ライフサイエンスコーパス: UCP3

1 rough up-regulation of uncoupling protein 3 (UCP3).

2 ncreased glucose and palmitate oxidation and UCP3.

3 ochrome oxidase, as well as ATP synthase and UCP3.

4 ently mediated by an increased expression of UCP3.

5 enovirus-mediated overexpression of UCP1 and UCP3.

6 possible regulator of fatty acid metabolism, UCP3.

7 ough the uncoupling proteins UCP1, UCP2, and UCP3.

8 onductance through effects on UCP1, UCP2 and UCP3.

9 and they are transported by UCP1, UCP2, and UCP3.

10 suggesting tissue-specific effects of human UCP3.

11 of ROS is increased in mitochondria lacking UCP3.

12 e-induced hyperthermia requires UCP1 but not UCP3.

13 thesize mRNA for the long isoform (UCP3L) of UCP3.

14 not associated with changes in expression of UCP3.

15 ther member of the uncoupling protein termed UCP3.

16 and a C-->T silent polymorphism in exon 3 of UCP3.

17 ave cloned a third member of the UCP family, UCP3.

18 P2) without concomitant increases in UCP1 or UCP3.

19 -activated receptor-stimulated expression of UCP3.

20 nsulinemia in mice down-regulates myocardial UCP3.

21 , is required to glutathionylate and inhibit UCP3.

22 A prevents hypoxia-mediated up-regulation of UCP3.

23 andidate regulatory factors that up-regulate UCP3.

24 The impact of the UCP2 -866G>A and UCP3 -55C>T variants on prospective risk of type 2 diabe

25 oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein.

26 Loss of both UCP1 and UCP3 accelerate the loss of body temperature compared to

27 These data suggest that UCP3 accounts for much of the proton leak in skeletal mu

28 infusion caused significant increases in the UCP3/actin mRNA ratio compared with saline-infused fed c

29 late but not pyruvate/malate), indicative of UCP3 activation by endogenous reactive oxygen species.

30 The results indicate that mitochondrial UCP3 activity affects metabolism well beyond fatty acid

31 P3 Tg mice highlights that changes in muscle UCP3 activity can also affect other organ systems, presu

32 cid oxidation; however, the global impact of UCP3 activity on skeletal muscle and whole-body metaboli

33 Surprisingly, when UCP3 activity was inhibited by GDP (rats) or in the abse

34 ed increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition o

35 her understand possible interactions between UCP3 and other genes.

36 Consistent with the up-regulation of UCP3 and PPARalpha is the concomitant increase in the ex

37 GC1alpha, transcriptional coactivator of the UCP3 and PPARalpha-activated genes.

38 ypoxia robustly up-regulates skeletal muscle UCP3 and that the absence of UCP3 in primary skeletal my

39 rough the uncoupling proteins UCP1, UCP2 and UCP3 and the adenine nucleotide translocase (ANT).

40 the C75-induced increases of skeletal muscle UCP3 and whole body fatty acid oxidation and C75-induced

41 e oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was inc

42 also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling.

43 present knowledge regarding UCP1, UCP2, and UCP3, and review proposed functions for the two new unco

44 keletal muscle mRNA levels encoding UCP2 and UCP3 are correlated among individuals and may be coordin

45 Both uncoupling protein 1 (UCP1) and UCP3 are important for mammalian thermoregulation.

46 ce that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ra

47 UCP2 and UCP3 are present at much lower abundance than UCP1, and

48 aising the possibility that abnormalities in UCP3 are responsible for obesity in these models.

49 posure, the biological functions of UCP2 and UCP3 are unknown.

50 Together the results expose UCP3 as a critical regulator of long-chain fatty acid ox

51 These studies identify UCP3 as an important mediator of physiological thermogen

52 doxycycline resulted in detectable levels of UCP3 at 12 h and 2.2-fold induction at 7 days compared w

53 om (UCP1), 70 microm (UCP2), and 120 microm (UCP3) at pH 7.2.

54 consistent with the hypothesis that UCP2 and UCP3 behave as uncoupling proteins in the cell.

55 Ion flux studies show that purified UCP2 and UCP3 behave identically to UCP1.

56 aride thermogenesis requires skeletal muscle UCP3 but not UCP1.

