ライフサイエンスコーパス: MC4R

1 MC4R agonists function to lower food intake and weight.

2 MC4R cycles constantly between the plasma membrane and e

3 MC4R cycles constitutively and is internalized at the sa

4 MC4R desensitization and increased AgRP expression are t

5 MC4R effects on energy expenditure and glucose metabolis

6 MC4R endocytosis is required to maintain MC4R responsive

7 MC4R interacts with melanocortin receptor accessory prot

8 MC4R is a critical regulator of energy homeostasis and f

9 MC4R responds to an agonist, alpha-melanocyte-stimulatin

10 MC4R undergoes constitutive internalization and recyclin

11 MC4R-dependent effects of RYGB still occurred in mice wi

12 MC4Rs in autonomic brainstem neurons (including the para

13 MC4Rs in autonomic neurons mediate beneficial effects of

14 The melanocortin receptor 4 (MC4R) is a target for obesity therapies because its acti

15 The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a t

16 (-)(2)(3)), TMEM18 (P = 3.24 x 10(-)(1)(7)), MC4R (P = 4.41 x 10(-)(1)(7)), TNNI3K (P = 4.32 x 10(-)(

17 tors in the model for MC4R-low sucrose 27.7, MC4R-medium sucrose 22.6).

18 linear mixed-effects model, intercept 57.8, MC4R group factor -26.2, factors in the model for MC4R-l

19 tory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appe

20 Six mutations affecting MC4R function, including three that may be private to Pi

21 aptly positioned to activate vagal afferent MC4Rs.

22 neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathw

23 rease was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood

24 to alpha-melanocyte-stimulating hormone, an MC4R agonist, by blocking ligand binding and by directin

25 s, melanocyte stimulating hormone induces an MC4R-dependent and sustained Ca(2+) signal, which requir

26 In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure

27 eover, we demonstrate that the ability of an MC4R agonist delivered to PVN to inhibit food intake is

28 he largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF

29 Two SNPs near the BAT2 and MC4R genes and 3 SNPs within the FTO, SEC16B, and SH2B1

30 B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes.

31 TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8

32 g variants near IHH and DLEU7 for height and MC4R for BMI.

33 ic of agonist-occupied MC4R to lysosomes and MC4R desensitization.

34 the melanocortin 1 and 4 receptors (MC1R and MC4R) in the skin and the brain, respectively, via unkno

35 Melanocortin-3 and 4 receptors (MC3R and MC4R) can regulate energy homeostasis, but their respect

36 he melanocortin-3 and -4 receptors (MC3R and MC4R).

37 complicated signalling pathways of MC3R and MC4R.

38 truncation decreases potency at the MC3R and MC4R.

39 nist at MC2R, which was observed in MC3R and MC4R.

40 that were MC3R agonists (EC50 < 1000 nM) and MC4R antagonists (5.7 < pA2 < 7.8).

41 rbamazepine-induced dermatologic outcome and MC4R with atypical antipsychotic weight gain.

42 ype animals is blocked by Ca(2+) removal and MC4R antagonists.

43 wing that the haploinsufficiency of SIM1 and MC4R results in obesity.

44 om a high-fat diet, the effects of which are MC4R-dependent.

45 Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic re

46 ricular nucleus (PVN), which are known to be MC4R-positive.

47 nd axonal projections of the neurons bearing MC4Rs that control feeding remain unknown.

48 Because MC4R is known to be expressed in vagal afferent neurons

49 selectively targeted by G(q/11)alpha-biased MC4R agonists as a potential treatment for obesity.

50 , expressed later in development, also binds MC4R but increases ligand sensitivity.

51 In cell culture, this protein binds MC4R and reduces the ability of the receptor to bind its

52 In the lipid-stressed cells, MC4R and clathrin were redistributed to the plasma membr

53 nglion (NG), we also systematically compared MC4R-expressing vagal and spinal afferent neurons.

54 In contrast, MC4R agonists activate sympathetic preganglionic neurons

55 In contrast, MC4Rs in cholinergic preganglionic motor neurons (sympat

56 KX4-mediated Ca(2+) extrusion in controlling MC4R signaling and feeding behavior.

57 pared with lean and weight-matched controls, MC4R deficient individuals exhibited a markedly increase

58 Thus, decreased MC4R signaling in melanocortin obesity syndrome consiste

59 e 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only i

60 ther attractin or MGRN1 blocks ASP-dependent MC4R degradation and promotes increased trafficking of i

61 potentiated by the ARC(POMC) neuron-derived MC4R agonist, alpha-melanocyte stimulating hormone (alph

62 by blocking ligand binding and by directing MC4R trafficking to the lysosome.

