Nishio Miki, Yamaguchi Keiko, Otani Junji, Yuguchi Katsuya, Kohno Daisuke, Sasaki Tsutomu, Kitamura Tadahiro, Shinohara Masakazu, Soga Tomoyoshi, Kawamura Koichi, Sasaki Atsuo T, Oshima Masashi, Hikasa Hiroki, Woo Minna, Sasaki Takehiko, Nishina Hiroshi, Nakao Kazuwa, Maehama Tomohiko, Suzuki Akira
Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
Proc Natl Acad Sci U S A. 2025 Apr 29;122(17):e2424741122. doi: 10.1073/pnas.2424741122. Epub 2025 Apr 21.
There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, "beiging," and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.
目前，由于身体活动减少、食物摄入过多和/或遗传易感性，全球肥胖及肥胖相关疾病（如2型糖尿病）呈流行趋势。Hippo-YAP1信号通路作为一个潜在的治疗靶点受到关注，因为体外培养的小鼠未成熟脂肪细胞中YAP1/TAZ激活可通过抑制PPARγ活性来抑制其分化。然而，YAP1激活在体内成熟脂肪细胞中的作用仍不清楚。MOB1在肥胖时表达增加，是Hippo核心分子复合物的枢纽，负向调节YAP1/TAZ激活。因此，我们构建了特异性在成熟脂肪细胞中缺失的aMob1DKO突变小鼠。与对照组相比，高脂饮食喂养的aMob1DKO小鼠表现出有益变化，与抵抗饮食诱导的肥胖一致。突变体的基础脂肪分解、“米色化”和能量消耗增加，白色脂肪组织中的ROS产生和炎症受到抑制。胰岛素敏感性和葡萄糖耐量得到改善，异位脂肪堆积减少。这些变化大多依赖于在aMob1DKO小鼠成熟白色脂肪组织中观察到的YAP1激活。改善脂质代谢的FGF21通过YAP1激活直接上调，aMob1DKO小鼠中观察到的许多表型也依赖于FGF21。因此，aMob1DKO小鼠是研究饮食诱导肥胖的代谢效应和预防糖尿病的一个有趣模型。我们的研究表明，脂肪细胞中存在YAP1-FGF21轴，这可能是肥胖的一个潜在治疗靶点。
