Taken together, human studies based principally on genetic polymorphisms have provided evidence promoting a role of CART in body weight regulation in humans. Altered CART expression has generally been associated with an elevated genetic predisposition to overweight and obesity, indirectly substantiating the anorexigenic nature of the peptide, although results from the literature show both anorexigenic and orexigenic properties of CART in animal studies. It is also noteworthy to address the plausible challenges imposed on the translatability of results obtained from animal models to the human system, considering the discernible difference in the anatomy of central CART-containing neurons between the two, as discussed above. Furthermore, although overall support has been gained for the hypothesis that inherited variations in CART could influence the development of obesity, such genetic linkage was absent for some other sequence variants detected within the gene, where the polymorphisms have been speculated as insufficient to disturb the peptide structure or create topological and conformational changes in the protein that would ultimately affect the functional activity of the peptide (Echwald et al., 1999; Walder et al., 2000; Rogge et al., 2008). Indeed, recent studies conducting an alanine scan for assessing the importance of the structure-activity relationship of CART demonstrated the dependence of anorexigenic potency on individual disulfide bridges in the peptide (Maixnerova et al., 2007; Maletinska et al., 2007; Blechova et al., 2013). To elucidate the contribution of specific disulfide bridges to maintaining the stability and biological function of CART, analogs with only one or two among the three disulfide bridges in the intact peptide were synthesized, with which binding activities as well as metabolic effects were measured in both cell and animal systems (Maixnerova et al., 2007). Intriguingly, results from binding experiments in PC12 rat pheochromocytoma cells (Maixnerova et al., 2007; Maletinska et al., 2007; Lin et al., 2011) indicated that the preservation of two particular disulfide bridges as well as the full-length peptide was imperative for biological activity, where high affinity of the analog to PC12 cells in both states of native phenotype and differentiated into neurons was measured (Blechova et al., 2013). In mice subjected to i.c.v. administration of the same analog, strong and long-lasting anorexigenic potency was exhibited during food consumption and behavioral tests, further purporting that one particular disulfide bridge could be omitted without a loss of bioactive function (Blechova et al., 2013).