WWP1 modulates metabolic adaptation in white adipose tissue but does not significantly modify caloric...

Caloric restriction (CR) extends lifespan across diverse species. While the WW domain-containing E3 ubiquitin ligase1 (WWP1) is an essential mediator of dietary restriction-induced longevity in Caenorhabditis elegans, its role in mammalian CR remains unclear. In this study, we investigated the role of WWP1 in CR-mediated longevity and metabolic adaptation using systemic Wwp1 knockout (KO) mice. Male wild-type (WT) and Wwp1 KO mice were subjected to either ad libitum (AL) feeding or long-term CR (70% of AL intake) and monitored throughout their natural lifespan. As a result, Wwp1 deficiency did not markedly modify the CR-associated survival response in mice. Despite comparable food intake, CR-Wwp1 KO mice after middle age exhibited a modest increase in body weight compared with CR WT mice. WWP1 deficiency selectively enhanced CR-induced, Srebp-1c-dependent expression of proteins involved in de novo fatty acid synthesis in epididymal WAT, whereas hepatic lipid metabolism was unaffected. Collectively, our results demonstrated that, unlike in C. elegans, WWP1 is not required for CR-induced longevity in mammals; rather, it acts as a partial suppressor of CR-driven de novo fatty acid metabolism, limits energy storage and lipid retention in WAT.