PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice.
PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice.
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DOI：
10.1073/pnas.1814522115
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发表时间：
2018-11-27
影响因子：
11.1
通讯作者：
Kliewer SA
中科院分区：
文献类型：
--
作者：
Katafuchi T;Holland WL;Kollipara RK;Kittler R;Mangelsdorf DJ;Kliewer SA
小泛素相关修饰物的共价连接(SUMO化)是一种翻译后修饰，调节许多转录因子的活性。核受体过氧化物酶体增殖物激活受体γ(PPARγ)是脂肪生成的主要调节因子，也是噻唑烷二酮类糖尿病药物的靶点。尽管TZD具有强大的胰岛素增敏特性，但它们的使用受到体重增加等不良影响的限制。在这里，我们提供了明确的证据，证明在小鼠体内，PPARγ在赖氨酸-107位发生SUMO化，阻止这种修饰可以通过调节白色脂肪组织中区别基因网络的表达来选择性地增强PPARγ的胰岛素增敏活性。我们的工作表明，抑制PPARγSUMO化可能是设计更安全的PPARγ药物的一种策略。核受体过氧化物酶体增殖物激活受体γ(PPARγ)是脂肪细胞分化的主要调节因子，也是治疗2型糖尿病的胰岛素增敏药物的靶点。在基于细胞的体外研究中，PPARγ的转录活性被其N端K107位的小泛素相关修饰物(SUMO化)的共价连接所抑制。然而，这种翻译后修饰是否与体内相关仍不清楚。在这里，使用纯合突变小鼠(K107R)，阻止该位置的SUMO化，我们证明了在白色脂肪组织中，PPARγ在K107处发生SUMO化。我们进一步表明，在饮食诱导肥胖的背景下，PPARγ-K107R突变小鼠增强了胰岛素敏感性，而没有相应的肥胖增加，这通常伴随着TZD激活PPARγ。因此，PPARγ-K107R突变在体外刺激脂肪细胞分化方面弱于TZD处理。此外，我们还发现，K107R突变小鼠腹股沟和附睾部白色脂肪组织的基础转录和TZD依赖的转录都发生了显著的变化。我们的结论是，PPARγK107上的SUMO化可能是生理上相关的，并可作为将PPARγ的有益的胰岛素增敏作用与其体重增加的不良反应分开的一个药理靶点。
Covalent attachment of small ubiquitin-related modifier (SUMOylation) is a posttranslational modification that regulates the activity of many transcription factors. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator of adipogenesis and the target of the thiazolidinedione (TZD) diabetes drugs. Although the TZDs have potent insulin-sensitizing properties, their use is limited by adverse effects such as weight gain. Here we provide unequivocal evidence that PPARγ is SUMOylated in mice at lysine-107 and that preventing this modification selectively enhances the insulin-sensitizing activity of PPARγ by regulating the expression of a discriminate network of genes in white adipose tissue. Our work suggests that inhibiting PPARγ SUMOylation may be a strategy for designing safer PPARγ drugs. The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain.
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