Deletion or inhibition of PTPRO prevents ectopic fat accumulation and induces healthy obesity with markedly reduced systemic inflammation
Deletion or inhibition of PTPRO prevents ectopic fat accumulation and induces healthy obesity with markedly reduced systemic inflammation
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DOI：
10.1016/j.lfs.2022.121292
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发表时间：
2022-12-23
期刊：
影响因子：
6.1
通讯作者：
Noda，Masaharu
中科院分区：
文献类型：
--
作者：
Shintani，Takafumi;Suzuki，Ryoko;Noda，Masaharu
目的慢性炎症在肥胖引起的代谢疾病中起着至关重要的作用。 O 型蛋白酪氨酸磷酸酶受体 (PTPRO) 是受体样蛋白酪氨酸磷酸酶 R3 亚家族的成员。我们之前提出了 PTPRO 在胰岛素受体失活中的作用。本研究旨在阐明 PTPRO 在控制葡萄糖和脂质代谢以及肥胖引起的全身炎症中的作用。材料和方法通过喂食高脂肪/高蔗糖饮食（HFHSD），研究了超肥胖 Ptpro-KO 小鼠的脂肪组织和肝脏中的脂质积累、炎症细胞因子的表达以及与全身炎症相关的胰岛素抵抗。还检查了施用 PTPRO 特异性抑制剂 AKB9778、toob/ob 小鼠和培养的 3T3-L1 前脂肪细胞的效果。主要发现Ptpro 在内脏白色脂肪组织和巨噬细胞中高表达。饲喂 HFHSD 的 Ptpro-KO 小鼠超肥胖，但肝脏中没有异位脂肪堆积、脂质和葡萄糖稳态功能障碍、全身炎症或胰岛素抵抗。 AKB9778 的施用在高度肥胖/ob 小鼠中再现了 Ptpro-KO 小鼠的“健康肥胖表型”。此外，抑制 PTPRO 通过增加波形蛋白中 Tyr(117) 的磷酸化来促进脂肪细胞中脂滴的生长。 意义 超肥胖 Ptpro-KO 小鼠的健康全身状况和炎症减弱与脂肪组织扩张和 NF-κb 低活化有关。因此，PTPRO可能是改善肝脏脂肪变性和代谢功能障碍的一个有前景的靶点。
AimsChronic inflammation plays crucial roles in obesity-induced metabolic diseases. Protein tyrosine phosphatase receptor type O (PTPRO) is a member of the R3 subfamily of receptor-like protein tyrosine phosphatases. We previously suggested a role for PTPRO in the inactivation of the insulin receptor. The present study aimed to elucidate the involvement of PTPRO in the control of glucose and lipid metabolism as well as in obesity-induced systemic inflammation.Materials and methodsLipid accumulation in adipose tissue and the liver, the expression of inflammatory cytokines, and insulin resistance associated with systemic inflammation were investigated in hyper-obesePtpro-KO mice by feeding a high-fat/high-sucrose diet (HFHSD). The effects of the administration of AKB9778, a specific inhibitor of PTPRO, toob/obmice and cultured 3T3-L1 preadipocyte cells were also examined.Key findingsPtprowas highly expressed in visceral white adipose tissue and macrophages.Ptpro-KO mice fed HFHSD were hyper-obese, but did not have ectopic fat accumulation in the liver, dysfunctional lipid and glucose homeostasis, systemic inflammation, or insulin resistance. The administration of AKB9778 reproduced “the healthy obese phenotypes” ofPtpro-KO mice in highly obeseob/obmice. Furthermore, the inhibition of PTPRO promoted the growth of lipid droplets in adipocytes through an increase in the phosphorylation of Tyr(117) in vimentin.SignificanceHealthy systemic conditions with the attenuation of inflammation in hyper-obesePtpro-KO mice were associated with the expansion of adipose tissue and low activation of NF-κb. Therefore, PTPRO may be a promising target to ameliorate hepatic steatosis and metabolic dysfunction.