GDF15 and its receptors as pathways mediating smoking related weight change.

BACKGROUND

Smokers have lower body weight than non-smokers, while smoking cessation results in weight gain. Understanding the mechanisms involved can help identify potential therapeutic targets to enhance smoking cessation.

METHODS

We measured plasma levels of growth/differentiation factor 15 (GDF15), a stress-responsive protein, and its two receptors (proto-oncogene tyrosine-protein kinase receptor Ret [RET], GDNF family receptor alpha-like [GFRAL]) among 3936 Chinese adults (mean BMI 24.0 kg/m), using Olink and SomaScan platforms. We assessed associations of individual proteins and GDF15/receptor ratios with smoking and adiposity using linear regression. In two-sample Mendelian randomization (MR) analyses, we used genetic variants for smoking intensity from publicly available GWAS as instruments to assess their causal associations with adiposity and plasma levels of proteins in East Asian and European populations. We further assessed the effects of GDF15 and GDF15/receptor ratios in mediating smoking-related weight change.

FINDINGS

Overall, smokers had significantly lower BMI (23.1 [0.2] kg/m) than never-smokers (24.0 [0.1] kg/m), while former smokers had the highest levels of BMI (24.6 [0.2] kg/m) and other measures of adiposity (e.g., waist circumference, waist/hip ratio, and body fat percentage). In observational analyses, smoking was positively associated with GDF15 and with GDF15/receptor ratios from both platforms, with GDF15 levels increasing steeply with number of cigarettes smoked on the assessment day. In MR analyses, smoking intensity was significantly associated with a reduced BMI in East Asians and with higher GDF15 levels in both East Asian and European populations. SomaScan_GDF15 partially mediated the associations of smoking with all adiposity measures, while Olink_GDF15 mediated the association with body fat percentage. The GDF15/RET ratio more robustly mediated the smoking-adiposity relationships than GDF15 alone in both platforms.

INTERPRETATION

In Chinese adults GDF15 plays a role in mediating smoking-related weight change, and could serve as a therapeutic target to facilitate smoking cessation and minimise cessation-induced weight gain.

FUNDING

British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.