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Ya-xiong Tao - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological characterization of three chicken Melanocortin-3 Receptor mutants
    Domestic animal endocrinology, 2020
    Co-Authors: Hai-jie Zhang, Zhi-qiang Wang, Z.-h. Cui, Min Liu, Tianqi Min, X. Xiao, Ya-xiong Tao
    Abstract:

    The Melanocortin-3 Receptor (MC3R) is a G protein-coupled Receptor and potentially important in production traits. Three naturally occurring mutations (M54L, G104S, and L151R) in chicken MC3R (cMC3R) were reported previously to be associated with production traits. Here, we inserted the full-length cMC3R coding sequence into pcDNA3.1(+) and generated the 3 mutations by site-directed mutagenesis. The total and cell surface expression of the Receptors was measured by flow cytometry. We analyzed the pharmacological characteristics, including binding and cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) signaling, using 6 ligands ([Nle4, D-Phe7]-α-melanocyte stimulating hormone (MSH), α-, β-, γ-, and D-Trp8-γ-MSHs, and agouti-related peptide). All mutants had similar total and cell surface expression as the wild-type (WT) cMC3R. M54L had similar pharmacological properties as the WT cMC3R. G104S did not exhibit any specific binding but had minimal response to α-, β-, γ-, and D-Trp8-γ-MSH, although it generated 24% WT response when stimulated by NDP-MSH. Although L151R had normal binding, the responses to agonists were reduced to approximately 25% of that of the WT. In MAPK signaling, all 3 mutants showed significantly increased agonist-stimulated phosphorylation of extracellular signal-regulated protein kinases 1/2, indicating the existence of biased signaling at G104S and L151R. In summary, our studies demonstrated that although all 3 mutations are significantly associated with production traits, only G104S and L151R had severe defects in Receptor pharmacology. How M54L might cause production trait differences remains to be investigated.

  • Characterization of channel catfish (Ictalurus punctatus) Melanocortin-3 Receptor reveals a potential network in regulation of energy homeostasis.
    General and comparative endocrinology, 2019
    Co-Authors: Li-kun Yang, Zheng-rui Zhang, Haishen Wen, Ya-xiong Tao
    Abstract:

    The Melanocortin-3 Receptor (MC3R) is known to be involved in regulation of energy homeostasis, regulating feed efficiency and nutrient partitioning in mammals. Its physiological roles in non-mammalian vertebrates, especially economically important aquaculture species, are not well understood. Channel catfish (Ictalurus punctatus) is the main freshwater aquaculture species in North America. In this study, we characterized the channel catfish MC3R. The mc3r of channel catfish encoded a putative protein (ipMC3R) of 367 amino acids. We transfected HEK293T cells with ipMC3R plasmid for functional studies. Five agonists, including adrenocorticotropin, α-melanocyte stimulating hormone (α-MSH), β-MSH, [Nle4, D-Phe7]-α-MSH, and D-Trp8-γ-MSH, were used in the pharmacological studies. Our results showed that ipMC3R bound β-MSH with higher affinity and D-Trp8-γ-MSH with lower affinity compared with human MC3R. All agonists could stimulate ipMC3R and increase intracellular cAMP production with sub-nanomolar potencies. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation could also be triggered by ipMC3R. The ipMC3R exhibited constitutive activities in both cAMP and ERK1/2 pathways, and Agouti-related protein served as an inverse agonist at ipMC3R, potently inhibiting the high basal cAMP level. Moreover, we showed that Melanocortin Receptor accessory protein 2 (MRAP2) preferentially modulated ipMC3R in cAMP production rather than ERK1/2 activation. Our study will assist further investigation of the physiological roles of the ipMC3R, especially in energy homeostasis, in channel catfish.

  • Mutations in Melanocortin-3 Receptor Gene and Human Obesity.
    Progress in molecular biology and translational science, 2016
    Co-Authors: Zhao Yang, Ya-xiong Tao
    Abstract:

    The prevalence of obesity calls for novel therapeutic targets. The Melanocortin-3 Receptor (MC3R) has been increasingly recognized as an important regulator of energy homeostasis and MC3R has been intensively analyzed in molecular genetic studies for obesity-related traits. Twenty-seven MC3R mutations and two common polymorphic variants have been identified so far in different cohorts. The mutant MC3Rs demonstrate multiple defects in functional analysis and can be cataloged into different classes according to Receptor life cycle based classification system. Although the pathogenic role of MC3R in human obesity remains controversial, recent findings in the noncanonical signaling pathway of MC3R mutants have provided new insights. Potential therapeutic strategies for obesity related to MC3R mutations are highlighted.

