De acute daling van leptine na een energiearme voeding : een biologische indicator voor de gevoeligheid voor het ontwikkelen van overgewicht?

The last decades the prevalence of obesity has been increasing. However, large inter-individual differences in weight gain are observed. Poor energy intake regulation is one of the possible mechanisms behind a large susceptibility to weight gain. The hormone leptin is suggested to have a key-role in the regulation and restoration of energy balance. Therefore, we hypothesized that the acute leptin decline after energy restriction might be a marker for the susceptibility to weight gain. In other words, is the leptin response an individual trait that is related to the ability to restore energy balance and is it therefore related to the susceptibility to weight gain? To test this hypothesis we conducted three controlled intervention studies in which male subjects received an energy restriction of ~65% during a few days. First of all, we performed a reliability study in we which assessed the reliability of the insulin and ghrelin response on short-term (3 weeks) and long-term (1½ year). On the short-term, the leptin decline had a relatively high reliability (Intra Class Correlation [95%-Confidence interval]=0.66 [0.33; 0.85]) compared to the decline in insulin (ICC=0.45 [0.03; 0.74]) and the increase in ghrelin (ICC=0.34 [0; 0.67]). On the long-term however, the acute leptin response showed a lower reliability (ICC=0.34 [0; 0.67]). After that, we hypothesized that the leptin responsiveness to energy restriction is affected by the functionality of the leptin receptor; therefore we explored the effect of three common polymorphisms in the leptin receptor gene (Lys109Arg, Gln223Arg and Lys656Asn) on the acute leptin decline. The analyses revealed no statistically significant differences in leptin response between genotypes, i.e. between carriers and non-carriers of the mutant allele. Next, we investigated whether the acute decline in leptin is a biomarker for weight gain with different (intermediate) endpoints, i.e. appetite, energy intake compensation, and retrospective weight gain. We hypothesised that the decline in leptin is related to subjective appetite ratings, ratings that reflect hunger, fullness, desire to eat, prospective consumption, and total appetite. We observed that the magnitude of the acute decline was indeed positively associated with the increase in hunger (r=0.42; p<0.05), desire to eat (r=0.39; p<0.05), and total appetite (r=0.35; p<0.05). Next, we investigated the association between the amount of energy that is compensated in the days following energy restriction and the magnitude of the leptin decline during energy restriction. Although we found that leptin levels declined by 24% [95%-Confidence Interval: -33%; -15.9%] and subjects showed compensatory behaviour (143 ± 27% on the first day and 124 ± 20% on the second day after energy restriction), no association was observed between the magnitude of the leptin decline and energy intake compensation (r=0.22; ns). Lastly, we investigated whether individuals with stable weight show larger leptin declines to energy restriction than individuals who gained weight. Proportionally, an 8% smaller decrease in leptin was observed in men with retrospective weight gain. However, in a selected subgroup with a larger difference in retrospective weight gain, this difference in leptin response was not found; therefore, we concluded that the data did not provide convincing evidence for our hypothesis that men who gained weight are less leptin responsive to changes in energy balance than men who were weight stable.Overall, we conclude that the leptin decline to energy restriction is not a good biomarker for the susceptibility to weight gain. However, it may be a good indicator for energy balance or the increase in appetite during energy restriction.