INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France.
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Inovarion, 75013 Paris, France.
Cell Rep. 2018 Sep 11;24(11):2957-2971.e6. doi: 10.1016/j.celrep.2018.08.032.
Hypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. This phenotype is driven by HIF1A activation that orchestrates inadequate WAT remodeling and disrupts mitochondrial activity, which can be reversed by pharmacological or genetic HIF1A inhibition. Correlation analysis of gene expression in human adipose tissue reveals a negative relationship between GPS2 and HIF1A, adipocyte hypertrophy, and insulin resistance. We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status in mice and humans.
肥大的白色脂肪组织 (WAT) 代表了一种与人类 2 型糖尿病风险相关的适应不良机制。然而，导致 WAT 肥大的分子事件还没有明确界定。在这里，我们证明了在肥胖过程中，脂肪细胞中辅阻遏物 GPS2 的缺失会引发脂肪细胞肥大。在小鼠中脂肪细胞特异性 GPS2 缺失 (GPS2 AKO) 会导致脂肪细胞肥大、炎症和线粒体功能障碍在剩余能量时。这种表型是由 HIF1A 激活驱动的，它协调了不充分的 WAT 重塑并破坏了线粒体活性，这可以通过药理学或遗传 HIF1A 抑制来逆转。对人类脂肪组织基因表达的相关性分析表明，GPS2 与 HIF1A、脂肪细胞肥大和胰岛素抵抗呈负相关。因此，我们提出，肥胖相关的脂肪细胞 GPS2 缺失会导致小鼠和人类的 WAT 扩张和糖尿病前状态的适应性不良。
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