  • Functions of DPLIY motif and helix 8 of human Melanocortin-3 Receptor.
    Journal of molecular endocrinology, 2015
    Co-Authors: Zhao Yang, Zhi-li Huang, Ya-xiong Tao
    Abstract:

    The Melanocortin-3 Receptor (MC3R) is a member of the family A G protein-coupled Receptors (GPCRs). The MC3R remains the most enigmatic of the Melanocortin Receptors with regard to its physiological functions, especially its role in energy homeostasis. The N/DPxxY motif and the eighth helix (helix 8) in the carboxyl terminus of GPCRs have been identified to be important for Receptor expression, ligand binding, signal transduction and internalization. To gain a better understanding of the structure-function relationship of MC3R, we performed a systematic study of all 20 residues in this domain using alanine-scanning mutagenesis. We showed that although all mutants were expressed normally on the cell surface, eleven residues were important for ligand binding and one was indispensable for downstream cAMP generation. F347A showed constitutive activity in cAMP signaling while all the other mutants had normal basal activities. We studied the signaling capacity of nine mutants in the ERK1/2 signaling pathway. All of these mutants showed normal basal ERK1/2 phosphorylation levels. The pERK1/2 levels of six binding- or signaling-defective mutants were enhanced upon agonist stimulation. The unbalanced cAMP and pERK1/2 signaling pathways suggested the existence of biased signaling in MC3R mutants. In summary, we showed that the DPLIY motif and helix 8 was important for MC3R activation and signal transduction. Our data led to a better understanding of the structure-function relationship of MC3R.

  • Biased signaling in naturally occurring mutations in human Melanocortin-3 Receptor gene.
    International journal of biological sciences, 2015
    Co-Authors: Fan Yang, Hui Huang, Ya-xiong Tao
    Abstract:

    The Melanocortin-3 Receptor (MC3R) is primarily expressed in the hypothalamus and plays an important role in the regulation of energy homeostasis. Recently, some studies demonstrated that MC3R also signals through mitogen-activated protein kinases (MAPKs), especially extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2 signaling is known to alter gene expression, potentially contributing to the prolonged action of Melanocortins on energy homeostasis regulation. In the present study, we performed detailed functional studies on 8 novel naturally occurring MC3R mutations recently reported, and the effects of endogenous MC3R agonist, α-melanocyte stimulating hormone (MSH), on ERK1/2 signaling on all 22 naturally occurring MC3R mutations reported to date. We found that mutants D158Y and L299V were potential pathogenic causes to obesity. Four residues, F82, D158, L249 and L299, played critical roles in different aspects of MC3R function. α-MSH exhibited balanced activity in Gs-cAMP and ERK1/2 signaling pathways in 15 of the 22 mutant MC3Rs. The other 7 mutant MC3Rs were biased to either one of the signaling pathways. In summary, we provided novel data about the structure-function relationship of MC3R, identifying residues important for Receptor function. We also demonstrated that some mutations exhibited biased signaling, preferentially activating one intracellular signaling pathway, adding a new layer of complexity to MC3R pharmacology.

José Luis Santos - One of the best experts on this subject based on the ideXlab platform.

  • Effect of the Melanocortin-3 Receptor Thr6Lys and Val81Ile genetic variants on body composition and substrate oxidation in Chilean obese children
    Journal of physiology and biochemistry, 2011
    Co-Authors: Ana María Obregón, Erik Díaz, José Luis Santos
    Abstract:

