Taking the present results into consideration, the Rspo3-induced reconstitution of hepatic metabolic zonation, which is disturbed in obesity, plays an important role in regulating local hepatic and systemic metabolism of nutrients and may restore the systemic composition of adipose tissues while improving skeletal muscle quality, by producing a newly identified complicated inter-organ communication system. This evidence concerns the gene RSPO3 and obesity due to melanocortin 4 receptor deficiency.