We will summarize the current evidence linking these genes to obesity pathophysiology and present two novel clinical cases carrying both UCP3 p. Val192Ile (c.574G > A) and PCSK1 p.Asn221Asp (c.661 A > G) variants, contributing to the growing body of knowledge on the genetic underpinnings of obesity. Here, PCSK1 is linked to obesity due to melanocortin 4 receptor deficiency.