in moderately obese men

“…HOMA-IR was calculated according to the following equation (22): insulin (lU/mL) · fasting glucose (mmol/L)/ 22.5. Details of the methods were described previously (23).…”