Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Cell Metab. 2020 Oct 6;32(4):665-675.e6. doi: 10.1016/j.cmet.2020.08.016. Epub 2020 Sep 16.
The thiazolidinediones (TZDs) are ligands of PPARγ that improve insulin sensitivity, but their use is limited by significant side effects. Recently, we demonstrated a mechanism wherein TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at serine 273. However, the role of this modification hasn't been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ that cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm insulin sensitivity. RNA-seq in these mice reveals reduced expression of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find Gdf3 inhibits BMP signaling and insulin signaling in vitro. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylation and focus attention on a putative target, Gdf3.
噻唑烷二酮类（TZDs）是 PPARγ 的配体，可改善胰岛素敏感性，但由于其严重的副作用，其应用受到限制。最近，我们证明了一种机制，即 TZDs 通过与受体激动和脂肪生成不同的机制改善胰岛素敏感性：逆转肥胖相关的 PPARγ 丝氨酸 273 磷酸化。然而，这种修饰的作用尚未通过遗传方法进行测试。在这里，我们证明编码不能在 S273 磷酸化的 PPARγ 等位基因的小鼠对胰岛素抵抗具有保护作用，而体重或与 TZD 相关的副作用没有差异。实际上，高胰岛素-正葡萄糖钳夹实验证实了胰岛素敏感性。这些小鼠的 RNA-seq 显示 Gdf3 的表达减少，Gdf3 是 BMP 家族的一员。外源性表达 Gdf3 足以诱导瘦健康小鼠的胰岛素抵抗。我们发现 Gdf3 在体外抑制 BMP 信号和胰岛素信号。总之，这些结果强调了 PPARγ S273 磷酸化的致糖尿病作用，并将注意力集中在一个潜在的靶点 Gdf3 上。
