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Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice

文献类型：期刊论文

作者He, Min1,2; Su, Haoran1; Gao, Weiwei1; Johansson, Stina M.1; Liu, Qing1,2; Wu, Xiaoyan1,2; Liao, Jiayu1; Young, Andrew A.1; Bartfai, Tamas3; Wang, Ming-Wei1,2,3
刊名PLOS ONE
出版日期2010-12-03
卷号5期号:12
ISSN号1932-6203
DOI10.1371/journal.pone.0014205
文献子类Article
英文摘要Background: Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance. Methodology/Principal Findings: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, beta-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of beta-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment. Conclusions/Significance: Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism.
WOS关键词BETA-CELL ; LIPID-METABOLISM ; ADIPOSE-TISSUE ; BODY-WEIGHT ; DIABETES-MELLITUS ; GLUCOSE-TRANSPORT ; HIGH-FAT ; EXENATIDE EXENDIN-4 ; ENERGY HOMEOSTASIS ; HEPATIC BIOMARKERS
资助项目Ministry of Science and Technology of China[2009ZX09302-001] ; Chinese Academy of Sciences[KSCX1-YW-02-2] ; Chinese Academy of Sciences[KSCX2-YW-R-17] ; Natural Science Foundation of China[30628024] ; Natural Science Foundation of China[30623008] ; Shanghai Science and Technology Development Fund[08DZ2291300] ; Shanghai Science and Technology Development Fund[09DZ2291200] ; Shanghai Science and Technology Development Fund[074319114]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000284939600002
出版者PUBLIC LIBRARY SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/278695]  
专题国家新药筛选中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者He, Min
作者单位1.Natl Ctr Drug Screening, Shanghai, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China;
3.Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA
推荐引用方式
GB/T 7714		 He, Min,Su, Haoran,Gao, Weiwei,et al. Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice[J]. PLOS ONE,2010,5(12).
APA He, Min.,Su, Haoran.,Gao, Weiwei.,Johansson, Stina M..,Liu, Qing.,...&Wang, Ming-Wei.(2010).Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice.PLOS ONE,5(12).
MLA He, Min,et al."Reversal of Obesity and Insulin Resistance by a Non-Peptidic Glucagon-Like Peptide-1 Receptor Agonist in Diet-Induced Obese Mice".PLOS ONE 5.12(2010).

入库方式： OAI收割

来源：上海药物研究所

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