57 ) was tightly bound to uncoupling protein 3 (UCP3), but this complex was disrupted in cells treated w

58 s is the first enzyme identified to regulate UCP3 by glutathionylation and is the first study on the

59 These results confirm that Grx2 deactivates UCP3 by glutathionylation.

60 Sustained down-regulation of cardiac UCP3 by hyperinsulinemia may partly explain the poor pro

61 (-/-) mice had no detectable immunoreactive UCP3 by Western blotting.

62 wild type mice, an effect that was absent in UCP3(-/-) cells.

63 targeting abrogated DOX-induced loss of COX1-UCP3 complexes and respiratory chain defects.

64 transfection with a tetracycline-repressible UCP3 construct.

65 P<0.05), although muscle uncoupling protein (UCP3) content and maximal mitochondrial function were un

66 a twofold increase in uncoupling protein 3 (UCP3) content, ATP-to-O ratios and proton leak kinetics

67 Unexpectedly, UCP3 deletion in ob/ob mice reduced FA oxidation but had

68 SNRK also decreases cardiac cell death in a UCP3-dependent manner.

69 Grx2 (Grx2(-/-)) increased proton leak in a UCP3-dependent manner.

70 was the same between groups, indicating that UCP3 does not appear to function as a translocator for l

71 Furthermore, UCP3 does not appear to have a major role in FFA translo

72 ite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regula

73 The phenotype of Ucp1/Ucp3 double knockout mice was indistinguishable from Ucp

74 Furthermore, the ability to prevent UCP3 downregulation or to reproduce the uncoupling respo

75 The absence of a UCP3 effect in white women is intriguing and needs to be

76 uced insulin secretion, the mechanism of the UCP3 effect is currently unknown.

77 The data indicate that UCP3 encodes a muscle-specific uncoupling protein that m

78 In mice completely lacking UCP3 (ucp3(-/-)), Ex/R failed to induce uncoupling activity.

79 For the UCP3 exon 5 variant, REE was significantly (P = 0.019) l

80 In contrast, the role of UCP3, expressed in both skeletal muscle and brown adipos

81 y expenditure, has been reported to increase UCP3 expression in muscle.

82 we show that skeletal muscle-specific human UCP3 expression is able to significantly rescue LPS, but

83 iduals and may be coordinately regulated; 2) UCP3 expression is not regulated by differential effects

84 UCP3 expression is rapidly downregulated by hyperglycemi

85 by fasting did not reproduce the increase in UCP3 expression observed in fasted animals.

86 potential mediator of the increase in muscle UCP3 expression that occurs during fasting.

87 mechanism by which insulin inhibits cardiac UCP3 expression through activation of the lipogenic fact

88 al muscle and in brown fat, neither UCP2 nor UCP3 expression was affected by diet in A/J, B6, or KsJ

89 Decreased UCP3 expression was linked to the development of selecti

90 thyronine (T(3))-treated (model of increased UCP3 expression), and acute 2,4-dinitrophenol (DNP)-trea

91 hort periods of time, alters skeletal muscle UCP3 expression, affecting energy production and physica

92 e the fasting-induced increase in quadriceps UCP3 expression.

93 ctions as a novel regulatory pathway driving UCP3 expression.

94 l muscle and change in uncoupling protein 3 (UCP3) expression during the transition from the fed to f

95 Uncoupling protein 3 (UCP3) expression increases dramatically in skeletal musc

96 fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure.

97 The physiological role of UCP3 following a 48-h fast in skeletal muscle remains to

98 If the newly discovered UCP2 and UCP3 function similarly, they will enhance peripheral en

99 ined the intron-exon structure for the human UCP3 gene and determined that UCP3S is generated when a

100 These findings suggest a role of UCP2-UCP3 gene cluster haplotypes in diabetes; in particular,

101 otide polymorphisms (SNPs) at the 70-kb UCP2-UCP3 gene cluster in relation to type 2 diabetes risk in

102 The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, an

103 Genetic variants in the UCP2-UCP3 gene cluster, located on chromosome 11q13, may play

104 The UCP3 gene is located close to that encoding UCP2, in a c

105 The UCP2 and UCP3 genes are located adjacent to one another on mouse

106 se kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy hom

107 The UCP2/UCP3 genetic locus may play a role in childhood body wei

108 However, whether or not UCP3 glutathionylation is mediated enzymatically has rem

109 ogical agents, such as diamide, to alter the UCP3 glutathionylation state.