63 s to fold similarly to kalata B1 but display MC4R activity were investigated.

64 results from Gsalpha mutations and that DMH MC4R/Gsalpha signaling is important for regulation of en

65 Endogenous MC4R agonists possess a critical pharmacophore (HFRW), a

66 Furthermore, MTII and endogenous MC4R agonists increased protein kinase A (PKA)-catalyzed

67 pothalamic GT1-7 cells expressing endogenous MC4R.

68 pressing immunoreactivity for the endogenous MC4R agonist alpha-melanoctyte-stimulating hormone cours

69 Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected t

70 is expressed in tissues that do not express MC4R, and that the deletion of MRAP2 does not recapitula

71 C4R-deficient mice, and mice that re-express MC4R specifically in autonomic neurons after RYGB or sha

72 hypothalamic area (LHA) is known to express MC4Rs and to receive input from leptin-responsive arcuat

73 Finally, MC4R-dependent oxytocin expression in the PVN, a key ess

74 ress disrupts steps of endocytosis following MC4R localization to clathrin-coated sites and exclusion

75 2) for BAT2 to 2.16 (95% CI: 1.39, 3.37) for MC4R.

76 group factor -26.2, factors in the model for MC4R-low sucrose 27.7, MC4R-medium sucrose 22.6).

77 e the activity of the core pharmacophore for MC4R and provide a rationale for careful assay selection

78 These results identify a novel role for MC4R(LHA) signaling in the control of sympathetic nerve

79 ith MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation

80 etes than noncarriers, indicating a role for MC4Rs in the effects of RYGB.

81 genic MC4R-GFP mouse to record directly from MC4R neurons.

82 s in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohy

83 Maternal risk allele score and SNPs in FTO, MC4R, and TMEM18 were positively associated with prepreg

84 stly associated with adult BMI (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, SEC16B,

85 provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare varia

86 iants near the Melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adipo

87 in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extr

88 suppression of GH release in rapidly growing MC4R deficient (MC4RKO) mice, confirming that increased

89 reduction of food intake following hindbrain MC4R activation is mediated by central vagal afferent en

90 ors were utilized to refine a model of human MC4R in the active state (R(*)), which was used to gener

91 The mutation of residues in the human MC4R--such as Leu106 of extracellular loop 1, and Asp122

92 tially affect adiposity via the hypothalamic MC4R pathway.

93 Together this study identifies MC4R deletion as a novel and potentially clinically impo

94 These data implicate MC4R in extreme SGA-induced weight gain and related meta

95 to extend beyond individuals with defects in MC4R signalling, encompassing physiological changes cent

96 restores obesity-associated hypertension in MC4R null mice.

97 raffic to iBAT is significantly increased in MC4R(LHA) mice, which accompanies a significant elevatio

98 source where glucose uptake is increased in MC4R(LHA) mice.

99 owever, the G protein(s) that is involved in MC4R-mediated suppression of food intake and linear grow

100 patients with loss of function mutations in MC4R.

101 h (2) late-onset, genetic-induced obesity in MC4R(-/-) mice in which diabetes secondarily precipitate

102 confirmed that GFP was genuinely produced in MC4R-expressing neurons in the DRG.

103 Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of fe

104 otes hyperlipidemia and hypothalamic injury, MC4R agonists are nevertheless more effective to reduce

105 esting that CREB1 is not required for intact MC4R signaling.

106 omotes increased trafficking of internalized MC4R to the cell surface, but it does not restore alpha-

107 Our findings provide new insights into MC4R signaling in the LHA and its potential implications

108 ational development as well as insights into MC4R structure ad function.

109 The current study investigated MC4R expression in dorsal root ganglia (DRG) of the MC4R

110 gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohist

111 (SIM1)(+) neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia.

112 notan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP- sensitive potassium channel-

113 We found that LHA MC4R-GFP neurons coexpress neurotensin as well as the le

114 Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental

115 and constant signaling by an obesity-linked MC4R variant, I316S, that otherwise is retained in the E

116 ion was synthesized and observed to maintain MC4R potency.

117 MC4R endocytosis is required to maintain MC4R responsiveness to alpha-MSH by constantly eliminati

118 nds, while replacing Ala with Ser maintained MC4R potency.

119 This makes MC4R a logical target for pharmacological therapy for th

120 or agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R.

