title: A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Fu
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Turner
authors.forename: L-N
authors.initials: LN
authors.lastname: Zhang
authors.forename: T-C
authors.initials: TC
authors.lastname: Dong
authors.forename: M
authors.initials: M
authors.lastname: Gu
authors.forename: S J
authors.initials: SJ
authors.lastname: Leslie
authors.forename: J-Y
authors.initials: JY
authors.lastname: Li
authors.forename: F-J
authors.initials: FJ
authors.lastname: Nan
authors.forename: J
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats
chemical_list: D007004:Hypoglycemic Agents
references.citation: Biochim Biophys Acta. 2012 Feb;1820(2):133-50
references.pmid: 22155143
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):7933-8
references.pmid: 17470778
references.citation: J Biol Chem. 2006 Oct 20;281(42):31478-85
references.pmid: 16935857
references.citation: Annu Rev Nutr. 2008;28:13-33
references.pmid: 18407744
references.citation: Mol Cell Biochem. 1974 Nov 15;5(1-2):69-77
references.pmid: 4610359
references.citation: Physiol Genomics. 2005 Apr 14;21(2):193-200
references.pmid: 15687481
references.citation: Nat Protoc. 2006;1(3):1112-6
references.pmid: 17406391
references.citation: Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1736-45
references.pmid: 17848638
references.citation: Gastroenterol Clin North Am. 2005 Mar;34(1):91-104
references.pmid: 15823441
references.citation: Am J Physiol. 1996 May;270(5 Pt 1):E768-75
references.pmid: 8967464
references.citation: Methods Cell Biol. 1976;13:29-83
references.pmid: 177845
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Am J Clin Nutr. 2005 Jul;82(1 Suppl):222S-225S
references.pmid: 16002825
references.citation: Nat Med. 2000 Oct;6(10):1115-20
references.pmid: 11017142
references.citation: Dis Model Mech. 2012 Sep;5(5):621-6
references.pmid: 22915024
references.citation: Diabetes. 2008 May;57(5):1414-8
references.pmid: 18285556
references.citation: Physiology (Bethesda). 2011 Jun;26(3):192-205
references.pmid: 21670165
references.citation: Diabetes. 2010 Jan;59(1):256-65
references.pmid: 19833880
references.citation: Physiol Behav. 2004 Dec 30;83(4):573-8
references.pmid: 15621062
references.citation: Nature. 2000 Jul 27;406(6794):415-8
references.pmid: 10935638
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2771-6
references.pmid: 21282637
references.citation: Ann N Y Acad Sci. 2002 Jun;967:363-78
references.pmid: 12079864
references.citation: Diabetes. 2010 Jul;59(7):1657-66
references.pmid: 20413511
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11371-6
references.pmid: 11027337
references.citation: J Clin Invest. 2004 Nov;114(9):1281-9
references.pmid: 15520860
references.citation: Cell Metab. 2012 Jul 3;16(1):104-12
references.pmid: 22727014
references.citation: Nature. 2004 Apr 1;428(6982):569-74
references.pmid: 15058305
references.citation: J Biol Chem. 1957 May;226(1):497-509
references.pmid: 13428781
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2058-63
references.pmid: 14769942
references.citation: Diabetes. 2001 Dec;50(12):2786-91
references.pmid: 11723062
references.citation: Cell Metab. 2008 Jan;7(1):45-56
references.pmid: 18177724
references.citation: J Cell Sci. 2009 Jan 1;122(Pt 1):145-55
references.pmid: 19066287
references.citation: Obes Rev. 2001 Nov;2(4):255-65
references.pmid: 12119996
references.citation: Cell. 2008 Oct 3;135(1):61-73
references.pmid: 18854155
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7627-8
references.pmid: 18509057
references.citation: Nat Rev Drug Discov. 2010 Jun;9(6):465-82
references.pmid: 20514071
references.citation: Diabetologia. 2006 Apr;49(4):784-91
references.pmid: 16501941
references.citation: Biochem J. 2011 Apr 15;435(2):297-312
references.pmid: 21726199
references.citation: J Clin Invest. 2006 Mar;116(3):615-22
references.pmid: 16511594
references.citation: J Clin Endocrinol Metab. 2007 Jun;92(6):2292-9
references.pmid: 17356053
references.citation: Biochim Biophys Acta. 2006 Nov;1760(11):1682-9
references.pmid: 17049164
references.citation: J Clin Invest. 1990 Nov;86(5):1423-7
references.pmid: 2243122
references.citation: Nat Protoc. 2007;2(2):287-95
references.pmid: 17406588
references.citation: Proc Nutr Soc. 2009 Nov;68(4):378-84
references.pmid: 19698204
references.citation: Genes Dev. 1996 May 1;10(9):1096-107
references.pmid: 8654925
references.citation: Trends Endocrinol Metab. 2006 Nov;17(9):365-71
references.pmid: 17010638
references.citation: J Clin Endocrinol Metab. 2011 Mar;96(3):775-81
references.pmid: 21190973
references.citation: Cell Metab. 2006 Mar;3(3):223-9
references.pmid: 16517409
references.citation: J Clin Invest. 1995 Dec;96(6):2914-23
references.pmid: 8675663