A study by researchers from Oxford Population Health and Peking University has shed new light on the mechanisms associated with weight gain after stopping smoking. The study is published in eBioMedicine.
Tobacco smoking remains a major global driver of disability and death, particularly in China, the world’s largest consumer of tobacco. The health benefits of stopping smoking cessation are well-known and unquestionable. However, smokers’ concerns over post-cessation weight gain can be a significant barrier to quitting.
The biological mechanisms underlying this association are incompletely understood; clarifying these could identify targets for future treatments that may mitigate this weight gain and facilitate higher cessation rates.
Growth/differentiation factor 15 (GDF15) is a protein that suppresses appetite through activation of receptor proteins (GDNF family receptor alpha-like (or GFRAL) and proto-oncogene tyrosine kinase receptor Ret (RET)) in the hindbrain, a part of the brain located at its base near the spinal cord.
The plasma levels of these three proteins were measured among 3936 relatively lean participants from the China Kadoorie Biobank using Olink and SomaScan proteomic platforms. This study explored their potential roles in mediating smoking-related weight changes.
Key findings:
- Current smokers had lower BMI than never-smokers (23.1 kg/m2), while former smokers had the highest BMI (24.6 kg/m2). Similar trends were also observed for other adiposity measures.
- In observational analyses, smoking was positively associated with GDF15 and GDF15/receptor ratios across both assay platforms. GDF15 levels rose steeply with the number of cigarettes smoked on the day of assessment, suggesting an acute dose-response relationship.
- GDF15 levels quantified using the SomaScan platform appeared to mediate the associations of smoking with all adiposity measures, while GDF15 levels measured using the Olink platform mediated the association with body fat percentage.
- The GDF15/RET ratio more robustly mediated the smoking-adiposity relationships than GDF15 alone.
- Mendelian randomisation analyses in East Asian and European ancestry populations found smoking intensity was associated with lower BMI (East Asians) and higher GDF15 levels (both populations), suggesting a potential causal role for GDF15.
Alexander Tinworth, a lead author of the study and British Heart Foundation Centre of Research Excellence funded DPhil student at Oxford Population Health, said ‘The high rates of current smoking among Chinese men represents a major public health challenge for the 21st century. As increasing numbers of smokers attempt to quit, understanding how smoking cessation affects weight and the potential underlying mechanisms, is important to fully realise the health benefits of quitting, both at the individual and population level.’
Professor Zhengming Chen, a senior author and UK Principal Investigator of the China Kadoorie Biobank, added ‘These findings suggest a potential strategy to support smoking cessation by maintaining GDF15 levels post-cessation, potentially through agents like metformin, which is known to increase GDF15 and has been linked to weight loss.’
The study provides novel insights into the GDF15-GFRAL-RET axis as a pathway mediating smoking’s impact on body weight and composition. The researchers emphasise the need for further studies using experimental data to confirm the findings which might then be used to inform a clinical trial to evaluate interventions that modulate GDF15 as a means of mitigating smoking cessation-related weight gain and improving quit rates.