Among the most abundantly expressed genes in human adipose tissue of healthy humans with normal BMI, the top significantly downregulated genes at 1 and 2 years of CR are shown in Figure 1E. Interestingly, among the top genes, 3 genes inhibited by CR, (SPARC, CRYAB, and CLU) have previously been associated with improved metabolic outcomes after weight loss in individuals with obesity (28–30). Here, CRYAB is linked to obesity due to melanocortin 4 receptor deficiency.