121 ressed melanocortin-3 and -4 receptors (MC3R/MC4R) have been studied as possible targets for weight m

122 with DMH-specific deficiency of melanocortin MC4R receptors, which are known to activate Gsalpha.

123 I), and the highly selective, small-molecule MC4R agonist, Pf-446687, enhanced partner preference for

124 c peptide template that identified a lead nM MC4R ligand.

125 that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient

126 he LHA improves glucose intolerance in obese MC4R-null mice without affecting body weight or circulat

127 died C57BL/6 mice with diet-induced obesity, MC4R-deficient mice, and mice that re-express MC4R speci

128 somes as well as traffic of agonist-occupied MC4R to lysosomes and MC4R desensitization.

129 ulate nociception, but the site of action of MC4R signaling on nociception remains to be elucidated.

130 afish by specifically blocking the action of MC4R.

131 Activation of MC4R causes dramatic weight loss in rodent models, and m

132 We also show that the activity of MC4R PVN neurons is controlled by the constitutive activ

133 However, carriers of MC4R (I251L), a rare variant associated with increased w

134 proteins allow for developmental control of MC4R activity, with MRAP2a blocking its function and sti

135 del of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin ac

136 has signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel

137 Coupling of MC4R to Kir7.1 may explain unusual aspects of the contro

138 nalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.

139 ation prevents the glucoregulatory effect of MC4R(LHA) signaling.

140 are thought to decrease the effectiveness of MC4R agonists as an antiobesity treatment.

141 We conclude that increased effectiveness of MC4R agonists in obesity may be an unexpected outcome of

142 e used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood.

143 enous receptors, constitutive endocytosis of MC4R and agonist-dependent internalization of beta(2)AR

144 n also inhibited constitutive endocytosis of MC4R by approximately 5-fold, while not affecting recycl

145 ta indicate that constitutive endocytosis of MC4R is clathrin- and cholesterol-dependent.

146 ores normal weight and metabolic features of MC4R-null mice, a model of human obesity.

147 Inhibition of MC4R endocytosis by clathrin depletion decreased the num

148 Studies show that inhibition of MC4R signaling can acutely increase the consumption of h

149 C4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striat

150 The loss of MC4R function increased over time (25-50%) and was parti

151 Clinical observations suggest that loss of MC4R function may enhance growth hormone (GH)-mediated g

152 that hyperphagia following germline loss of MC4R in male mice promotes growth while suppressing the

153 Loss of MC4R is known to induce hyperphagia and hypometabolism i

154 eptor number indicating that a population of MC4R at the cell surface becomes nonfunctional.

155 ely 5-fold, while not affecting recycling of MC4R or agonist-dependent internalization of beta(2)AR.

156 phagia, has focused attention on the role of MC4R in feeding behavior and macronutrient intake.

157 s of the hypothalamus (PVN) is a key site of MC4R action.

158 wever, lipid stress disrupted later steps of MC4R and transferrin receptor internalization to endosom

159 me time exhibited additive effects on top of MC4R deficiency on lipid and glucose metabolism.

160 dependent mechanism promoting trafficking of MC4R and likely MC1R away from the lysosome toward the c

161 milar rate in patients with rare variants of MC4R and noncarriers.

162 Deletion of MC4Rs in cholinergic neurons resulted in elevated levels

163 omic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain

164 basis for the feeding-regulating effects of MC4Rs.

165 Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sym

166 Restoring expression of MC4Rs specifically in the LHA improves glucose intoleran

167 rtin neurons, the physiological functions of MC4Rs in the LHA are incompletely understood.

168 Reexpression of MC4Rs on single-minded 1 (SIM1)(+) neurons in mice other

169 Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventr

170 n of the AUUAAA hexamer had little effect on MC4R 3'end processing but small changes in the short DSE

171 gulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequen

172 nd thereby indicate that this 5-HT(2C)R/POMC-MC4R/SIM1 circuit may yield a more refined target to exp

173 rain melanocortin system, including the POMC-MC4R pathway, a mechanism also activated by leptin to mo

174 , and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC

175 (16%) or CGRP (13%), suggesting preferential MC4R expression in C-fiber nonpeptidergic neurons.

176 he location and nature of obesity-preventing MC4R-expressing neurons are unknown.

177 reveal this function to be mediated by a PVH(MC4R)-->lateral parabrachial nucleus (LPBN) pathway.