    Mice genetically deficient in the Melanocortin-3 Receptor gene are characterized by normal body weight, increased body fat, mild hypophagia, reduced locomotor activity, and increased respiratory quotient compared with wild-type mice. In humans, the 6Lys–81Ile haplotype of Melanocortin-3 Receptor (MC3R) gene has been associated with childhood obesity, higher body fat percentage, and reduced fat oxidation compared to non-carriers. The aim of this study was to evaluate the association between MC3R 6Lys–81Ile haplotype with body composition and substrate oxidation in response to moderate exercise in obese children. Eight Chilean obese children (aged 8–12) carriers of MC3R 6Lys–81Ile haplotype were compared with eight age–gender-matched obese non-carriers. Children were identified through a previous cross-sectional study on genetic determinants of childhood obesity (n = 229). Genotypes for MC3R Thr6Lys and Val81Ile were determined by polymerase chain reaction–restriction fragment length polymorphism. Body composition was assessed by the four-compartment model (dual-energy X-ray absorptiometry, total body water by the deuterium dilution technique, and total fat mass by air-displacement plethysmography). Substrate oxidation was assessed by indirect calorimetry in response to moderate exercise (60% VO2 max). Wilcoxon matched-pairs test was used to compare quantitative variables. No significant differences among carriers and non-carriers were found in anthropometrical and body composition measurements. The Carriers of the 6Lys–81Ile haplotype showed higher respiratory quotient (p = 0.06) and a significantly higher glucose oxidation (p = 0.01) compared with non-carriers after standardization for fat-free mass. Our results are consistent with a possible participation of MC3R 6Lys–81Ile variants in glucose oxidation in response to moderate exercise.

  • Allelic variants of Melanocortin 3 Receptor Gene (MC3R) and weight loss in obesity: A randomised trial of Hypo-Energetic High- versus Low-Fat diets
    PloS one, 2011
    Co-Authors: José Luis Santos, Rolando De La Cruz, Claus Holst, Katrine Grau, Carolina Naranjo, Alberto Maiz, Arne Astrup, Wim H. M. Saris, Ian A. Macdonald, Jean-michel Oppert
    Abstract:

    Introduction The Melanocortin system plays an important role in energy homeostasis. Mice genetically deficient in the Melanocortin-3 Receptor gene have a normal body weight with increased body fat, mild hypophagia compared to wild-type mice. In humans, Thr6Lys and Val81Ile variants of the Melanocortin-3 Receptor gene (MC3R) have been associated with childhood obesity, higher BMI Z-score and elevated body fat percentage compared to non-carriers. The aim of this study is to assess the association in adults between allelic variants of MC3R with weight loss induced by energy-restricted diets. Subjects and Methods This research is based on the NUGENOB study, a trial conducted to assess weight loss during a 10-week dietary intervention involving two different hypo-energetic (high-fat and low-fat) diets. A total of 760 obese patients were genotyped for 10 single nucleotide polymorphisms covering the single exon of MC3R gene and its flanking regions, including the missense variants Thr6Lys and Val81Ile. Linear mixed models and haplotype-based analysis were carried out to assess the potential association between genetic polymorphisms and differential weight loss, fat mass loss, waist change and resting energy expenditure changes. Results No differences in drop-out rate were found by MC3R genotypes. The rs6014646 polymorphism was significantly associated with weight loss using co-dominant (p = 0.04) and dominant models (p = 0.03). These p-values were not statistically significant after strict control for multiple testing. Haplotype-based multivariate analysis using permutations showed that rs3827103–rs1543873 (p = 0.06), rs6014646–rs6024730 (p = 0.05) and rs3746619–rs3827103 (p = 0.10) displayed near-statistical significant results in relation to weight loss. No other significant associations or gene*diet interactions were detected for weight loss, fat mass loss, waist change and resting energy expenditure changes. Conclusion The study provided overall sufficient evidence to support that there is no major effect of genetic variants of MC3R and differential weight loss after a 10-week dietary intervention with hypo-energetic diets in obese Europeans.

  • Melanocortin-3 Receptor gene variants: association with childhood obesity and eating behavior in Chilean families.
    Nutrition, 2010
    Co-Authors: Ana María Obregón, Paola Amador, Macarena Valladares, Gerardo Weisstaub, Raquel Burrows, José Luis Santos
    Abstract:

