1699-P: Foxo1-Akt负反馈通路在脂肪细胞中的作用机制

IF 7.5 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2020-06-01 DOI:10.2337/db20-1699-p

T. Ohno, Hiraku Ono, K. Yokote

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引用次数: 0

摘要

目的：FoxO1是丝氨酸/苏氨酸激酶Akt的底物。尽管FoxO1被Akt磷酸化，并被胰岛素刺激失活，但据报道FoxO1的组成型激活可增强Akt的磷酸化。因此，FoxO1的组成型激活可能通过Akt磷酸化模拟胰岛素的功能。方法：腺病毒在3T3-L1脂肪细胞中过表达组成活性FoxO1（CA-FoxO1），研究胰岛素信号传导和下游作用的变化。结果：CA-FoxO1诱导分化的3T3-L1脂肪细胞Akt磷酸化。关于下游作用，CA-FoxO1显著增强了葡萄糖摄取（与对照组相比为148.6%，P=0.030），GLUT4易位（297.6%，P结论：即使在分化的3T3-L1脂肪细胞中，FoxO1的组成型激活也能诱导Akt磷酸化，但FoxO1激活仅模拟葡萄糖的代谢功能，而不模拟胰岛素的增殖或致癌功能。FoxO1在脂肪细胞中激活对胰岛素的选择性模拟可以改善葡萄糖代谢，降低肿瘤发生的风险FoxO1-Akt反馈的增加不是先前报道的PI3-激酶的IR-β或p110α亚基的增加，而是主要在PI3-激酶下游。披露T.Ohno：没有。H.小野：没有。K.Yokote：研究支持；自己Astellas Pharma股份有限公司、Daiichi Sankyo、Eli Lilly Japan K.K.、Kowa Company、有限公司、Kyowa Hakko Kirin Co.，有限公司、Merck Sharp&Dohme Corp.、Mitsubishi Tanabe Pharma Corporation、Mochida Pharmaceutical Co.，有限公司、Nippon Boehringer Ingelheim Co。，住友大日本制药有限公司有限公司、大正制药有限公司有限公司、武田制药有限公司、帝京制药有限公司。议长团；自己Abbott、Astellas Amgen、AstraZeneca K.K.、Bayer股份有限公司、FUJIFILM Pharmaceuticals U.S.A.、股份有限公司、Kaken Pharmacecal Co.，有限公司、Sanwa Kagaku Kenkyusho。

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1699-P: Mechanisms and Roles of Foxo1-Akt Negative Feedback Pathway in Adipocytes

Objective: FoxO1 is a substrate of serine/threonine-kinase Akt. Although FoxO1 is phosphorylated by Akt and inactivated by insulin stimulation, constitutive activation of FoxO1 is reported to enhance Akt phosphorylation. Therefore, constitutive activation of FoxO1 may mimic insulin’s functions via Akt phosphorylation. Methods: Constitutively-active FoxO1 (CA-FoxO1) in 3T3-L1 adipocytes is overexpressed by adenovirus and Changes in insulin signaling and downstream actions was studied. Results: CA-FoxO1 induced Akt phosphorylation in differentiated 3T3-L1 adipocytes. Regarding downstream actions, CA-FoxO1 significantly enhanced glucose uptake (148.6% compared to controls, P =0.030), GLUT4 translocation (297.6%, P Conclusion: Constitutive activation of FoxO1 induced Akt phosphorylation even in differentiated 3T3-L1 adipocytes, but FoxO1 activation mimicked only metabolic functions of glucose but not proliferative or oncogenic functions of insulin. This selective mimicking of insulin by FoxO1 activation in adipocytes may improve glucose metabolism with a low risk of tumorigenesis. The mechanisms of FoxO1-Akt feedback is suggested not to be the increase in IR-β or p110α subunit of PI 3-kinase as previously reported, but to be mainly downstream of PI 3-kinase. Disclosure T. Ohno: None. H. Ono: None. K. Yokote: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker’s Bureau; Self; Abbott, Astellas Amgen, AstraZeneca K.K., Bayer Inc., FUJIFILM Pharmaceuticals U.S.A., Inc., Kaken Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.