110 ted by GDP (rats) or in the absence of UCP3 (ucp3(-/-)), H(2)O(2) emission was significantly (p < 0.0

111 Ucp3 has been proposed to influence metabolic efficiency

112 to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regul

113 This study demonstrates that UCP3 has uncoupling activity and that its absence may le

114 ased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity.

115 Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial

116 sly that mitochondrial uncoupling protein 3 (UCP3) improves functional recovery of the rodent heart d

117 in relation to variation in UCP1, UCP2, and UCP3 in 141 women aged 18-21 y.

118 In contrast, overexpression of UCP3 in 3T3-L1 adipocytes did not alter glucose uptake,

119 evated lipid metabolism, yet the function of UCP3 in a physiological context remains controversial.

120 Of note, UCP2 and UCP3 in both mice and humans colocalize in P1 and BAC ge

121 UCP1 and UCP3 in brown adipose tissue mediate early and late phas

122 xpression of uncoupling protein 1 (UCP1) and UCP3 in brown adipose tissue.

123 The loss of UCP3 in DRG neurons may represent a significant contribu

124 We expressed UCP2 and UCP3 in Escherichia coli and reconstituted the detergent

125 ating glucose metabolism, we expressed human UCP3 in L6 myotubes by adenovirus-mediated gene transfer

126 Expression of UCP3 in L6 myotubes increased 2-deoxyglucose uptake 2-fo

127 ild-type individuals, implicating a role for UCP3 in metabolic fuel partitioning.

128 sis and support a renewed focus on targeting UCP3 in metabolic physiology.

129 bolites that distinguish mice overexpressing UCP3 in muscle, both at rest and after exercise regimens

130 skeletal muscle UCP3 and that the absence of UCP3 in primary skeletal myocytes exacerbates hypoxia-in

131 Lastly, the knockdown of UCP3 in rat L6 myocytes also decreased oleate oxidation

132 the first evidence of uncoupling activity by UCP3 in skeletal muscle in vivo.

133 herefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induce

134 se ob/ob mice led to increased expression of UCP3 in skeletal muscle.

135 iochemistry/morphology and that induction of UCP3 in vivo mediates an increase in uncoupling activity

136 ason, we examined the expression of UCP2 and UCP3 in white adipose tissue and interscapular brown adi

137 Expression of human UCP3 in yeast resulted in a drastic decrease of mitochon

138 nvestigate the role of uncoupling protein 3 (UCP3) in cardiac energy metabolism, cardiac O(2) consump

139 To clarify the role of uncoupling protein-3 (UCP3) in skeletal muscle, we used NMR and isotopic label

140 The functions of its homologues, UCP2 and UCP3, in other tissues are debated.

141 Other postulated roles for UCP3 include regulation of fatty acid metabolism, adapti

142 We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a spl

143 Functional promoter variants UCP2 and UCP3 increase the prospective risk of diabetes.

144 on glucose uptake, and wortmannin inhibited UCP3-induced GLUT4 cell surface recruitment.

145 68514- rs647126-rs1800006, spanning the UCP2-UCP3 intergenic and UCP3 regions) as significantly assoc

146 tochondrial membrane potential, showing that UCP3 is a functional uncoupling protein.

147 UCP3 is a mitochondrial membrane protein expressed in hu

148 Thus UCP3 is a strong candidate to explain the effects of thy

149 Our study shows that UCP3 is also coincident with these quantitative trait lo

150 icipate in thermogenesis and energy balance, UCP3 is an important obesity candidate gene.

151 UCP3 is expressed at high levels in muscle and rodent br

152 Interestingly, UCP3 is expressed not only in muscle, but also in DRG ne

153 Unlike UCP1 and UCP2, UCP3 is expressed preferentially and at high levels in h

154 trast to UCP1, UCP2 is expressed widely, and UCP3 is expressed preferentially in skeletal muscle.