    Abstract Objective To evaluate the association between Melanocortin-3 Receptor common genetic polymorphisms with childhood obesity and eating behavior in Chilean families. Methods Two hundred twenty-nine obese children (6–12 y old, body mass index >95th percentile of Centers for Disease Control and Prevention/National Center for Health Statistics, 2000) and 270 parents were selected. Genotypes for MC3R genetic markers −239A > G, 17C > A (Thr6Lys), 241 G > A (Val81Ile), +2138InsCAGACC, and microsatellite D20s32e were determined. Eating behavior scores were computed using the Child Eating Behavior Questionnaire and a shorter version of the Three Factor Eating Questionnaire adapted for evaluating eating inclinations in children. Genotype-obesity associations were assessed by the Transmission Disequilibrium Test. Non-parametric tests were used to compare eating behavior scores across study groups. Results Allelic frequencies of −239 G, 17A, 241A, and +2138InsCAGACC were estimated as 4.5%, 5.9%, 5.6%, and 17.6%, respectively, in obese children. The Transmission Disequilibrium Test in case–parent trios revealed no significant associations between childhood obesity and genetic markers, including the microsatellite D20s32e. In girls, we found significantly higher scores of the emotional eating subscale in carriers of the +2138InsCAGACC compared with non-carriers ( P  = 0.04). In boys, carriers of 17A and 241A showed lower scores for the emotional eating subscale ( P  = 0.01), whereas carriers of +2138InsCAGACC showed significantly lower scores for the enjoyment of food subscale compared with non-carriers ( P  = 0.04). Conclusions There is not sufficient evidence to support the contribution for common Melanocortin-3 Receptor variants in childhood obesity. However, our results are concordant for a role of Melanocortin-3 Receptor variants in some dimensions of eating behavior such as emotional eating and enjoyment of food.

  • Melanocortin-3 Receptor gene variants: association with childhood obesity and eating behavior in Chilean families.
    Nutrition (Burbank Los Angeles County Calif.), 2010
    Co-Authors: Ana María Obregón, Paola Amador, Macarena Valladares, Gerardo Weisstaub, Raquel Burrows, José Luis Santos
    Abstract:

    To evaluate the association between Melanocortin-3 Receptor common genetic polymorphisms with childhood obesity and eating behavior in Chilean families. Two hundred twenty-nine obese children (6-12 y old, body mass index >95th percentile of Centers for Disease Control and Prevention/National Center for Health Statistics, 2000) and 270 parents were selected. Genotypes for MC3R genetic markers -239A>G, 17C>A (Thr6Lys), 241G>A (Val81Ile), +2138InsCAGACC, and microsatellite D20s32e were determined. Eating behavior scores were computed using the Child Eating Behavior Questionnaire and a shorter version of the Three Factor Eating Questionnaire adapted for evaluating eating inclinations in children. Genotype-obesity associations were assessed by the Transmission Disequilibrium Test. Non-parametric tests were used to compare eating behavior scores across study groups. Allelic frequencies of -239G, 17A, 241A, and +2138InsCAGACC were estimated as 4.5%, 5.9%, 5.6%, and 17.6%, respectively, in obese children. The Transmission Disequilibrium Test in case-parent trios revealed no significant associations between childhood obesity and genetic markers, including the microsatellite D20s32e. In girls, we found significantly higher scores of the emotional eating subscale in carriers of the +2138InsCAGACC compared with non-carriers (P=0.04). In boys, carriers of 17A and 241A showed lower scores for the emotional eating subscale (P=0.01), whereas carriers of +2138InsCAGACC showed significantly lower scores for the enjoyment of food subscale compared with non-carriers (P=0.04). There is not sufficient evidence to support the contribution for common Melanocortin-3 Receptor variants in childhood obesity. However, our results are concordant for a role of Melanocortin-3 Receptor variants in some dimensions of eating behavior such as emotional eating and enjoyment of food. 2010 Elsevier Inc. All rights reserved.

Nosratola D. Vaziri - One of the best experts on this subject based on the ideXlab platform.

  • role of γ melanocyte stimulating hormone renal Melanocortin 3 Receptor system in blood pressure regulation in salt resistant and salt sensitive rats
    Metabolism-clinical and Experimental, 2009
    Co-Authors: Gangadarshni Chandramohan, Nicquanna Durham, Satyesh K. Sinha, Keith C. Norris, Nosratola D. Vaziri
    Abstract:

