ライフサイエンスコーパス: UCP3

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

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

3 ently mediated by an increased expression of UCP3.

4 enovirus-mediated overexpression of UCP1 and UCP3.

5 possible regulator of fatty acid metabolism, UCP3.

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

7 onductance through effects on UCP1, UCP2 and UCP3.

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

9 suggesting tissue-specific effects of human UCP3.

10 of ROS is increased in mitochondria lacking UCP3.

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

12 not associated with changes in expression of UCP3.

13 ther member of the uncoupling protein termed UCP3.

14 e-induced hyperthermia requires UCP1 but not UCP3.

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

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

17 P2) without concomitant increases in UCP1 or UCP3.

18 -activated receptor-stimulated expression of UCP3.

19 nsulinemia in mice down-regulates myocardial UCP3.

20 ncreased glucose and palmitate oxidation and 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 in murine skeletal muscle, and expression of UCP3, AAC1, or AAC2, and PDH phosphorylation status did

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

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

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

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

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

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

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

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

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

36 Early upregulation of mitochondrial genes (Ucp3 and Cpt1) and downregulation of key glycolytic gene

37 her understand possible interactions between UCP3 and other genes.

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

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

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

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

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

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

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

45 carrier and decreased the activity of UCP1, UCP3, and complex III of the respiratory chain alongside

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

47 of UCP3, decreased in L littermates on GD60 (UCP3, APOB, ALDOB) or GD90 (PNPLA3, TF), albeit in the c

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

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

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

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

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

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

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

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

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

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

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

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

60 aride thermogenesis requires skeletal muscle UCP3 but not UCP1.

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

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

63 These results confirm that Grx2 deactivates UCP3 by glutathionylation.

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

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

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

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

68 transfection with a tetracycline-repressible UCP3 construct.

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

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

71 iron metabolism increased or, in the case of UCP3, decreased in L littermates on GD60 (UCP3, APOB, AL

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

89 UCP3 expression is rapidly downregulated by hyperglycemi

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

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

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

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

94 Decreased UCP3 expression was linked to the development of selecti

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

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

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

98 ctions as a novel regulatory pathway driving UCP3 expression.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

116 Ucp3 has been proposed to influence metabolic efficiency

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

150 68514- rs647126-rs1800006, spanning the UCP2-UCP3 intergenic and UCP3 regions) as significantly assoc

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

152 UCP3 is a mitochondrial membrane protein expressed in hu

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

170 hondrial efficiency, which is abolished with UCP3 knockdown.

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

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

173 absent in skeletal muscle mitochondria from UCP3 knockout mice.

174 absent in skeletal muscle mitochondria from UCP3 knockout mice.

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

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

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

178 Increased UCP3 levels do not automatically increase mitochondrial

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

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

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

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

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

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

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

186 ssociated with increased uncoupling protein (UCP3) levels.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

204 UCP3 mRNA levels were also regulated by dexamethasone, l

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

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

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

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

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

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

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

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

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

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

215 UCP3 overexpression increased lactate release 1.5- to 2-

216 UCP3 overexpression increased phosphotyrosine-associated

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

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

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

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

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

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

223 10-bp region required for ATF-1 induction of UCP3 promoter activity.

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

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

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

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

228 HF increased cardiac UCP3 protein.

229 00006, spanning the UCP2-UCP3 intergenic and UCP3 regions) as significantly associated with greater t

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

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

232 UCP3 RNA levels are regulated by hormonal and dietary ma

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

234 Thus, UCP3 stimulates glucose transport and GLUT4 translocatio

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

259 The UCP3 variant was not significantly associated with metab

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

261 keletal muscle while increased expression of UCP3 was observed only in skeletal muscle.

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

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