DKFZ Junior Group Metabolism and Stem Cell Plasticity, German Cancer Research Center, Heidelberg, Germany.
Division Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
EMBO Mol Med. 2018 Aug;10(8). doi: 10.15252/emmm.201708613.
Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on function reveal novel unexpected aspects of the pharmacological targeting of PPARg.
大多数抗糖尿病药物治疗疾病症状，而不是脂肪组织功能障碍作为代谢综合征和 2 型糖尿病的关键致病原因。通过核受体 PPARγ（以格列酮治疗为例）对脂肪组织进行药理学靶向，介导有效的胰岛素增敏作用。然而，为了开发具有较少副作用的新方法，需要更好地了解特定于上下文的 PPARγ反应。在这里，我们确定转录共因子 Cited4 作为人源和鼠源脂肪祖细胞中罗格列酮的靶标和介质，它促进了罗格列酮依赖性转录程序的特定集合。在小鼠中，Cited4 是罗格列酮在皮下脂肪中特异性诱导产热表达所必需的。这种表型在雌性中具有高穿透性，在β-肾上腺素能刺激的褐色化中并不明显。有趣的是，这种特定的缺陷与系统产热能力降低以及在接受罗格列酮治疗时胰岛素敏感性受损有关，但在雄性小鼠中则没有。我们关于 Cited4 功能的发现揭示了 PPARγ 药理学靶向的新的意想不到的方面。