    Abstract Melanocortin 3 Receptor (MC3-R) has high affinity and specificity to γ melanocyte-stimulating hormone ( γ MSH), a natriuretic peptide involved in regulation of blood pressure (BP) and sodium excretion. Recent studies showing increased MC3-R expression and elevated plasma γ MSH in normal rats fed a high-salt diet support the role of this system in sodium homeostasis. We hypothesized that dysregulation of MC3-R response to dietary salt may contribute to salt retention and BP elevation in salt-sensitive hypertension. We examined renal MC3-R expression, plasma γ MSH concentration, and response to MC3-R agonist and antagonist in Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats fed high-salt (8%) or low-salt (0.07%) diets for 3 weeks. Consumption of high-salt diet significantly increased BP in the DSS but not the DSR group. High-salt diet led to a 5-fold increase in plasma γ MSH and a 2-fold increase in renal MC3-R in DSR rats. Plasma γ MSH and renal MC3-R abundance in DSS rats were maximally elevated on low-salt diet and remained unchanged on high-salt diet. Administration of MC3-R agonist melanotan II significantly lowered BP and raised fractional Na excretion in the DSR but not the DSS rats consuming high-salt diet. In contrast, MC3-R antagonist SHU9119 significantly raised BP and lowered fractional Na excretion in both groups. Thus, the data suggest that γ MSH–renal MC3-R pathway is activated and appears to be biologically functional in the DSS rats.

  • Role of γ melanocyte-stimulating hormone―renal Melanocortin 3 Receptor system in blood pressure regulation in salt-resistant and salt-sensitive rats
    Metabolism: clinical and experimental, 2009
    Co-Authors: Gangadarshni Chandramohan, Nicquanna Durham, Satyesh K. Sinha, Keith C. Norris, Nosratola D. Vaziri
    Abstract:

    Abstract Melanocortin 3 Receptor (MC3-R) has high affinity and specificity to γ melanocyte-stimulating hormone ( γ MSH), a natriuretic peptide involved in regulation of blood pressure (BP) and sodium excretion. Recent studies showing increased MC3-R expression and elevated plasma γ MSH in normal rats fed a high-salt diet support the role of this system in sodium homeostasis. We hypothesized that dysregulation of MC3-R response to dietary salt may contribute to salt retention and BP elevation in salt-sensitive hypertension. We examined renal MC3-R expression, plasma γ MSH concentration, and response to MC3-R agonist and antagonist in Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats fed high-salt (8%) or low-salt (0.07%) diets for 3 weeks. Consumption of high-salt diet significantly increased BP in the DSS but not the DSR group. High-salt diet led to a 5-fold increase in plasma γ MSH and a 2-fold increase in renal MC3-R in DSR rats. Plasma γ MSH and renal MC3-R abundance in DSS rats were maximally elevated on low-salt diet and remained unchanged on high-salt diet. Administration of MC3-R agonist melanotan II significantly lowered BP and raised fractional Na excretion in the DSR but not the DSS rats consuming high-salt diet. In contrast, MC3-R antagonist SHU9119 significantly raised BP and lowered fractional Na excretion in both groups. Thus, the data suggest that γ MSH–renal MC3-R pathway is activated and appears to be biologically functional in the DSS rats.

Gangadarshni Chandramohan - One of the best experts on this subject based on the ideXlab platform.

  • role of γ melanocyte stimulating hormone renal Melanocortin 3 Receptor system in blood pressure regulation in salt resistant and salt sensitive rats
    Metabolism-clinical and Experimental, 2009
    Co-Authors: Gangadarshni Chandramohan, Nicquanna Durham, Satyesh K. Sinha, Keith C. Norris, Nosratola D. Vaziri
    Abstract:

    Abstract Melanocortin 3 Receptor (MC3-R) has high affinity and specificity to γ melanocyte-stimulating hormone ( γ MSH), a natriuretic peptide involved in regulation of blood pressure (BP) and sodium excretion. Recent studies showing increased MC3-R expression and elevated plasma γ MSH in normal rats fed a high-salt diet support the role of this system in sodium homeostasis. We hypothesized that dysregulation of MC3-R response to dietary salt may contribute to salt retention and BP elevation in salt-sensitive hypertension. We examined renal MC3-R expression, plasma γ MSH concentration, and response to MC3-R agonist and antagonist in Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats fed high-salt (8%) or low-salt (0.07%) diets for 3 weeks. Consumption of high-salt diet significantly increased BP in the DSS but not the DSR group. High-salt diet led to a 5-fold increase in plasma γ MSH and a 2-fold increase in renal MC3-R in DSR rats. Plasma γ MSH and renal MC3-R abundance in DSS rats were maximally elevated on low-salt diet and remained unchanged on high-salt diet. Administration of MC3-R agonist melanotan II significantly lowered BP and raised fractional Na excretion in the DSR but not the DSS rats consuming high-salt diet. In contrast, MC3-R antagonist SHU9119 significantly raised BP and lowered fractional Na excretion in both groups. Thus, the data suggest that γ MSH–renal MC3-R pathway is activated and appears to be biologically functional in the DSS rats.

