melanocortin receptor

Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) are involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has critical developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems, including energy homeostasis imbalance, melanocortin and reproductive system alterations and brain mass reduction in young adult mice...

Of the three Food and Drug Administration-approved melanocortin peptide drugs, two possess a cyclic scaffold, demonstrating that cyclized melanocortin peptides have therapeutic relevance. An extracyclic Arg residue, critical for pharmacological activity in the approved melanocortin cyclic drug setmelanotide, has also been demonstrated to increase the signal when fluorescently labeled cell-penetrating cyclic peptides are incubated with HeLa cells, with the maximal signal observed with three extracyclic Arg amino acids...

INTRODUCTION: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive...

A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure-activity relationship (SAR) studies led to the discovery of 17h (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of 17h suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg...

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity...

INTRODUCTION: The purine analog 6-thioguanine (6TG), an old drug approved in the 60s to treat acute myeloid leukemia (AML), was tested in the diabetic retinopathy (DR) experimental in vivo setting along with a molecular modeling approach. METHODS: A computational analysis was performed to investigate the interaction of 6TG with MC1R and MC5R. This was confirmed in human umbilical vein endothelial cells (HUVECs) exposed to high glucose (25 mM) for 24 h...

BACKGROUND: Melanocortin 3 and 5 receptors ( i.e., MC3 R and MC5 R) belong to the melanocortin family. However, data regarding their role in inflammatory bowel diseases (IBD) are currently unavailable. AIM: This study aims to ascertain their expression profiles in the colonic mucosa of Crohn's disease (CD) and ulcerative colitis (UC), aligning them with IBD disease endoscopic and histologic activity. METHODS: Colonic mucosal biopsies from CD/UC patients were sampled, and immunohistochemical analyses were conducted to evaluate the expression of MC3 R and MC5 R...

CONTEXT: Melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity. OBJECTIVE: We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here, we aimed to functionally characterize these variants by analyzing four different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants...

Cutaneous melanoma, a lethal skin cancer, arises from malignant transformation of melanocytes. Solar ultraviolet radiation (UVR) is a major environmental risk factor for melanoma since its interaction with the skin generates DNA damage, either directly or indirectly via oxidative stress. Pheomelanin pigments exacerbate oxidative stress in melanocytes by UVR-dependent and independent mechanisms. Thus, oxidative stress is considered to contribute to melanomagenesis, particularly in people with pheomelanic pigmentation...

OBJECTIVE: To broaden the currently limited reach of genomic innovations, research is needed to understand how psychosocial and cultural factors influence reactions to genetic testing in diverse subgroups. Cancer fatalism is important in cancer prevention and deserves theoretical and empirical attention in the context of genomics and behavior change. METHODS: The current study employed data from a randomized controlled trial (N = 593) offering skin cancer genetic testing (using the melanocortin-1 receptor [MC1R] gene) in primary care in Albuquerque, New Mexico, USA...

Ultraviolet (UV) radiation plays a crucial role in the development of melanoma and non-melanoma skin cancers. The types of UV radiation are differentiated by wavelength: UVA (315 to 400 nm), UVB (280 to 320 nm), and UVC (100 to 280 nm). UV radiation can cause direct DNA damage in the forms of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). In addition, UV radiation can also cause DNA damage indirectly through photosensitization reactions caused by reactive oxygen species (ROS), which manifest as 8-hydroxy-2'-deoxyguanine (8-OHdG)...

Mutations leading to a reduced or loss of function in genes of the leptin-melanocortin system confer a risk for monogenic forms of obesity. Yet, gain of function variants in the melanocortin-4-receptor (MC4R) gene predispose to a lower BMI. In individuals with reduced body weight, we thus expected mutations leading to an enhanced function in the respective genes, like leptin (LEP) and MC4R. Therefore, we have Sanger sequenced the coding regions of LEP and MC4R in 462 female patients with anorexia nervosa (AN), and 445 healthy-lean controls...

INTRODUCTION: Stress may pose a serious challenge to immune homeostasis. Stress however also may prepare the immune system for challenges such as wounding or infection, which are likely to happen during a fight or flight stress response. METHODS: In common carp ( Cyprinus carpio L.) we studied the stress-induced redistribution of neutrophils into circulation, and the expression of genes encoding CXC chemokines known to be involved in the regulation of neutrophil retention (CXCL12) and redistribution (CXCL8), and their receptors (CXCR4 and CXCR1-2, respectively) in blood leukocytes and in the fish hematopoietic organ - the head kidney...

Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical condition, obesity is an intricate disease with a multifactorial aetiology. Understanding the precise cause of obesity remains a challenge; nevertheless, there seems to be a complex interplay among biological, psychosocial and behavioural factors. Studies on the genetic factors of obesity have revealed several pathways in the brain that play a crucial role in food intake regulation...

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss of function variants that decrease receptor signaling on one extreme and gain of function that may result in biased signaling or constitutive activity, originally modeled on prototypical rhodopsin GPCR variants identified in retinitis pigmentosa, on the other...

Background: Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin pigmentation through microphthalmia-associated transcription factor M (MITF-M). Toll-like receptor 4 (TLR4), a receptor of endotoxin lipopolysaccharide (LPS), is distributed in immune and other cell types including melanocytes where LPS/TLR4 activate transcriptional activity of nuclear factor (NF)-κB to express cytokines in innate immunity...

Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity that is mainly determined by its N-terminal domain. We previously reported that zebrafish MC4R exhibited a much higher basal cAMP level in comparison to mammalian MC4Rs. However, the functional evolution of constitutive activities in chordate MC4Rs remains to be elucidated. Here we cloned and compared the constitutive activities of MC4Rs from nine vertebrate species and showed that the additive action of the N-terminus with the extracellular region or transmembrane domain exhibited a combined pharmacological effect on the MC4R constitutive activity...

Objective: It is well established that melanocortin-4 receptor ( MC4R ) rs17782313 locus polymorphism is associated with increased obesity risk and that obesity is strongly associated with an enhanced risk of all metabolic syndrome (MS) components. Thus, in this study, we examined the association between the MC4R rs17782313 locus polymorphism and the risk of the remaining MS components, namely, diabetes, hypertension, low high-density lipoprotein (HDL), and hypertriglyceridemia. Methods: We performed an extensive literature screening across six scientific databases, namely, PubMed, Embase, Web of Science, Medline, ScienceDirect, CNKI, and WanFang employing a specific search strategy...

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk...

α-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether α-MSH could be involved in pathological cardiac remodeling. We found that α-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable α-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction...