A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

doi:10.1007/s00125-013-2987-9

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	A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake
	Fu, Y. -Y.2; Zhang, M.2 ; Turner, N.1,3; Zhang, L. -N.2; Dong, T. -C.2; Gu, M.2 ; Leslie, S. J.3; Li, J. -Y.2; Nan, F. -J.2; Li, J.2
刊名	DIABETOLOGIA
	2013-10
卷号	56 期号:10 页码:2297-2307
关键词	Cell type-specific Chemical uncoupler Metabolic diseases Obesity
ISSN号	0012-186X
DOI	10.1007/s00125-013-2987-9
文献子类	Article
英文摘要	Decreasing mitochondrial coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. Here we identified a novel mitochondrial uncoupler that promoted uncoupled respiration in a cell type-specific manner and investigated its effects on modulation of energy metabolism in vivo and in vitro. We screened a collection of mitochondrial membrane potential depolarising compounds for a novel chemical uncoupler on isolated skeletal muscle mitochondria using a channel oxygen system. The effect on respiration of metabolic cells (L6 myotubes, 3T3-L1 adipocytes and rat primary hepatocytes) was examined and metabolic pathways sensitive to cellular ATP content were also evaluated. The chronic metabolic effects were investigated in high-fat diet-induced obese mice and standard diet-fed (SD) lean mice. The novel uncoupler, CZ5, promoted uncoupled respiration in a cell type-specific manner. It stimulated fuel oxidation in L6 myotubes and reduced lipid accumulation in 3T3-L1 adipocytes but did not affect gluconeogenesis or the triacylglycerol content in hepatocytes. The administration of CZ5 to SD mice increased energy expenditure (EE) but did not affect body weight or adiposity. Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via both increased EE and suppressed energy intake. The reduced adiposity was associated with the restoration of expression of key metabolic genes in visceral adipose tissue. This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.
资助项目	National Natural Science Foundation of China[81001463] ; National Natural Science Foundation of China[81125023] ; National Natural Science Foundation of China[81273566] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09304011] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2012ZX09301-001-004] ; National Science and Technology Major Projects for Major New Drugs Innovation and Development[2013ZX09507002] ; National Program on Key Basic Research Project[2012CB524906] ; National Program on Key Basic Research Project[G1998051104] ; Chinese Academy of Science[XDA01040303] ; Shanghai Commission of Science and Technology[11DZ2292200] ; National Health and Medical Research Council of Australia[00000000] ; Australian Research Council[00000000]
WOS关键词	ADIPOSE TRIGLYCERIDE LIPASE ; MUSCLE INSULIN-RESISTANCE ; STIMULATED GLUCOSE-UPTAKE ; SKELETAL-MUSCLE ; ADIPOCYTE DIFFERENTIATION ; MITOCHONDRIAL DYSFUNCTION ; DIABETES-MELLITUS ; MAJOR DETERMINANT ; IN-VITRO ; EXPRESSION
WOS研究方向	Endocrinology & Metabolism
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000324062800024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277452]
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	Li, J. -Y.
作者单位	1.Univ New S Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW, Australia 2.Chinese Acad Sci, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Garvan Inst Med Res, Diabet & Obes Res Program, Sydney, NSW, Australia;
推荐引用方式 GB/T 7714	Fu, Y. -Y.,Zhang, M.,Turner, N.,et al. A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake[J]. DIABETOLOGIA,2013,56(10):2297-2307.
APA	Fu, Y. -Y..,Zhang, M..,Turner, N..,Zhang, L. -N..,Dong, T. -C..,...&Li, J..(2013).A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake.DIABETOLOGIA,56(10),2297-2307.
MLA	Fu, Y. -Y.,et al."A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake".DIABETOLOGIA 56.10(2013):2297-2307.