  • Role of γ melanocyte-stimulating hormone―renal Melanocortin 3 Receptor system in blood pressure regulation in salt-resistant and salt-sensitive rats
    Metabolism: clinical and experimental, 2009
    Co-Authors: Gangadarshni Chandramohan, Nicquanna Durham, Satyesh K. Sinha, Keith C. Norris, Nosratola D. Vaziri
    Abstract:

    Abstract Melanocortin 3 Receptor (MC3-R) has high affinity and specificity to γ melanocyte-stimulating hormone ( γ MSH), a natriuretic peptide involved in regulation of blood pressure (BP) and sodium excretion. Recent studies showing increased MC3-R expression and elevated plasma γ MSH in normal rats fed a high-salt diet support the role of this system in sodium homeostasis. We hypothesized that dysregulation of MC3-R response to dietary salt may contribute to salt retention and BP elevation in salt-sensitive hypertension. We examined renal MC3-R expression, plasma γ MSH concentration, and response to MC3-R agonist and antagonist in Dahl salt-sensitive (DSS) and Dahl salt-resistant (DSR) rats fed high-salt (8%) or low-salt (0.07%) diets for 3 weeks. Consumption of high-salt diet significantly increased BP in the DSS but not the DSR group. High-salt diet led to a 5-fold increase in plasma γ MSH and a 2-fold increase in renal MC3-R in DSR rats. Plasma γ MSH and renal MC3-R abundance in DSS rats were maximally elevated on low-salt diet and remained unchanged on high-salt diet. Administration of MC3-R agonist melanotan II significantly lowered BP and raised fractional Na excretion in the DSR but not the DSS rats consuming high-salt diet. In contrast, MC3-R antagonist SHU9119 significantly raised BP and lowered fractional Na excretion in both groups. Thus, the data suggest that γ MSH–renal MC3-R pathway is activated and appears to be biologically functional in the DSS rats.

Victor J. Hruby - One of the best experts on this subject based on the ideXlab platform.

  • Melanocortin 3 Receptor activation with d trp8 γ msh suppresses inflammation in apolipoprotein e deficient mice
    European Journal of Pharmacology, 2020
    Co-Authors: James J Kadiri, Minying Cai, Victor J. Hruby, Keshav Thapa, Katja Kaipio, Petteri Rinne
    Abstract:

    Abstract The Melanocortin MC1 and MC3 Receptors elicit anti-inflammatory actions in leukocytes and activation of these Receptors has been shown to alleviate arterial inflammation in experimental atherosclerosis. Thus, we aimed to investigate whether selective targeting of Melanocortin MC3 Receptor protects against atherosclerosis. Apolipoprotein E deficient (ApoE−/−) mice were fed high-fat diet for 12 weeks and randomly assigned to receive either vehicle (n = 11) or the selective Melanocortin MC3 Receptor agonist [D-Trp(8)]-gamma-melanocyte-stimulating hormone ([D-Trp8]-γ-MSH; 15 μg/day, n = 10) for the last 4 weeks. Lesion size as well as macrophage and collagen content in the aortic root plaques were determined. Furthermore, leukocyte counts in the blood and aorta and cytokine mRNA expression levels in the spleen, liver and aorta were quantified. No effect was observed in the body weight development or plasma cholesterol level between the two treatment groups. However, [D-Trp8]-γ-MSH treatment significantly reduced plasma levels of chemokine (C–C motif) ligands 2, 4 and 5. Likewise, cytokine and adhesion molecule expression levels were reduced in the spleen and liver of γ-MSH-treated mice, but not substantially in the aorta. In line with these findings, [D-Trp8]-γ-MSH treatment reduced leukocyte counts in the blood and aorta. Despite reduced inflammation, [D-Trp8]-γ-MSH did not change lesion size, macrophage content or collagen deposition of aortic root plaques. In conclusion, the findings indicate that selective activation of Melanocortin MC3 Receptor by [D-Trp8]-γ-MSH suppresses systemic and local inflammation and thereby also limits leukocyte accumulation in the aorta. However, the treatment was ineffective in reducing atherosclerotic plaque size.

