SPARC and obesity due to melanocortin 4 receptor deficiency: 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).