Nature Communications ( IF 14.7 ) Pub Date : 2022-10-14 , DOI: 10.1038/s41467-022-33842-4
Masaji Sakaguchi 1 , Shota Okagawa 1 , Yuma Okubo 1 , Yuri Otsuka 1 , Kazuki Fukuda 1, 2 , Motoyuki Igata 1 , Tatsuya Kondo 1 , Yoshifumi Sato 3 , Tatsuya Yoshizawa 3 , Takaichi Fukuda 4 , Kazuya Yamagata 2, 3 , Weikang Cai 5 , Yu-Hua Tseng 6 , Nobuo Sakaguchi 7, 8 , C Ronald Kahn 6 , Eiichi Araki 1, 2
|
Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.
中文翻译:

磷酸酶保护因子 alpha4 (α4) 通过调节胰岛素信号参与脂肪细胞维持和线粒体稳态
胰岛素信号通过蛋白质磷酸化网络介导。该网络的失调是肥胖、2 型糖尿病和代谢综合征的核心。在这里,我们研究了磷酸酶结合蛋白 Alpha4 (α4) 的作用,它对于丝氨酸/苏氨酸蛋白磷酸酶 2A (PP2A) 在脂肪细胞的胰岛素作用/抵抗中至关重要。出乎意料的是,尽管蛋白磷酸酶 2A (PP2A) 水平降低,但脂肪细胞特异性 α4 失活会损害胰岛素诱导的 Akt 介导的丝氨酸/苏氨酸磷酸化。有趣的是,α4 的缺失也降低了胰岛素诱导的胰岛素受体酪氨酸磷酸化。这是通过减少 α4 与 Y-box 蛋白 1 的结合而发生的,导致酪氨酸磷酸酶蛋白酪氨酸磷酸酶 1B (PTP1B) 表达增强。而且,雄性小鼠脂肪细胞特异性敲除 α4 导致脂肪生成受损和线粒体氧化改变,导致炎症增加、全身胰岛素抵抗、肝脂肪变性、胰岛增生和产热受损。因此,α4 /Y-box 蛋白 1(YBX1) 介导的胰岛素受体信号通路参与维持胰岛素敏感性、正常脂肪组织稳态和全身代谢。