Obesity is a chronic metabolic disorder pathologically defined by sustained positive energy balance (energy intake > energy expenditure), leading to excessive adipose tissue accumulation that adversely impacts systemic health. It is intricately linked to the development of various diseases (Koskinas et al., 2024; Miethe et al., 2020; Piché et al., 2020; Purdy et al., 2021; Seravalle and Grassi, 2017; Hibbert et al., 2012). Obesity poses significant social and public health challenges (Pan et al., 2021; Zeng et al., 2021; Wang et al., 2021). Increased triglyceride synthesis or reduced catabolism result in fat accumulation, whereas the inhibition of triglyceride synthesis or promotion of energy expenditure and lipolysis are common strategies for treating obesity (Nye et al., 2008; Chen and Farese, 2000; Marlatt and Ravussin, 2017; Hill et al., 2012).

Yes-associated protein (YAP), a key mediator downstream of the Hippo pathway, is activated through a cascade reaction initiated by the activation of the signal transducers MST1/2, followed by phosphorylation of LATS1/2 and YAP. Phosphorylated YAP binds to 14-3-3 proteins in the cytoplasm and undergoes either ubiquitylation or proteasomal degradation, consequently impeding its translocation into the nucleus (Ibar and Irvine, 2020; Totaro et al., 2018; Ma et al., 2019; Fu et al., 2022; Hong et al., 2016; Piccolo et al., 2014). A large number of studies have demonstrated that YAP is involved in various cellular processes, including cell contact inhibition, mechanotransduction, cell differentiation, cell proliferation, apoptosis, and cancer progression (Koo and Guan, 2018; Moya and Halder, 2019; Driskill and Pan, 2023; Cheng et al., 2022; Li et al., 2023; Elbediwy and Thompson, 2018; Dey et al., 2020; Lu et al., 2024). In 2005, Hong et al. reported that the transcriptional coactivator with PDZ-binding motif (TAZ), a paralog of YAP, suppresses mesenchymal stem cell adipogenesis (Hong et al., 2005). Subsequently, numerous studies have underscored the important role of the Hippo pathway in adipogenic differentiation in vitro (Wang et al., 2020; Kamura et al., 2018; El Ouarrat et al., 2020; Lorthongpanich et al., 2019; Pan et al., 2018). However, in vivo studies have reported conflicting findings regarding the effects of YAP on lipogenesis and obesity (Wang et al., 2020; Lee et al., 2022; Choi et al., 2024). Therefore, our study aimed to investigate the role of YAP in obesity using a Yap adipose-specific knockout mouse model fed a high-fat diet (HFD).

In this study, we observed that YapaKO enhanced HFD-induced obesity in male, but not in female mice. This effect is potentially due to suppressed lipolytic activity, which results from a decreased expression of triglyceride lipolytic enzymes, including ATGL and HSL. Additionally, the inhibition of lipolytic activity by Yap knockout led to reduced levels of circulating free fatty acids (FFA) during fasting, making male mice unable to maintain core body temperature after cold exposure, and showing impaired exercise capability in the fasted state.