Novel Small-Molecule PGC-1 alpha Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice

doi:10.2337/db12-0703

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	Novel Small-Molecule PGC-1 alpha Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice
	Zhang, Li-Na; Zhou, Hua-Yong; Fu, Yan-Yun; Li, Yuan-Yuan; Wu, Fang; Gu, Min; Wu, Ling-Yan; Xia, Chun-Mei; Dong, Tian-Cheng; Li, Jing-Ya
刊名	DIABETES
	2013-04
卷号	62 期号:4 页码:1297-1307
ISSN号	0012-1797
DOI	10.2337/db12-0703
文献子类	Article
英文摘要	Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1 alpha expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1 alpha promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1 alpha expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1 alpha mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1 alpha expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1 alpha and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1 alpha and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1 alpha in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes. Diabetes 62:1297-1307, 2013
资助项目	National Natural Science Foundation of China[81001463] ; National Natural Science Foundation of China[81125023] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09304011] ; National Program on Key Basic Research Project[2012CB524906] ; National Program on Key Basic Research Project[G1998051104] ; Shanghai Commission of Science and Technology[11DZ2292200]
WOS关键词	ACTIVATED PROTEIN-KINASE ; GAMMA COACTIVATOR-1-ALPHA EXPRESSION ; ENERGY-METABOLISM ; SKELETAL-MUSCLE ; OXIDATIVE-PHOSPHORYLATION ; PGC-1 COACTIVATORS ; INSULIN-RESISTANCE ; GENE-EXPRESSION ; RECEPTOR-ALPHA ; POTENTIAL ROLE
WOS研究方向	Endocrinology & Metabolism
语种	英语
出版者	AMER DIABETES ASSOC
WOS记录号	WOS:000316526000040
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277676]
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药物化学研究室药理学第一研究室药物安全性评价中心
通讯作者	Li, Jia
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Li-Na,Zhou, Hua-Yong,Fu, Yan-Yun,et al. Novel Small-Molecule PGC-1 alpha Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice[J]. DIABETES,2013,62(4):1297-1307.
APA	Zhang, Li-Na.,Zhou, Hua-Yong.,Fu, Yan-Yun.,Li, Yuan-Yuan.,Wu, Fang.,...&Li, Jia.(2013).Novel Small-Molecule PGC-1 alpha Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice.DIABETES,62(4),1297-1307.
MLA	Zhang, Li-Na,et al."Novel Small-Molecule PGC-1 alpha Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice".DIABETES 62.4(2013):1297-1307.