Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.
Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity.
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白色脂肪组织（WAT）中的米色脂肪细胞与经典的棕色脂肪细胞相似，因为它们可以燃烧脂质产生热量。因此，WAT褐变中米色脂肪细胞含量的增加将增加能量消耗并减少肥胖。在这里，我们报告Notch1或其信号介导Rbpjin小鼠的脂肪特异性失活导致WAT褐变和解偶联蛋白1（Ucp1）表达升高，解偶联蛋白1是产热的关键调节因子。因此，与野生型小鼠相比，Notch 突变体表现出更高的能量消耗、更好的葡萄糖耐量和改善的胰岛素敏感性，并且更能抵抗高脂肪饮食引起的肥胖。相比之下，Notch1 的脂肪特异性激活会导致相反的表型。在分子水平上，Notch 信号传导的组成型激活会抑制白色脂肪细胞中的 Ppargc1a 和 Prdm16 转录，而 Notch 抑制则会诱导 Ppargc1a 和 Prdm16 的转录。值得注意的是，在肥胖小鼠中对 Notch 信号传导进行药理学抑制可改善肥胖、降低血糖并增加白色脂肪中 Ucp1 的表达。因此，Notch 信号传导可能成为肥胖和 2 型糖尿病的治疗靶点。
Beige adipocytes in white adipose tissue (WAT) are similar to classical brown adipocytes in that they can burn lipids to produce heat. Thus, an increase in beige adipocyte content in WAT browning would raise energy expenditure and reduce adiposity. Here we report that adipose-specific inactivation ofNotch1or its signaling mediatorRbpjin mice results in browning of WAT and elevated expression of uncoupling protein 1 (Ucp1), a key regulator of thermogenesis. Consequently, as compared to wild-type mice, Notch mutants exhibit elevated energy expenditure, better glucose tolerance and improved insulin sensitivity and are more resistant to high fat diet–induced obesity. By contrast, adipose-specific activation of Notch1 leads to the opposite phenotypes. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces,Ppargc1aandPrdm16transcription in white adipocytes. Notably, pharmacological inhibition of Notch signaling in obese mice ameliorates obesity, reduces blood glucose and increases Ucp1 expression in white fat. Therefore, Notch signaling may be therapeutically targeted to treat obesity and type 2 diabetes.
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影响因子：
64.8
作者：
Gerhart-Hines Z;Feng D;Emmett MJ;Everett LJ;Loro E;Briggs ER;Bugge A;Hou C;Ferrara C;Seale P;Pryma DA;Khurana TS;Lazar MA
通讯作者：
Lazar MA
影响因子：
8.5
作者：
Huang, Y.;Yang, X.;Lin, Y.
通讯作者：
Lin, Y.
影响因子：
3.7
作者：
Kinameri, Emi;Inoue, Takashi;Aruga, Jun;Imayoshi, Itaru;Kageyama, Ryoichiro;Shimogori, Tomomi;Moore, Adrian W.
通讯作者：
Moore, Adrian W.
影响因子：
29
作者：
Ohno H;Shinoda K;Spiegelman BM;Kajimura S
通讯作者：
Kajimura S
影响因子：
82.9
作者：
Lidell, Martin E.;Betz, Matthias J.;Enerback, Sven
通讯作者：
Enerback, Sven