155 e recently cloned uncoupling protein homolog UCP3 is expressed primarily in muscle and therefore may

156 These data suggest that Ucp3 is not a major determinant of metabolic rate but, r

157 Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier sup

158 Uncoupling protein-3 (UCP3) is a mitochondrial protein that can diminish the m

159 Human uncoupling protein 3 (UCP3) is a mitochondrial transmembrane carrier that unco

160 Uncoupling protein-3 (UCP3) is a recently identified candidate mediator of ada

161 of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene.

162 Uncoupling protein 3 (UCP3) is highly selectively expressed in skeletal muscle

163 Uncoupling protein 3 (UCP3) is the skeletal muscle enriched uncoupling protein

164 at expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly incr

165 hondrial efficiency, which is abolished with UCP3 knockdown.

166 stions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice).

167 beling experiments to evaluate the effect of UCP3 knockout (UCP3KO) in mice on the regulation of ener

168 absent in skeletal muscle mitochondria from UCP3 knockout mice.

169 absent in skeletal muscle mitochondria from UCP3 knockout mice.

170 We have produced a Ucp3 knockout mouse to test these hypotheses.

171 The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of

172 uence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet

173 Increased UCP3 levels do not automatically increase mitochondrial

174 In particular, muscle UCP3 levels were decreased 3-fold in hypothyroid rats an

175 White adipose UCP3 levels were greatly increased by treatment with the

176 th a medium-chain fatty acid or by restoring UCP3 levels with 24 h of food withdrawal.

177 Ralpha expression, fatty acid oxidation, and UCP3 levels with decreased glycolysis.

178 ctron transport chain complexes I and IV and UCP3 levels.

179 ion, and mitochondrial uncoupling protein 3 (UCP3) levels, while increasing glycolysis, all of which

180 e in the mitochondrial uncoupling protein 3 (UCP3) levels.

181 ssociated with increased uncoupling protein (UCP3) levels.

182 Biochemical studies indicate that UCP2 and UCP3, like UCP1, have uncoupling activity.

183 To test the hypothesis that UCP3 may be involved in the translocation of long chain

184 This seemingly paradoxical induction of UCP3 may be linked to the use of free fatty acid as a fu

185 that the investigation of the regulation of UCP3 may identify novel hypoxia-responsive regulatory pa

186 These studies show that although UCP3 may mediate mitochondrial uncoupling and reduced CE

187 The newly described uncoupling protein 3 (UCP3) may make an important contribution to thermogenesi

188 n African American women, possibly linked to UCP3, may be implicated in their susceptibility to obesi

189 The Ucp3 (-/-) mice had no detectable immunoreactive UCP3 by

190 athionylation state of uncoupling protein-3 (UCP3) modulates the leak of protons back into the mitoch

191 ynthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effe

192 sociated with increased PGC-1alpha, UCP2 and UCP3 mRNA and decreased reactive oxygen species producti

193 onstrate that despite a 2-3-fold increase in UCP3 mRNA and protein expression in skeletal muscle duri

194 ter treatment correlates with an increase in UCP3 mRNA and protein expression.

195 Compared with fed levels, UCP3 mRNA and protein levels in the gastrocnemius increa

196 UCP3 mRNA and protein levels increased 8.1-fold (+/- 1.1

197 Levels of muscle Ucp3 mRNA are increased by thyroid hormone and fasting.

198 We have confirmed that a 10-fold increase in UCP3 mRNA levels occurs in rat quadriceps muscle between

199 UCP3 mRNA levels were also regulated by dexamethasone, l

200 ld, whereas HFS had no significant effect on UCP3 mRNA.

201 Despite the lack of UCP3, no consistent phenotypic abnormality was observed.

202 nergy and mitochondrial biogenesis (via PGC, UCP3, NRF2, AMPK, MAPK1, and CAMK4).

203 cans did not suggest a significant effect of UCP3 on body composition in this group.

204 inhibitor genistein abolished the effect of UCP3 on glucose uptake, and wortmannin inhibited UCP3-in

205 Uncoupling was not driven by increased UCP3 or ANT1 expression.

206 he addition of palmitate (known activator of UCP3) or under substrate conditions eliciting substantia

207 rly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes.

