Updated project metadata. Obesity is characterized by excess energy storage which results in dysfunctional white adipose tissue (WAT) and in turn leads to metabolic diseases. Lifestyle changes especially calorie restriction (CR) reduces the risk for age and obesity-associated complications. The impact of CR on obesity has mainly been examined with human intervention studies, which indicated alterations in circulating adipokines. However, a detailed understanding of CR-induced adipocyte secretome changes remains elusive. Therefore, we investigated the effect of CR on the secretion profile of mature human adipocytes by using proteomics technology with bioinformatic analysis. We demonstrated CR-mediated adipocyte triglyceride reduction, which resulted in a positive effect on adipokine secretion indicating an improved inflammatory phenotype and alleviation of obesity-associated metabolic dysfunction including insulin resistance and glucose intolerance. Furthermore, 6 novel adipocyte-secreted proteins were identified which were regulated by CR. Since resveratrol (RSV) mimics CR we compared results from this study with data from our previous RSV study on the adipocyte secretome. We observed that both treatment strategies lead to a less inflammatory phenotype and an altered adipokine profile indicating improvement of metabolic complications even though the CR and RSV adipocyte secretomes differed from each other.