Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3.
Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3.
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DOI：
10.1016/j.cmet.2020.08.016
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发表时间：
2020-10-06
期刊：
影响因子：
29
通讯作者：
Banks AS
中科院分区：
文献类型：
--
作者：
Hall JA;Ramachandran D;Roh HC;DiSpirito JR;Belchior T;Zushin PH;Palmer C;Hong S;Mina AI;Liu B;Deng Z;Aryal P;Jacobs C;Tenen D;Brown CW;Charles JF;Shulman GI;Kahn BB;Tsai LTY;Rosen ED;Spiegelman BM;Banks AS
噻唑烷二酮（TZDs）是PPARγ的配体，可改善胰岛素敏感性，但其使用受到明显副作用的限制。最近，我们证明了TZDs改善胰岛素敏感性的机制不同于受体激动作用和脂肪形成：逆转肥胖相关的PPARγ丝氨酸273磷酸化。然而，这种修饰的作用还没有经过基因测试。在这里，我们证明了编码PPARγ在S273不能磷酸化的等位基因的小鼠免受胰岛素抵抗，没有表现出体重或tzd相关副作用的差异。事实上，高胰岛素-正血糖钳夹实验证实了胰岛素敏感性。这些小鼠的RNA-seq显示BMP家族成员Gdf3的表达减少。Gdf3的异位表达足以诱导瘦、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磷酸化的糖尿病作用，并将注意力集中在一个假定的靶点Gdf3上。Hall等人的研究表明，缺乏PPARγ丝氨酸273磷酸化的小鼠在高脂肪饮食喂养中不会产生胰岛素抵抗，这与Gdf3水平的显著降低有关。Gdf3反过来在体内和体外都足以导致胰岛素信号受损。
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 which 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 focuses attention on a putative target, Gdf3. Hall et al. show that mice lacking phosphorylation at Serine 273 of PPARγ are protected from developing insulin resistance in response to high fat diet feeding, associated with dramatically reduced levels of Gdf3. Gdf3 in turn is sufficient to cause impaired insulin signaling both in vitro and in vivo.
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影响因子：
64.8
作者：
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影响因子：
64.8
作者：
Banks, Alexander S.;McAllister, Fiona E.;Camporez, Joao Paulo G.;Zushin, Peter-James H.;Jurczak, Michael J.;Laznik-Bogoslavski, Dina;Shulman, Gerald I.;Gygi, Steven P.;Spiegelman, Bruce M.
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通讯作者：
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影响因子：
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作者：
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