208 In contrast, UCP3-overexpressing mice were completely protected again

209 Male wild-type (WT) and muscle-specific UCP3-overexpressing transgenic (UCP3 Tg) C57BL/6J mice w

210 UCP3 overexpression increased lactate release 1.5- to 2-

211 UCP3 overexpression increased phosphotyrosine-associated

212 ariation in REE was seen for UCP1, UCP2, and UCP3 (p-55; exon 3a; and exon 3b) variants after adjustm

213 ) increased (isoform UCP2, p<0.0001; isoform UCP3, p=0.0036) and those of glucose transporter (GLUT4)

214 ssion of brown adipocyte-related genes UCP1, UCP3, PGC1alpha and PRDM16, as well as COX8B and ATP5B.

215 Mapping of UCP3 placed it to the same chromosomal region of UCP2 in

216 To determine the mechanisms by which UCP3 plays a role in regulating glucose metabolism, we e

217 lipid metabolism (uncoupling protein [UCP]1, UCP3, PPAR gamma coactivator 1alpha [PGC-1alpha], and CD

218 10-bp region required for ATF-1 induction of UCP3 promoter activity.

219 oblasts following cotransfection of a murine UCP3 promoter-luciferase construct and myoD we identifie

220 of activation, and a significant increase of UCP3 protein expression was observed in this group.

221 Human and mouse UCP3 protein sequences are 86% identical to each other,

222 induced a approximately 2-4-fold increase in UCP3 protein.

223 HF increased cardiac UCP3 protein.

224 00006, spanning the UCP2-UCP3 intergenic and UCP3 regions) as significantly associated with greater t

225 ion of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis.

226 DNA sequencing of UCP2 and UCP3 revealed three polymorphisms informative for associ

227 UCP3 RNA levels are regulated by hormonal and dietary ma

228 Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resista

229 Thus, UCP3 stimulates glucose transport and GLUT4 translocatio

230 on caused increased muscle and decreased BAT UCP3, suggesting that muscle assumes a larger role in th

231 derivatives in skeletal muscle and plasma of UCP3 Tg mice (e.g., Asp, Glu, Lys, Tyr, Ser, Met) were s

232 d, oxoproline, Gly, and Glu) were altered in UCP3 Tg mice across all training and exercise conditions

233 l of 80 metabolites accurately discriminated UCP3 Tg mice from WT when modeled within a specific exer

234 select metabolites were altered in liver of UCP3 Tg mice highlights that changes in muscle UCP3 acti

235 of dehydrogenase activity were increased in UCP3 Tg mice, suggestive of a shift in tissue NADH/NAD(+

236 cle-specific UCP3-overexpressing transgenic (UCP3 Tg) C57BL/6J mice were compared with or without a 5

237 O, GNB3, INSIG2, LEPR, PPARG, TNF, UCP2, and UCP3) that had been previously reported to be associated

238 e 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARalpha.

239 higher in adipose, heart (UCP2), and muscle (UCP3) tissues of mutant mice compared with those of the

240 In addition we have mapped UCP3 to the distal segment of human chromosome 11q13 (be

241 results suggest a contribution from UCP2 (or UCP3) to variation in metabolic rate in young Pima India

242 Here using a UCP3 transgene targeted to the basal epidermis, we show

243 ses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cut

244 PKCtheta activity in whole-body fat-matched UCP3 transgenic mice.

245 re performed in hearts of ob/ob mice lacking UCP3 (U3OB mice).

246 se questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice).

247 In mice completely lacking UCP3 (ucp3(-/-)), Ex/R failed to induce uncoupling activ

248 inhibited by GDP (rats) or in the absence of UCP3 (ucp3(-/-)), H(2)O(2) emission was significantly (p

249 Here, we show that mice lacking UCP3 (UCP3KO) have impaired sympathomimetic (methampheta

250 C(2) cardiomyoblasts stably transfected with UCP3 under control of a tetracycline-repressible promoto

251 signaling does not modulate hypoxia-induced UCP3 up-regulation and neither does HIF-1alpha activatio

252 h hypoxia-mediated ATF-1 phosphorylation and UCP3 up-regulation.

253 ex, we explored its role in hypoxia-mediated UCP3 up-regulation.

254 The UCP3 variant was not significantly associated with metab

255 Northern analysis showed that UCP3 was highly expressed in skeletal muscle in human, r

256 More recently, a third UCP (UCP3) was identified, which is expressed largely in skel

257 both short (UCP3S) and long (UCP3L) forms of UCP3, were highly correlated in individuals, indicating