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Melanocortin-4 receptor (MC4R) and melanocortin receptor accessory protein 2 (MRAP2) play important roles in the melanocortin system, and interaction of MC4R and MRAP2 is suggested to play pivotal role in energy balance of vertebrates. Orange-spotted grouper (Epinephelus coioides) is a widely cultured marine fish with high economic value in Asia. To explore potential interaction between grouper MC4R and MRAP2, herein we cloned grouper mc4r and mrap2. Grouper mc4r consisted of a 981 bp ORF encoding a putative protein of 327 amino acids, while the grouper mrap2 consisted of a 696 bp ORF encoding a putative protein of 232 amino acids. Sequence and phylogenetic analysis revealed that the grouper MC4R and MRAP2 were highly homologous at amino acid levels to several teleost MC4Rs and MRAP2s, respectively. qRT-PCR results showed that both mc4r and mrap2 were expressed primarily in the central nervous system. In the periphery, these genes were expressed more widely in male fish. The cloned grouper MC4R was functional, exhibiting high constitutive activity in cAMP pathway, capable of binding to three peptide agonists and increasing intracellular cAMP production dose-dependently. MRAP2 significantly decreased basal and agonist-stimulated cAMP signaling. MRAP2 also increased basal ERK1/2 activation but decreased ligand-induced stimulation when expressed at high levels. These data will facilitate future investigation of these molecules in regulating diverse physiological processes in orange-spotted grouper. Show less

Neuropeptide Y (NPY) is the most powerful central neuropeptide implicated in feeding regulation via its receptors. Understanding the role of NPY system is critical to elucidate animal feeding regulation. Unlike mammal, the possible mechanisms of NPY system in the food intake of teleost fish are mostly unknown. Therefore, we investigated the regulatory mechanism of NPY and NPY receptors in Siberian sturgeon. In this study, we cloned the cDNA encoding NPY, and assessed the effects of different energy status on npy mRNAs abundance. The expression of npy was decreased in the brain after feeding 1 and 3 h. Besides, the expression of npy was increased after fasting within 15 days, while exhibiting significant decrease after refeeding. In order to further characterize the role of NPY receptor in fish, we performed acute intraperitoneal (i.p.) injection of NPY Y1 and Y2 receptor agonists, which is [Leu 31, Pro 34] NPY and NPY13-36 respectively. The results showed that the food intake of Siberian sturgeon was increased within 30 mins after injection of both Y1 and Y2 receptor agonist. To explore the relationship between NPY, NPY receptors and another appetite peptides, we examined the level of npy, cocaine- and amphetamine-regulated transcript (cart) and melanocortin-4 receptor (mc4r) by injected Y1 and Y2 receptor agonist. The results suggested that cart expression was regulated by NPY which acts on Y1 receptor or Y2 receptor. While mc4r expression just was mediated by NPY and Y1 receptor. Show less

To improve the accuracy and genetic progress of blue fox breeding, the relationships between genetic polymorphisms and growth and reproductive traits of the blue fox were investigated. MC4R, MC3R, INHA and INHBA were selected as candidate genes for molecular evolution and statistical analyses. Single-factor variance analyses showed that the MC4R (g.267C > T, g.423C > T, and g.731C > A) and MC3R (g.677C > T) genotypes had significant impacts on body weight, chest circumference, abdominal perimeter and body mass index (BMI) (P < 0.05) in blue fox. The MC4R and MC3R combined genotypes had significant effects on the body weight and abdominal circumference. The different genotypes of INHA g.75G > A had significant effects on female fecundity, whereas the different genotypes of INHBA g.404G > T and g.467G > T and the INHA and INHBA combined genotypes had significant effects on male fecundity. The proteins encoded by the open reading frames (ORFs) of different polymorphic loci were predicted and analysed. The aims of this study were to identify genetic markers related to growth and reproduction in the blue fox and to provide an efficient, economical and accurate theoretical approach for auxiliary fox breeding. Show less

The high prevalence of childhood obesity in Mexico is alarming in the health-science field. We propose to investigate the contribution of adipokines and cytokines polymorphisms and common BMI/obesity-associated loci, revealed in genome-wide association studies in Caucasian adult cohorts, with childhood obesity. This study included 773 Mexican-Mestizo children (5-15 years old) in a case-control study. The polymorphisms included were Show less

The aims of this study were to establish the role of MC4Rrs17782313 and ENPP1rs1044498 gene polymorphisms on pre-pregnancy BMI and the newborn's status. We performed a cross-sectional study on 185 mothers and their offspring. The groups were divided into: control group- underweight or normal mothers with BMI Show less

Although the changes in DNA methylation are assumed to be due to the association between adverse intrauterine conditions and adult metabolic health, evidence from human studies is rare. Little is known about the changes in DNA methylation present at birth that affect metabolic profiles in childhood. Previous studies have shown that the melanocortin 4 receptor (MC4R) and hepatocyte nuclear factor 4 alpha (HNF4α) genes are associated with obesity and metabolic disorders. Thus, we investigated the associations of the DNA methylation statuses of MC4R and HNF4α in cord blood with metabolic profiles in childhood.We collected data from 90 children 7 to 9 years of age included in the Ewha Birth & Growth Cohort Study in Korea. DNA methylation was analyzed by pyrosequencing. The children were split into 2 groups according to the cutoff triglyceride (TG) levels (<110 and ≥110 mg/dL).The methylation statuses of MC4R and HNF4α at birth were significantly associated with the TG level in childhood (P < .05). It was interesting to note that the methylation statuses of MC4R and HNF4α in cord blood were significantly decreased, whereas childhood body mass index was significantly increased, in children with high TG levels compared with children with low TG levels (P < .05).Our findings show that the methylation statuses of MC4R and HNF4α at birth are associated with metabolic profiles in childhood. These epigenetic modifications occurring in early life may contribute to subsequent metabolic-related disorders. Thus, we suggest that DNA methylation status in cord blood may be predictive of the risk of developing metabolic syndrome. Show less

The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R, respectively) are established targets to treat diseases of positive- and negative-energy homeostasis. We previously reported [ Doering , S. R. ; J. Med. Chem. 2017 , 60 , 4342 - 4357 ] mixture-based positional scanning approaches to identify dual MC3R agonist and MC4R antagonist tetrapeptides. Herein, 46 tetrapeptides were chosen for MC3R agonist screening selectivity profiles, synthesized, and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors. Substitutions to the tetrapeptide template were selected solely based on MC3R agonist potency from the mixture-based screen. This study resulted in the discovery of compound 42 (Ac-Val-Gln-(pI)DPhe-DTic-NH Show less

Appetite and reproduction are closely related functions that are both regulated by brain hormones. Appetite stimulators include orexin and neuropeptide Y (NPY), and reproductive hormones include gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin, and neurokinin B (NKB). GnRH stimulates the secretion of pituitary gonadotropes, and kisspeptin and GnIH modulate this action. Kisspeptin secretion is further controlled by neurokinin B (NKB) and dynorphin A (Dyn). To better understand the mechanisms regulating appetite and reproduction in fish, we examined the effects of fasting, reproductive stage, gender, and strain on the brain mRNA expression of appetite (orexin and NPY) and reproductive (GnRH, kisspeptin, GnIH, and NKB) hormones in zebrafish. In order to compare strains, we used both wild-type and transparent Casper zebrafish. In female wild-type zebrafish, fasting increased the expression of all hormones investigated, with the exception of Kiss2. Only NPY and Kiss2 were increased in male wild-type zebrafish during fasting. In Casper zebrafish, only GnIH and NKB in males were affected by fasting, suggesting that Casper fish may be more resistant to fasting than wild fish. Fasting increased expressions of orexin, GnRH2, Kiss1, GnIH and NKB in wild-type females with more eggs or larger eggs relative to body weight, compared to those with fewer or smaller eggs, suggesting that more mature females are more affected by fasting. No significant interactions of fasting and reproductive stage were noted in female Casper fish. To investigate whether differences between Casper and wild-type fish were due to genes involved in pigmentation, we compared the brain mRNA expressions of enzymes involved in melanin synthesis (tyrosinase and tyrosine hydroxylase - TH), melanocortin receptors (MC3R and MC4R), and the melanocortin precursor (proopiomelanocortin - POMC) between the two strains. Casper zebrafish had lower levels of MC3R, tyrosinase, TH1, TH2, and POMC than wild-type fish. Overall, our results suggest the existence of gender- and reproductive stage-specific, as well as strain-specific variations in the mechanisms regulating feeding and reproduction in zebrafish, and that the melanocortin system and melanin pathways may be in part responsible for these differences between strains. Show less

The melanocortin-4 receptor (MC4R) facilitates hypothalamic-pituitary-adrenocortical (HPA) axis responses to acute stress in male rodents and is a well known to regulator of energy balance. Mutations in the MC4R is the most common monogenic cause of obesity in humans and has been associated with sex-specific effects, but whether stress regulation by the MC4R is sex-dependent, and whether the MC4R facilitates HPA responses to chronic stress, is unknown. We hypothesized that MC4R-signaling contributes to HPA axis dysregulation and metabolic pathophysiology following chronic stress exposure. We measured changes in energy balance, HPA axis tone, and vascular remodeling during chronic variable stress (CVS) in male and female rats with MC4R loss-of-function. Rats were placed into three groups ( Show less

Obesity is more prevalent in men than in women in China, especially within the middle-aged population. The present study aims to determine the contribution of sexual dimorphisms to obesity and related traits in terms of the mechanisms involving the obesity-related genetic variants among patients of Chinese Han ancestry with type 2 diabetes. In the Chinese National Diabetes and Metabolic Disorders Study, 2,555 out of 4,036 patients with type 2 diabetes were treatment naive, including 1,142 men and 1,413 women. Single-nucleotide polymorphisms (SNP) from 18 genomic loci previously found to be associated with obesity-related traits were successfully genotyped, and a genetic risk score (GRS) was constructed by summing the risk alleles for obesity. Single SNP analysis showed that genetic variants in SLC30A10, TMEM18, GNPDA2, PRL, TFAP2B, BDNF, MTCH2, FTO, and MC4R were nominally associated with waist circumference (WC), BMI, and risk for abdominal or general obesity in the untreated patients with type 2 diabetes, as well as in the total group of patients with type 2 diabetes (untreated and treated) (p < 0.05). Interactions between sex and SNP in PRL, MTCH2,and FTO were detected (p < 0.05). In the untreated patients with diabetes, the GRS was nominally associated with WC (β = 0.0032, SE = 0.0011; p = 0.003), BMI (β = 0.0030, SE = 0.0013; p = 0.027), and increased risk for abdominal (OR = 1.08; 95% CI 1.02-1.13; p = 0.004) or general obesity (OR = 1.07; 95% CI 1.02-1.13; p = 0.011) in men but not in women. GRS-sex interactions were detected in the determinant of WC (p = 0.019) and abdominal obesity (p = 0.016). Among patients aged 30-60 years, GRS was found to be significantly associated with WC (β = 0.0050, SE = 0.0016; p = 0.002) and abdominal obesity (OR = 1.10; 95% CI 1.04-1.17; p = 0.001) and nominally associated with BMI (β = 0.0057, SE = 0.0020; p = 0.005) and general obesity (OR = 1.07; 95% CI 1.01-1.14; p = 0.027) in men, whereas in women none of the associations were detected. GRS-sex interactions were present in the determinant of WC (p = 0.015), BMI (p = 0.032), and abdominal obesity (p = 0.012). Among patients aged 60 years or older, neither an association of GRS with obesity-related traits nor GRS-sex interactions were detected. Genetic factors contribute to obesity-related traits in a sex-dependent pattern among middle-aged Chinese, and men tend to be more susceptible to the genetic risk of obesity. Show less

Agmatine, an endogenous biogenic amine, is considered to be a central neurotransmitter. And it plays an important role in mammal feeding behavior. However, there were few studies on the effect of agmatine on feeding behavior in fishes. Here, we investigated the impact of intracerebroventricular (ICV) injections of agmatine (1.25-20 nmol/fish) on food intake in mandarin fish (Siniperca chuatsi). At 1-h post-injection, food intake showed a significant decrease in agmatine-treated fishes compared with the saline treated. Furthermore, the food intake in agmatine treatment mostly did not differ from that in saline treatment at 4--24-h post-injection as well as the results of genes expression of neuropeptide Y (NPY), agouti-regulated peptide (AgRP), and anorexigenic melanocortin 4 receptor (MC4R). In accordance with the insulin level increasing in liver, the gene expression of insulin receptor substrate (IRS2) was significantly higher in agmatine treatment compared to saline treatment at 1-h post-injection. Thus, the anorexigenic effect of agmatine is likely to decrease NPY and AgRP expression levels and increase MC4R and IRS2 levels which was coupled with stimulation of insulin secretion. Although these initial findings are limited in dose, the data firstly provides evidence for the anorectic effects of agmatine in fish. Show less

Feed efficiency (FE) is one of the most important traits in pig production. However, it is difficult and costly to measure it, limiting the collection of large amount of data for an accurate selection for better FE. Therefore, the identification of single-nucleotide polymorphisms (SNPs) associated with FE-related traits to be used in the genetic evaluation is of great interest of pig breeding programs for increasing the prediction accuracy and the genetic progress of these traits. The objective of this study was to identify SNPs significantly associated with FE-related traits: average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR). We also aimed to identify potential candidate genes for these traits. Phenotypic information recorded on a population of 2386 three-way crossbreed pigs that were genotyped for 51 468 SNPs was used. We identified three loci of quantitative trait (QTL) regions associated with ADG and three QTL regions associated with ADFI; however, no significant association was found for FCR. A false discovery rate (FDR) ≤ 0.005 was used as the threshold for declaring an association as significant. The QTL regions associated with ADG on Sus scrofa chromosome (SSC) 1 were located between 177.01 and 185.47 Mb, which overlaps with the QTL regions for ADFI on SSC1 (173.26 and 185.47 Mb). The other QTL region for ADG was located on SSC12 (2.87 and 3.22 Mb). The most significant SNPs in these QTL regions explained up to 3.26% of the phenotypic variance of these traits. The non-identification of genomic regions associated with FCR can be explained by the complexity of this trait, which is a ratio between ADG and ADFI. Finally, the genes CDH19, CDH7, RNF152, MC4R, PMAIP1, FEM1B and GAA were the candidate genes found in the 1 Mb window around the QTL regions identified in this study. Among them, the MC4R gene (SSC1) has a well-known function related to ADG and ADFI. In this study, we identified three QTL regions for ADG (SSC1 and SSC12) and three for ADFI (SSC1). These regions were previously described in purebred pig populations; however, to our knowledge, this is the first study to confirm the relevance of these QTL regions in a crossbred pig population. The potential use of the SNPs and genes identified in this study in prediction models that combine genomic selection and marker-assisted selection should be evaluated for increasing the prediction accuracy of these traits in this population. Show less

The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing sympathetic nervous system input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here, we demonstrate that reduction of brain-melanocortin signaling actively promotes fat mass gain by activating the lipogenic program and adipocyte and endothelial cell proliferation in white fat depots independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. Those vagally regulated obesogenic signals also contribute to the fat mass gain following chronic high-fat diet feeding. These data reveal a physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity. Show less

This investigation was undertaken to assess the population of indigenous (Bareilly local) pigs for meat quality genes (RYR1, PRKAG3, HFABP, MYF-5, and MC4R). The results showed that indigenous pigs were monomorphic at RYR1locus (100% NN genotype), HFABP locus (100% HH genotype), and MYF-5 locus (100% DD genotype). Homozygote RR and heterozygote QR genotypes were observed at PRKAG3 (c.599 G>A) SNP locus with 89 and 11% frequency. The frequency of wild (R) and mutant (Q) allele at the said locus was 95 and 5%. The MC4R SNP had three genotypes; homozygote AA with 5% frequency, heterozygote AG with 53% frequency, and homozygote GG with 42% frequency. Corresponding frequency of A and G allele was 32 and 68%, respectively. Monomorphic status at RYR1locus for NN genotype, HFABP locus for HH genotype, and MYF-5 locus for DD genotype indicated that favorable genes for quality pork production have been fixed in the population. The higher frequency of RR genotype (89%) at PRKAG3 and GG genotype (42%) at MC4R locus further explained the existence of favorable genotypes in indigenous pigs. Show less

Consumer preference for slow-growing broiler chickens is rising because of increased demand for high-quality poultry products. Korat chicken (KRC) is a slow-growing chicken generated in Thailand. A goal of the KRC breeding program is to produce meat with a low purine content to benefit an aging population, without interfering with growth performance. Thus, this study aimed to investigate the effects of genes encoding melanocortin 4 receptor (MC4R), calpain 1 (CAPN1), and adenylosuccinate lyase (ADSL) on body weight, muscle fiber, and content of purine and its derivatives (i.e., adenine, guanine, hypoxanthine, and xanthine), to develop molecular markers for breeding programs. Genotypes of MC4R, CAPN1, and ADSL were obtained from 583 KRCs by PCR-single-strand conformation polymorphism. The body weight and purine contents of the KRCs were measured every 2 wk until the KRCs reached market weight at 10 wk of age. A significant association between the MC4R genotype and body weight at 2, 4, and 10 wk of age was detected. KRC possessing the BB genotype of CAPN1 showed significantly heavier body weight at 6 wk of age and guanine content at 4 wk of age, and a smaller muscle fiber diameter in the breast muscle at 10 wk of age, compared with those of the other genotypes. In addition, high expression levels of the CAPN1 and ADSL genes were detected in the breast muscle at 2 wk of age. Although higher purine contents were detected at a young age, no significant associations with the MC4R, CAPN1, and ADSL genes were detected. Our results indicate that MC4R and CAPN1 could be used as genetic markers for growth and meat quality in the slow-growing chicken breeding program. Show less

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed. Show less

The paraventricular hypothalamus (PVH) plays a pivotal role in regulating energy balance, though circuit mechanisms remain obscure. In this issue of Neuron, Li et al. (2019b) identify a circuit involving PVH Show less

Nutrition of the newborn during the early postnatal period seems to be of capital importance and there is clinical evidence showing the protective effect of breastfeeding compared with formula feeding on childhood obesity and its comorbidities. Infants born small for gestation age may be more sensitive to the type of feeding during lactation. Here, we aimed to analyze the impact of birth weight and the type of infant feeding on the expression levels in peripheral blood cells of selected candidate genes involved in energy homeostasis in 5-year-old children, to find out potential early biomarkers of metabolic programming effects during this period of metabolic plasticity. Forty subjects were recruited at birth and divided in four groups according to birth weight (adequate or small for gestational age) and type of infant feeding (breastfeeding or formula feeding). They were followed from birth to the age of 5 years. At 5 years, no significant differences regarding anthropometric parameters were found between groups, and all children had normal biochemical values. Expression levels of UCP2 and MC4R in peripheral blood cells were lower and higher, respectively, in formula feeding children compared with breastfeeding ones (P = 0.002 and P = 0.064, two-way ANOVA). Differences were more marked and significant by Student's t test in small for gestation age children (P < 0.001 and P = 0.017, respectively). Transcript levels of FASN and FTO in peripheral blood cells were also different according to the type of infant feeding, but only in small for gestation age children. Altogether, these results suggest that small for gestation age infants are more sensitive to the type of feeding during lactation, and transcript levels of particular genes in peripheral blood cells, especially the MC4R/UCP2 mRNA ratio, may precisely reflect these effects in the absence of clear differences in phenotypic traits. Show less

Except for drinking water, most beverages taste bitter or sweet. Taste perception and preferences are heritable and determinants of beverage choice and consumption. Consumption of several bitter- and sweet-tasting beverages has been implicated in development of major chronic diseases. We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage consumption among ~370 000 participants of European ancestry, using a two-staged analysis design. Bitter beverages included coffee, tea, grapefruit juice, red wine, liquor and beer. Sweet beverages included artificially and sugar sweetened beverages (SSBs) and non-grapefruit juices. Five loci associated with total bitter beverage consumption were replicated (in/near GCKR, ABCG2, AHR, POR and CYP1A1/2). No locus was replicated for total sweet beverage consumption. Sub-phenotype analyses targeting the alcohol, caffeine and sweetener components of beverages yielded additional loci: (i) four loci for bitter alcoholic beverages (GCKR, KLB, ADH1B and AGBL2); (ii) five loci for bitter non-alcoholic beverages (ANXA9, AHR, POR, CYP1A1/2 and CSDC2); (iii) 10 loci for coffee; six novel loci (SEC16B, TMEM18, OR8U8, AKAP6, MC4R and SPECC1L-ADORA2A); (iv) FTO for SSBs. Of these 17 replicated loci, 12 have been associated with total alcohol consumption, coffee consumption, plasma caffeine metabolites or BMI in previous GWAS; none was involved in known sweet and bitter taste transduction pathways. Our study suggests that genetic variants related to alcohol consumption, coffee consumption and obesity were primary genetic determinants of bitter and sweet beverage consumption. Whether genetic variants related to taste perception are associated with beverage consumption remains to be determined. Show less

Mutations leading to a reduced function of the melanocortin-4 receptor (MC4R) exert a major gene effect on extreme obesity. Recently it was shown that the bone derived hormone lipocalin 2 (LCN2) binds to the MC4R and activates a MC4R dependent anorexigenic pathway. We identified mutations in both genes and screened the effects of Show less

To highlight the role of the brain melanocortin 4 receptor (MC4R) for sympathetic nervous system (SNS) activation in hypertension. Hypertension is the most significant risk factor for developing cardiovascular disease. Although excess weight gain is associated with at least two thirds of primary hypertension cases, the pathophysiological mechanisms involved remain the subject of intense investigation. Multiple studies demonstrate an important role for increased sympathetic nervous system (SNS) activity in development and maintenance of hypertension, and that the brain MC4R modulates SNS activity to thermogenic, cardiovascular, and kidney tissues. These studies also support the concept that MC4R activation is critical for obesity-induced hypertension as well as other forms of hypertension associated with increased SNS activity. MC4R is a potential target for antiobesity therapy, although there are challenges in using MC4R agonists to induce weight loss without evoking increases in SNS activity. Show less

Metabolic side effects such as weight gain and disturbed lipid metabolism are often observed in the treatment of atypical antipsychotic drugs (AAPDs), which contribute to an excessive prevalence of metabolic syndrome among schizophrenic patients. Great individual differences are observed but the underlying mechanisms are still uncertain. Research on pharmacogenomics indicates that gene polymorphisms involved in the pathways controlling food intake and lipid metabolism may play a significant role. In this review, relevant genes ( Show less

G We created mice (DMHGsKO) with G DMHGsKO mice developed severe, early-onset obesity associated with hyperphagia and reduced energy expenditure and locomotor activity, along with impaired brown adipose tissue thermogenesis. Studies in mice with loss of MC4R in the DMH suggest that defective DMH MC4R/G DMH G Show less

The five melanocortin receptors (MC1R-MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the ( Show less

The central melanocortin system is composed of neurons that express either the proopiomelanocortin (POMC) or the agouti-related protein (AgRP). POMC is cleaved in bioactive peptides, including the α-melanocyte-stimulating hormone (α-MSH). α-MSH activates the melanocortin-4 receptor (MC4R) inducing satiety, whereas AgRP acts as an inverse agonist of MC4R. However, only limited information is available regarding possible area-specific differences in the interaction between α-MSH and AgRP terminals on MC4R-expressing cells. Therefore, the objective of the present study was to compare the distribution pattern of α-MSH and AgRP terminals on the perikarya of MC4R-expressing neurons. We performed a triple-label immunofluorescence reaction in brain series of MC4R-reporter mice to visualize MC4R-expressing neurons together with AgRP and α-MSH terminals. POMC and AgRP neurons project to areas that contain MC4R-expressing cells, although several brain nuclei exhibit AgRP and α-MSH terminals, but they do no express MC4R, while other brain areas contain MC4R-expressing cells and receive no apparent innervation of AgRP and POMC neurons. AgRP terminals make more presumptive appositions than α-MSH on the soma of MC4R-expressing neurons of the medial preoptic area and paraventricular nucleus of the hypothalamus (Pa). Additionally, a higher percentage of MC4R cells receive at least one presumptive apposition from AgRP terminals in the median preoptic nucleus and Pa, compared to α-MSH appositions. Thus, our study revealed area-specific differences in the interaction between α-MSH and AgRP terminals and the soma of MC4R-expressing neurons. These findings provide new insights about the relationship between first- and second-order neurons of the central melanocortin system. Show less

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor whose disruption causes obesity. We functionally characterized 61 MC4R variants identified in 0.5 million people from UK Biobank and examined their associations with body mass index (BMI) and obesity-related cardiometabolic diseases. We found that the maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gα Show less

Deep brain stimulation of the subthalamic nucleus (STN-DBS) stimulation produces significant improvement of overall pain related to Parkinson disease; however, the mechanisms underlying analgesic effects of STN-DBS are still unknown. This report describes direct neuroanatomical evidence for the central melanocortinergic-opioidergic circuits in the STN. We investigated melanocortin-4 receptor (MC4R) and mu-opioid receptor (MOR)-positive expression of the STN in MC4R-GFP transgenic mice using fluorescence immunohistochemical detection. Immunohistochemistry showed a large number of MC4R-GFP- and MOR-positive neurons within the STN region, and approximately 50% of MC4R-GFP-positive neurons coexpressed MOR. The results of this study showed direct neuroanatomical evidence for the central melanocortinergic-opioidergic signaling in the STN region. These findings contribute to the view of melanocortinergic-opioidergic circuits in the subthalamic nucleus as a reliable source of modulating of nociception with therapeutic potential for alleviating pain. Show less