These results demonstrate a reduction in hepatic Rspo3 expression of only 20% to 40% to exacerbate obesity-associated features, suggesting that Rspo3 may be a key player contributing to the regulation of both hepatic metabolic zonation and systemic glucose metabolism, as well as body composition, via inter-organ communication systems. This evidence concerns the gene RSPO3 and obesity due to melanocortin 4 receptor deficiency.