Using trials of caloric restriction and bariatric surgery to explore the effects of adiposity on the circulating proteome

Abstract Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with weight. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial (DiRECT)) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively. Linear mixed models were used to estimate the effect of the interventions on circulating proteins. 23 proteins were altered in a consistent direction after both bariatric surgery and caloric restriction. We integrated Mendelian randomisation (MR) estimates of BMI effect which provided further corroborative evidence for a causal role of BMI in regulating the levels of six proteins including alcohol dehydrogenase-4, nogo receptor and interleukin-1 receptor antagonist protein. Further study into the role of these proteins in disease is warranted.