178 smission across the ARC(Glutamatergic)-->PVH(MC4R) synapse is potentiated by the ARC(POMC) neuron-der

179 ons in the paraventricular hypothalamus (PVH(MC4R) neurons).

180 g real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a func

181 , the satiating and appetitive nature of PVH(MC4R)-->LPBN neurons supports the principles of drive re

182 gate diabetes resolution in carriers of rare MC4R variants.

183 tion to a subset of melanocortin-4 receptor (MC4R(PVH)) cells, which are also responsive to CCK.

184 Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounce

185 SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM

186 ved residues of the melanocortin 4 receptor (MC4R) gene, contributing to the insatiable appetite foun

187 his locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by l

188 Melanocortin-4 receptor (MC4R) has an important regulatory role in energy homeost

189 The melanocortin-4 receptor (MC4R) has been broadly investigated.

190 The melanocortin-4 receptor (MC4R) has been studied extensively.

191 that absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characteriz

192 rrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of

193 Melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed in neuro

194 Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor expressed in the b

195 Melanocortin-4 receptor (MC4R) is a G-protein-coupled receptor expressed in the h

196 Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the parave

197 The melanocortin-4 receptor (MC4R) is essential for control of energy homeostasis in

198 The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of bod

199 Melanocortin-4 receptor (MC4R) ligands are known to modulate nociception, but the

200 n in the intronless melanocortin 4 receptor (MC4R) pre-mRNA.

201 signals in BDNF and melanocortin 4 receptor (MC4R) regions.

202 The Melanocortin-4 receptor (MC4R) regulates food intake, energy balance, and somatic

203 of function of the melanocortin 4 receptor (MC4R) results in hyperphagia, obesity and increased grow

204 nsufficiency of the melanocortin-4 receptor (MC4R) results in melanocortin obesity syndrome, the most

205 Melanocortin 4 receptor (MC4R) signaling mediates diverse physiological functions

206 Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency

207 e gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signa

208 e downstream of the melanocortin-4 receptor (MC4R), but this hypothesis has never been confirmed in v

209 gnalling though the melanocortin 4 receptor (MC4R), which is widely expressed in the hypothalamus, me

210 gRP) projections on melanocortin-4 receptor (MC4R)-expressing satiety neurons in the paraventricular

211 tasis including the melanocortin-4 receptor (MC4R).

212 hat also lacked the melanocortin-4 receptor (MC4R).

213 igh affinity to the melanocortin-4 receptor (MC4R); existing data show that alpha-MSH is an agonist t

214 Defects in melanocortin-4-receptor (MC4R) signalling result in hyperphagia, obesity and incr

215 Melanocortin-4-receptor (MC4R)-expressing neurons modulate food intake and prefer

216 tem, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that re

217 Melanocortin-4 receptors (MC4R) have weight-independent effects on glucose homeost

218 nated centrally by melanocortin-4 receptors (MC4R) in neurons of the hypothalamic paraventricular nuc

219 ands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus

220 Melanocortin-4 receptors (MC4Rs) are expressed by vagal afferent endings in the NT

221 Whether melanocortin 4 receptors (MC4Rs) in extra-hypothalamic neurons, including choliner

222 Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators

223 ctivation of brain melanocortin 4 receptors (MC4Rs) leads to reduced food intake, increased energy ex

224 Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however,

225 d that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished a

226 Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both nec

227 98 (0.06, 3.90), p = 0.04 and near rs571312 (MC4R): beta 2.15 (-0.03, 4.33) p = 0.05); and one SNP sh

228 known to associate with BMI: FTO(rs9939609); MC4R(rs17782313); and TMEM18(rs6548238).

229 The blood pressure response to the same MC4R agonist was only lost in animals lacking G(s)alpha

230 ven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and th

231 One is a selective MC4R agonist.

232 hemistry to develop novel, potent, selective MC4R agonists.

233 Surprisingly, MC4R function tested pharmacologically was normal in CRE

234 f appetite-reducing peptides by synthesizing MC4R agonists based on the insertion of the His-Phe-Arg-

235 We report that MC4R(LHA) signaling regulates glucose tolerance and symp

236 Here, we show that MC4R agonists inhibit parasympathetic preganglionic neur

237 We found that MC4Rs in sympathetic, but not parasympathetic, pre-gangl

238 Despite knowing that MC4Rs control food intake, we are yet to understand why

239 The MC4R exon was sequenced in 6,760 individuals of predomin

240 The MC4R genotype, postpartum weight reduction, and glycemic

241 The MC4R poly(A) site requires only the DSE and an A-rich up

242 KB1(GHFRWG;23-28) had a K(i) of 29 nm at the MC4R and was 107 or 314 times more selective over this r

243 ation hormone, but it was less potent at the MC4R, with an EC(50) of 580 nm for activation of the MC4

244 ependent rescue of the A(y) phenotype at the MC4R.

