The Interplay of UCP3 and PCSK1 Variants in Severe Obesity

Summary: Obesity is a heterogeneous and multifactorial disease with a strong genetic component. While polygenic obesity accounts for most common cases, rare monogenic variants contribute, particularly in severe, early-onset obesity. Among the lesser-studied candidates are UCP3 and PCSK1, genes involved in key metabolic pathways. Recent Findings: The UCP3 p.Val192Ile (c.574G > A) and PCSK1 p.Asn221Asp (c.661 A > G) variants have been independently associated with metabolic pathways, including fatty acid oxidation and hormone processing, as well as a modestly increased risk of obesity. Clinical and genetic characterization of two patients with severe early-onset obesity revealed the co-occurrence of these variants, which were associated with metabolic disturbances such as insulin resistance. Purpose of the Review: This narrative review examined the functional and clinical significance of UCP3 and PCSK1 variants in severe obesity, presenting two case reports to illustrate their potential impact. Our findings support a potential model in which rare variants in distinct metabolic genes may interact synergistically to exacerbate disease severity. Further studies are needed to elucidate their combined functional effects and contributions to obesity pathogenesis.