  • structural insights into selective ligand Receptor interactions leading to Receptor inactivation utilizing selective Melanocortin 3 Receptor antagonists
    Biochemistry, 2017
    Co-Authors: Minying Cai, Udaya Kiran Marelli, Blake Mertz, Johannes G Beck, Florian Opperer, Florian Rechenmacher, Horst Kessler, Victor J. Hruby
    Abstract:

    Systematic N-methylated derivatives of the Melanocortin Receptor ligand, SHU9119, lead to multiple binding and functional selectivity toward Melanocortin Receptors. However, the relationship between N-methylation-induced conformational changes in the peptide backbone and side chains and Melanocortin Receptor selectivity is still unknown. We conducted comprehensive conformational studies in solution of two selective antagonists of the third isoform of the Melanocortin Receptor (hMC3R), namely, Ac-Nle-c[Asp-NMe-His6-d-Nal(2′)7-NMe-Arg8-Trp9-Lys]-NH2 (15) and Ac-Nle-c[Asp-His6-d-Nal(2′)7-NMe-Arg8-NMe-Trp9-NMe-Lys]-NH2 (17). It is known that the pharmacophore (His6-DNal7-Arg8-Trp9) of the SHU-9119 peptides occupies a β II-turn-like region with the turn centered about DNal7-Arg8. The analogues with hMC3R selectivity showed distinct differences in the spatial arrangement of the Trp9 side chains. In addition to our NMR studies, we also carried out molecular-level interaction studies of these two peptides at the ...

  • Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor.
    Journal of medicinal chemistry, 2015
    Co-Authors: Alfonso Carotenuto, Francesco Merlino, Minying Cai, Diego Brancaccio, Ali Munaim Yousif, Ettore Novellino, Victor J. Hruby, Paolo Grieco
    Abstract:

    The Melanocortin Receptors 3 and 4 control energy homeostasis, food-intake behavior, and correlated pathophysiological conditions. The Melanocortin-4 Receptor (MC4R) has been broadly investigated. In contrast, the knowledge related to physiological roles of the Melanocortin-3 Receptor (MC3R) is lacking because of the limited number of known MC3R selective ligands. Here, we report the design, synthesis, biological activity, conformational analysis, and docking with Receptors of two potent and selective agonists at the human MC3 Receptor.

  • Structure-Activity Relationships of Cyclic Lactam Analogues of α-Melanocyte-Stimulating Hormone (α-MSH) Targeting the Human Melanocortin-3 Receptor
    Journal of medicinal chemistry, 2007
    Co-Authors: Alexander V. Mayorov, Minying Cai, James P. Cain, Matthew M. Dedek, Erin S. Palmer, April R. Van Scoy, Bahar Tan, Josef Vagner, Dev Trivedi, Victor J. Hruby
    Abstract:

    A variety of dicarboxylic acid linkers introduced between the α-amino group of Pro6 and the e-amino group of Lys10 of the cyclic lactam α-melanocyte-stimulating hormone (α-MSH)-derived Pro6-D-Phe7/D-Nal(2′)7-Arg8-Trp9-Lys10-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a β-turn-like structure with the D-Phe/D-Nal(2′) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH2)2-CO-Nle-D-Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic γ-melanocyte-stimulating hormone (γ-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important Melanocortin-3 Receptor.

  • Effects of selective modulation of the central Melanocortin-3-Receptor on food intake and hypothalamic POMC expression.
    Peptides, 2007
    Co-Authors: Michelle Lee, Minying Cai, Victor J. Hruby, Alexander V. Mayorov, Andrea Kim, Irene M. Conwell, Sharon L. Wardlaw
    Abstract:

    Abstract Hypothalamic POMC neurons regulate energy balance via interactions with brain Melanocortin Receptors (MC-Rs). POMC neurons express the MC3-R which can function as an inhibitory autoReceptor in vitro . We now demonstrate that central activation of MC3-R with ICV infusion of the specific MC3-R agonist, [ d -Trp 8 ]-γ-MSH, transiently suppresses hypothalamic Pomc expression and stimulates food intake in rats. Conversely, we also show that ICV infusion of a low dose of a selective MC3-R antagonist causes a transient decrease in feeding and weight gain. These data support a functional inhibitory role for the MC3-R on POMC neurons that leads to changes in food intake.