Obesity is characterized by the excessive accumulation of the white adipose tissue (WAT), but healthy expansion of WAT via adipocyte hyperplasia can offset the negative metabolic effects of obesity. Thus, identification of novel adipogenesis regulators that promote hyperplasia may lead to effective therapies for obesity-induced metabolic disorders. Using transcriptomic approaches, we identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as an inhibitor of adipogenesis. Gain or loss of function of TMBIM1 in preadipocytes inhibited or promoted adipogenesis, respectively. In vivo, in response to caloric excess, adipocyte precursor (AP)-specific Tmbim1 knockout (KO) mice displayed WAT hyperplasia and improved systemic metabolic health, while overexpression of Tmbim1 in transgenic mice showed the opposite effects. Moreover, mature adipocyte-specific Tmbim1 KO did not affect WAT cellularity or nutrient homeostasis. Mechanistically, TMBIM1 binds to and promotes the autoubiquitination and degradation of NEDD4, which is an E3 ligase that stabilizes PPARγ. Our data show that TMBIM1 is a potent repressor of adipogenesis and a potential therapeutic target for obesity-related metabolic disease.

肥胖的特点是白色脂肪组织 (WAT) 的过度积累，但通过脂肪细胞增生使 WAT 健康扩张可以抵消肥胖对代谢的负面影响。因此，鉴定促进增生的新型脂肪生成调节剂可能会导致肥胖引起的代谢紊乱的有效疗法。使用转录组学方法，我们确定了含有跨膜 BAX 抑制剂基序 1 (TMBIM1) 作为脂肪生成的抑制剂。前脂肪细胞中 TMBIM1 功能的获得或丧失分别抑制或促进脂肪生成。在体内，为了应对热量过剩，脂肪细胞前体 (AP) 特异性Tmbim1敲除 (KO) 小鼠表现出 WAT 增生并改善了全身代谢健康，而转基因小鼠中的Tmbim1显示出相反的效果。此外，成熟的脂肪细胞特异性Tmbim1 KO 不影响 WAT 细胞结构或营养稳态。从机制上讲，TMBIM1 与 NEDD4 结合并促进其自身泛素化和降解，NEDD4 是一种稳定 PPARγ 的 E3 连接酶。我们的数据表明，TMBIM1 是一种有效的脂肪生成抑制因子，也是肥胖相关代谢疾病的潜在治疗靶点。