245 upstream melanocortin receptors, because the MC4R antagonist, SHU9119, reversed Sirt1's effect on foo

246 ddition, we found an interaction between the MC4R genotype and postpartum weight reduction on changes

247 Reduced cholesterol did not change the MC4R dose-response curve to alpha-MSH, but it decreased

248 The peptide had higher affinity for the MC4R than the endogenous agonist, alpha-melanocyte stimu

249 HFRWG;23-28) is potent and selective for the MC4R.

250 a single variation at amino acid 156 in the MC4R from representative species of major cetacean linea

251 In the MC4R null background, G93A SOD1 mice become markedly hyp

252 ly unknown, role for Ca(2+) signaling in the MC4R pathway that leads to satiety, and a novel non-redu

253 rane conductances and gene expression in the MC4R PVN neuron.

254 ording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority o

255 ect, whereas deletion of both alleles of the MC4R actually decreases preference for palatable high-fa

256 ntrolled by the constitutive activity of the MC4R and that expression of the receptor mRNA and alpha-

257 Peptide agonists of the MC4R are characterized by the conserved sequence His(6)-

258 tein (GFP) is expressed under control of the MC4R gene promoter, we systemically investigated MC4R si

259 s study, we examined allelic variants of the MC4R in cetaceans.

260 Since the report of the MC4R knockout mouse in 1997, the field has been searchin

261 er intronless genes, 3'end processing of the MC4R primary transcript is independent of any auxiliary

262 nderstand why defects in the function of the MC4R receptor contribute to rapid linear growth.

263 with deletion of one or both alleles of the MC4R to model the human syndrome.

264 The adiposity-increasing allele (C) of the MC4R variant rs6567160 was associated with greater postp

265 tion in part through the potentiation of the MC4R, however, it is clear that MRAP2 is expressed in ti

266 Using male mice with germline loss of the MC4R, we assessed pulsatile GH release and insulin-like

267 pression in dorsal root ganglia (DRG) of the MC4R-GFP reporter mouse.

268 th an EC(50) of 580 nm for activation of the MC4R.

269 Formation of the MC4R/agonist complex in the ER stabilizes the receptor i

270 he(7) on the ligand and Ile125 of TM3 on the MC4R.

271 h a preponderance of studies focusing on the MC4R.

272 , and GABA from first-order neurons onto the MC4R PVN cells.

273 rying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI.

274 We sequenced the MC4R from 20 cetaceans, and pharmacologically characteri

275 We also sequenced the MC4R locus in patients undergoing RYGB to investigate di

276 We found that the MC4R genotype was associated with postpartum glycemic ch

277 gnition in humans, our data suggest that the MC4R may be a viable therapeutic target for enhancing so

278 These data suggest that the MC4R may be one gene involved in the evolution of feedin

279 ity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1(+),

280 We aimed to assess whether the MC4R genotype affected longitudinal changes in body weig

281 perature (T(IBAT)) and pretreatment with the MC4R antagonist, HS024 (0.072nmol) blocked the MC4-R ago

282 Thus, MC4Rs on SIM1(+) neurons, possibly in the paraventricula

283 TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body

284 st that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition

285 d high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compro

286 using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons.

287 ogether, our findings demonstrate variegated MC4R expression in different classes of vagal and spinal

288 We investigated whether MC4Rs mediate effects of RYGB, such as its weight-indepe

289 palmitate leaves unchanged the rate by which MC4R and transferrin receptor are constitutively exclude

290 f the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed

291 that the ER-targeted agonist associates with MC4R at this location, is transported to the cell surfac

292 fore the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutat

293 eals were comparable in the individuals with MC4R deficiency, liking ratings for the high sucrose mea

294 ight obtained was higher in individuals with MC4R deficiency.

295 Studies in patients with MC4R deficiency can provide insights into the role of th

296 Similarly, patients with MC4R deficiency consumed less of all three sucrose meals

297 We studied 24 obese patients with MC4R deficiency, and 80 healthy controls (40 obese, 40 l

298 Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obe

299 ffer between the three groups, patients with MC4R mutations consumed 95% more of the high fat meal th

300 side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood