ライフサイエンスコーパス: MC3R

1 MC3R cell types in DMH are sexually dimorphic.

2 MC3R deletion produced multiple forms of sexually dimorp

3 MC3R neurons in PVT are innervated by hypothalamic AgRP

4 MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchym

5 MC3R(hDM/hDM) impacts nutrient partitioning to generate

6 MC3R(hDM/hDM) mice do not have increased adipose tissue

7 MC3R-deficient (MC3R(-)(/)(-)) mice demonstrate increase

8 MC3R-deficient hepatocytes had blunted autophagosome-lys

9 MC3Rs are expressed in hypothalamic and limbic regions o

10 ociations of C17A + G241A and +2138InsCAGACC MC3R variants with children's energy balance.

11 tream neurons containing the melanocortin-3 (MC3R) and melanocortin-4 receptor (MC4R).

12 s, melanocortin-4 (MC4R) and melanocortin-3 (MC3R), are involved in the regulation of satiety and ene

13 ysiological effect that one MCR, MCR type 3 (MC3R), might have on vascular inflammation.

14 old was derived from results obtained from a MC3R mixture-based positional scanning campaign.

15 s blocked by a neutralizing antibody against MC3R.

16 and natural [agouti-related protein (AGRP)] MC3R antagonists but not by the MC4R antagonist Ac-Cys-N

17 Functional analysis of this altered MC3R (I183N) has indicated that the mutation completely

18 Agouti-related protein (AgRP), an MC3R/MC4R antagonist and MC4R inverse agonist, contains

19 Leptin-deficient and MC3R-/- mice regulate metabolic rate similarly to wild-t

20 Two melanocortin receptors (MC1 and MC3R) have been identified as main transducers of the an

21 MC1R and MC3R mRNA and protein were both expressed in the inflame

22 at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1

23 eceptors [melanocortin receptor-1 (MC1R) and MC3R-MC5R].

24 We studied MC4R and MC3R mutations detected in a total of 1821 adults (889 s

25 nces of all mutations found in both MC4R and MC3R.

26 vels are increased in MC3R(hDM/hDM) mice and MC3R(hDM/hDM) human subjects.

27 ptomic data showed coexpression of MRAP2 and MC3R in hypothalamic neurons that function in energy hom

28 ti-related peptide, pro-opiomelanocortin and MC3R.

29 ant effect on hypothalamic POMC, orexin, and MC3R levels.

30 enes including MPHOSPH9, TMEM127, ZRANB3 and MC3R.

31 Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each

32 reopening of the superior mesenteric artery, MC3R-null mice displayed a higher degree of plasma extra

33 Because MC3Rs are highly expressed in the ventral tegmental area

34 was used to examine the associations between MC3R polymorphisms and the measures of energy balance.

35 nce of a tonic inhibitory signal provided by MC3R in the mesenteric microcirculation of the mouse, ac

36 The impact of central MC3Rs on behavior and metabolism involves divergent path

37 To investigate the roles of central MC3Rs, we inserted a "lox-stop-lox" (LoxTB) 5' of the tr

38 This compound represents a first-in-class MC3R selective agonist.

39 MC3R-deficient (MC3R(-)(/)(-)) mice demonstrate increased fat mass, high

40 ons of Cre-recombinase to selectively delete MC3R from the medial hypothalamus (MH) in adult mice.

41 These data demonstrated MC3R deficiency caused a reduction of food intake and bo

42 useful for in vivo studies to differentiate MC3R vs MC4R physiological roles in animal models, such

43 Dorsal-medial hypothalamus (DMH) MC3R neurons increase locomotion and energy expenditure.

44 Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP),

45 who are overweight or obese did not enhance MC3R-driven signaling.

46 MC3R in AgRP neurons, 97% of which expressed MC3R.

47 Herein, 46 tetrapeptides were chosen for MC3R agonist screening selectivity profiles, synthesized

48 We thus report a role for MC3R in regulating hepatic autophagy and systemic adipos

49 main confers AGRP's distinct selectivity for MC3R and MC4R.

50 .9 nM for MC1R and >150-fold selectivity for MC3R and MC4R.

51 th altered thermal stability, resulting from MC3R activation.

52 42 (Ac-Val-Gln-(pI)DPhe-DTic-NH(2)), a full MC3R agonist that is 100-fold selective for the MC3R ove

53 rphisms in the melanocortin-3 receptor gene (MC3R) coding sequence, C17A and G241A, has been reported

54 le-mutant (C17A+G241A) human (MC3R(hDM/hDM)) MC3R, that MC3R(hDM/hDM) have greater weight and fat mas

55 In vitro and in vivo activation of hepatic MC3R upregulates autophagy through LC3II activation, TFE

56 the intracellular cAMP accumulation in human MC3R, MC4R, and MC5R revealed that the native peptide sh

57 Mice with partially inactive human MC3R due to obesogenic variants demonstrate similar hepa

58 is the most selective analogue for the human MC3R reported thus far.

59 however with poor selectivity for the human MC3R-MC5R.

60 /hWT)) and double-mutant (C17A+G241A) human (MC3R(hDM/hDM)) MC3R, that MC3R(hDM/hDM) have greater wei

61 we replace murine Mc3r with wild-type human (MC3R(hWT/hWT)) and double-mutant (C17A+G241A) human (MC3

62 attributed to a limited number of identified MC3R selective ligands.

63 kine generation; such effects were absent in MC3R-null mice.

64 ted LoF NSVs may suggest that dysfunction in MC3R is associated with decreased body height, obesity a

65 addition, the alpha-MSH-induced increase in MC3R neuron activity was independent of fast synaptic tr

66 The alpha-MSH induced increase in MC3R neuron firing rate is probably activity-dependent,

67 0), but not Arg(7), result in an increase in MC3R selectivity over the MC4R and MC5R and only agonist

68 Serum adiponectin levels are increased in MC3R(hDM/hDM) mice and MC3R(hDM/hDM) human subjects.

69 ng Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that t

70 mans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a lat

71 to antagonist at MC2R, which was observed in MC3R and MC4R.

72 ssing enhanced yellow fluorescent protein in MC3R neurons to test how alpha-MSH affects the activity

73 arcuate nucleus exerts an important role in MC3R-mediated effects on energy homeostasis, viral delet

74 mentary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific

75 -MSH led to accumulation of cAMP, indicating MC3R receptor functionality: this effect was blocked by

76 cking because of the limited number of known MC3R selective ligands.

77 ng two MC5R orthologues, while Fugu, lacking MC3R, has only four.

78 e endogenous nonselective agonists for MC1R, MC3R, MC4R, and MC5R.

79 he role of Phe(7) in ACTH on human (h) MC1R, MC3R, and MC4R binding and signaling.

80 ayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R.

81 etrapeptides synthesized, 13 possessed MC1R, MC3R, MC4R, and MC5R antagonist activity.

82 ty at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R.

83 ty at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R.

84 ty at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R.

85 h human melanocortin receptor subtypes MC1R, MC3R, MC4R, or MC5R, were then obtained and characterize

86 n 2 (FABP2), melanocortin 2 receptor (MC2R), MC3R, PPARG coactivator 1 alpha (PPARGC1A), and tumor ne

87 and suggest an important role for dorsal-MH MC3R signalling in energy rheostasis.

88 nomolar MC1R and MC5R potency but micromolar MC3R and MC4R agonist potency.

89 neurons without altering the activity of non-MC3R expressing VTA neurons.

90 ugh it did not affect the firing rate of non-MC3R VTA neurons.

91 and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia.

92 rmine whether MRAP2 affected the activity of MC3R, which is structurally similar to MC4R and which re

93 diated by alpha-MSH changing the activity of MC3R-expressing VTA neurons.

94 late, results primarily in the antagonism of MC3R and MC4R then allowed us to search the published li

95 dy is to determine the structural aspects of MC3R responsible for ligand binding and receptor signali

96 ever, the specific molecular determinants of MC3R responsible for ligand binding and receptor signali

97 ion of the signaling processes downstream of MC3R activation.

98 used to map signaling pathways downstream of MC3R and to deduce transcription factors responsible for

99 MRAP2 enhanced cAMP signaling downstream of MC3R, impaired beta-arrestin recruitment to MC3R, and re

100 Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry

101 Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP

102 as no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R.

103 ion to map changes in the mRNA expression of MC3R, pro-opiomelanocortin and agouti-related peptide fo

104 m MC4R neurons, the identity and function of MC3R-containing neurons are poorly understood.

105 respective roles especially the functions of MC3R need more exploration.

106 These data confirm the importance of MC3R signalling in human metabolism and suggest a previo

107 on energy rheostasis result from the loss of MC3R signalling in medial hypothalamic neurons and sugge

108 3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over f

109 At least one specific mutation of MC3R has been identified to be associated with human obe

110 ining the complicated signalling pathways of MC3R and MC4R.

111 alpha-MSH increased the firing rate of MC3R VTA neurons in acute brain slices from mice, althou

112 We Sanger sequenced the coding region of MC3R in 185 children or adolescents with short normal st

113 her variant in the 3' untranslated region of MC3R, has also been described.

114 implicate MRAP2 as an important regulator of MC3R function and provide further evidence for the cruci

115 anorectic agents was a generalized result of MC3R antagonism.

116 thalamic brain regions mediating the role of MC3R in energy homeostasis.

117 cuate nucleus also contribute to the role of MC3R in energy rheostasis.

118 rformed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anore

119 tor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor.

120 These results suggest that actions of MC3Rs impacting on energy homeostasis involve both centr

121 ptide template were selected solely based on MC3R agonist potency from the mixture-based screen.

122 lly, we show that the effect of alpha-MSH on MC3R neuron firing rate is probably activity-dependent.

123 mutations impairing the function of MC4R or MC3R were associated with severe obesity in North Americ

124 ectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising ago

125 MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, in

126 The three most potent MC3R agonists, 18 [Ac-Arg-Arg-(pI)DPhe-Tic-NH2], 1 [Ac-H

127 The ability of MRAP2 to promote MC3R signaling was suppressed by alanine mutagenesis of

128 Consistently, chemogenetic activation of PVT MC3R neurons increases anxiety-related behavior and redu

129 ng in hungry mice, whereas inhibition of PVT MC3R neurons reduces anxiety-related behavior.

130 These studies position PVT MC3R neurons as important cellular substrates linking en

131 In contrast, the prevalence of rare MC3R variants was not significantly increased in severel

132 esses downstream of melanocortin 3 receptor (MC3R) activation by endogenous agonists derived from the

133 and antagonists of melanocortin-3 receptor (MC3R) and MC4R point to the importance of the CNS melano

134 ortin (POMC) at the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) and has been pr

135 The melanocortin-3 receptor (MC3R) gene is pleiotropic, influencing body composition,

136 hile stimulation of melanocortin 3 receptor (MC3R) inhibits PVN MC4R activity.

137 The melanocortin-3 receptor (MC3R) is an important component of the melanocortin syst

138 The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibit

139 ogical roles of the melanocortin-3 receptor (MC3R) is lacking because of the limited number of known

140 ed an impact of the melanocortin 3 receptor (MC3R) on the regulation of body weight, linear growth an

141 The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein

142 Here, we find melanocortin 3 receptor (MC3R) regulates hepatic autophagy in addition to its pre

143 ')(7)), reported as melanocortin-3 receptor (MC3R) subtype-specific agonists in two separate publicat

144 in homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined.

145 lated receptor, the Melanocortin-3 receptor (MC3R), could also be a cause of severe human obesity.

146 Melanocortin-3 receptor (MC3R), primarily expressed in the hypothalamus, plays an

147 ogical roles of the melanocortin-3 receptor (MC3R).

148 ive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioural response to both anorexic

149 Melanocortin-3-receptor (MC3R) signalling regulates energy rheostasis in adult mi

150 ous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits pot

151 ous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits pot

152 Melanocortin-3 receptors (MC3R) are highly expressed in the VTA, suggesting that t

153 Melanocortin-3 receptors (MC3R) have a contextual role in appetite control that is

154 Melanocortin-3 and 4 receptors (MC3R and MC4R) can regulate energy homeostasis, but thei

155 gonizes the melanocortin-3 and -4 receptors (MC3R and MC4R).

156 melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R, respectively) are established targets to

157 melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are involved in the metabolic and food intak

158 melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are key regulators of body weight and energy

159 The melanocortin-3 and -4 receptors (MC3R, MC4R) have been implicated in energy homeostasis a

160 nist of the melanocortin-3 and -4 receptors (MC3R, MC4R).

161 y expressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for wei

162 For example, melanocortin-3 receptors (MC3Rs) are expressed in the ventral tegmental area (VTA)

163 Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of en

164 ta-arrestin recruitment to MC3R, and reduced MC3R internalization.

165 The previously reported MC3R/MC4R antagonist Ac-DPhe(pI)-Arg-Nal(2')-Arg-NH(2) w

166 ogical treatment of animals with a selective MC3R agonist ([D-Trp(8)]-gamma-melanocyte-stimulating ho

167 lpha-MSH, melanotan II (MTII), and selective MC3R or MC4R agonists were all inhibitory, reducing the

168 e of the recent description of the selective MC3R agonist [d-Trp(8)]-gamma-melanocyte-stimulating hor

169 ata support the development of the selective MC3R agonist [d-Trp(8)]-gamma-MSH for the treatment of i

170 publications, were found to lack significant MC3R agonist activity.

171 In summary, MC3Rs expressed in Nkx2.1(+ve) neurons are sufficient to

172 cytes that accumulate more triglyceride than MC3R(hWT/hWT) MSCs.

173 from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons a

174 Our results demonstrate that MC3R deletion in MH increases feeding and weight gain fo

175 Together, these results demonstrate that MC3R-mediated effects on energy rheostasis result from t

176 Here we present evidence that MC3R regulates the timing of sexual maturation, the rate

177 C17A+G241A) human (MC3R(hDM/hDM)) MC3R, that MC3R(hDM/hDM) have greater weight and fat mass, increase

178 Single-molecule pull-down assays showed that MC3R and MRAP2 interacted in HEK293 cells.

179 luorescence photobleaching steps showed that MC3R and MRAP2 readily formed heterodimers, most commonl

180 However, our data suggest that MC3R mutations are not associated with severe obesity in

181 P1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enha

182 tensively studied, little is known about the MC3R.

183 ght stimulatory activity was observed at the MC3R (at up to 100 microM concentration).

184 native peptide shows potent activity at the MC3R (EC(50) = 5.9 nM) and is about 50-100-fold selectiv

185 further truncation decreases potency at the MC3R and MC4R.

186 = 3 nM), which is more potent than 7 at the MC3R but not as selective.

187 1 order of magnitude (IC(50) = 6 nM) at the MC3R compared with that of the natural molecule and an i

188 and 250-fold increase in selectivity at the MC3R compared with the MC4R and MC5R, respectively.

189 10-fold more potent (IC(50) = 8.8 nM) at the MC3R compared with the native peptide but lacks subtype

190 electivity of 1-2 orders of magnitude at the MC3R over the MC4R and MC5R.

191 c challenges, as well as to characterize the MC3R expressing cells in dorsal MH.

192 melanocortin neurons selectively express the MC3R, which provides a neuroanatomical basis for a dual-

193 highly selective antagonist analogue for the MC3R (560-fold vs the hMC4R and about 3000-fold vs the h

194 ly, the DTyr(1) peptide is selective for the MC3R (EC(50) = 12 nM) by 40-200-fold compared with the M

195 50) = 11 nM) analogues are selective for the MC3R by 1 and 2 orders of magnitude compared with the MC

196 ecule and an increase in selectivity for the MC3R by 2 orders of magnitude compared with the activity

197 ggest a previously-unrecognized role for the MC3R in adipose tissue development.

198 R agonist that is 100-fold selective for the MC3R over the muM MC4R partial agonist pharmacology.

199 bility of ligands that are selective for the MC3R.

200 ream target regulators that take part in the MC3R signaling cascade.

201 ously showed that intra-VTA injection of the MC3R agonist, MTII, decreases home-cage food intake and

202 be for the investigation of the roles of the MC3R and MC4R in diseases of dysregulated energy homeost

203 Here, we examined the role of the MC3R and the melanocortin system in regulating the respo

204 eletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved

205 Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control mu

206 agonist selectivity for the MC4R versus the MC3R.

207 15-fold selectivity for the MC4R versus the MC3R.

208 gonist ligand for the hMC5R (560-fold vs the MC3R and 1000-fold vs the MC4R); (2) compound 7, Ac-c[Cy

209 ed G protein-coupled receptors, of which the MC3R and MC4R subtypes are implicated in the regulation

210 rent target transcription factors within the MC3R signaling cascade play important roles in immune re

211 Therefore, MC3R is a potential therapeutic target for disorders cha

212 tion of calories, whereas signalling through MC3R primarily regulates the disposition of calories int

213 spectively, and had no detectable binding to MC3R.

214 y from ADA (the adenosine deaminase gene) to MC3R (the melanocortin 3 receptor gene).

215 MC3R, impaired beta-arrestin recruitment to MC3R, and reduced MC3R internalization.

216 by alanine mutagenesis of five MRAP2 and two MC3R transmembrane residues identified by structural hom

217 viously reported children homozygous for two MC3R sequence variants (C17A+G241A) have greater fat mas

218 Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase

219 he His(6) position can determine MC4R versus MC3R agonist selectivity and that chemically nonreactive

220 tified a new and novel >200-fold MC4R versus MC3R selective peptide Tyr-c[Asp-D-Phe-Arg-Trp-Asn-Ala-P

221 VMH MC3R signaling was not sufficient to rescue the lean mas

222 metabolism involves divergent pathways; VMH MC3R signaling improves metabolic homeostasis but does n

223 Although restoring VMH MC3R signaling also had a modest impact on obesity, mark

224 To target VMH MC3R expression, we used the steroidogenic factor-1 Cre

225 receptor (Mc3R)-expressing VMH neurons (VMH(MC3R)) sense glucose changes both directly and indirectl

226 synaptic nodes that potentially regulate VMH(MC3R) neuronal activity, including inputs from proopiome

227 We find that VMH(MC3R) neuron activation blunts, and their silencing enha

228 Overall, these findings demonstrate that VMH(MC3R) neurons are a glucose-responsive hypothalamic subp

229 ment of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the M

230 VTA MC3R neurons were broadly connected to neurons across th

231 ovide a foundation for future studies of VTA MC3R neurons and the circuits containing them in the con

232 both the efferent projection patterns of VTA MC3R neurons and the location of the neurons providing a

233 gnificantly increased the firing rate of VTA MC3R neurons without altering the activity of non-MC3R e

234 st how alpha-MSH affects the activity of VTA MC3R neurons.

235 te nucleus made few direct synapses onto VTA MC3R neurons or any of the other major neuronal subtypes

236 pitous discovery of nine compounds that were MC3R agonists (EC50 < 1000 nM) and MC4R antagonists (5.7

237 duced length and fat-free mass compared with MC3R(hWT/hWT).

238 mistry and their perikarya distribution with MC3R and MC4R by double in situ hybridization.

239 o both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain f