Control de la ingesta alimentaria: rol del receptor 4 de melanocortina en el desarrollo de obesidad / Role of melanocortin receptor 4 in the control of food intake and the development of obesity

Arquate nucleus, a convergence site of peripheral and central signals, plays a fundamental role in the control of food intake. Orexigenic neurons that secrete neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and anorexigenic neurons secreting Pro-opiomelanocortin (POMC) are involved in this action. Both groups of neurons respond to peripheral signals such as insulin and leptin and are reciprocally inhibited. alpha Type melanocyte stimulating hormone (alphaMSH), liberated by POMC neurons, reduces food intake activating melanocortin receptor 4 (MC4R), located in second order neurons of the paraventricular nucleus. NPY/AgRP antagonize the effects of this peptide on MC4R receptors,maintaining an inhibitory tone on áMHS liberation, mediated by the activation of gabaergic receptors of POMC neurons. The study of these mechanisms will allow the development of new medications, especially MC4R agonists, to reduce nutrient intake...

Melanocortin-4 receptor expression in the cuneiform nucleus is involved in modulation of opioidergic signaling / 华中科技大学学报（医学）（英德文版）

Substantial evidence has suggested that deep brain stimulation of the cuneiform nucleus has become a remarkable treatment option for intractable pain, but the possible mechanism is poorly understood. Using a melanocortin-4 receptor (MC4R)-green fluorescent protein (GFP) reporter knockin mouse, we showed that a large number of MC4R-GFP-positive neurons were expressed in the cuneiform nucleus. Immunofluorescence revealed that approximately 40%-50% of MC4R-GFP-positive neurons expressed mu opioid receptors, indicating that they were opioidergic signaling. Our findings support the hypothesis that MC4R expression in the cuneiform nucleus is involved in the modulation of opioidergic signaling.

Molecular Dynamics Simulation of Β-Melanotropin Stimulating Hormone (Β-MSH) Docked Onto the Receptor MC4R.

Melanocortin system is composed of four peptide hormones known as α, β, γ and adrenocorticotropic hormone (ACTH), derived from post-translational cleavage of a polypeptide precursor ‘proopiomelanocortin (POMC)’. Among these hormones; β-melanotropin stimulating hormone (β-MSH), an 18 amino acid residue peptide fragment is an important hormone as it is involved in activation of MC4R to induce lean phenotype ‘balance between energy intake and energy expenditure’. In addition to this, MC4R is also involved in the modulation of erectile function, including the spinal cord and pelvic ganglion of rats and the penis of both rats and humans, providing an anatomical basis for melanocortin effects on sexual function. MC4R is one of the five melanocortin receptors (MC1R–MC5R) which have been characterized with tissue-specific expression patterns and different binding affinities for each of the melanocortin hormones to regulate various biological functions. In the present work, 3D models of MC4R and β-MSH have been predicted, followed by docking and molecular dynamics simulation. While the 3D model of MC4R receptor has been predicted through threading approach, structure of β- MSH was built based on ab initio technique. The β-MSH model was later successfully docked onto the MC4R protein. Molecular dynamics (MD) simulation for 15 ns was used to compute the electrostatic solvation energy as well as binding energy between MC4R with β-MSH model under implicit solvent conditions.

Receptor-4 de melanocortina / Melanocortin-4 receptor: relevance in eating behaviour

The melanocortin-4 receptor (MC4R) is a G-protein-linked receptor widely expressed in the hypothalamus and in other central nervous system regions crucially involved in energy homeostasis. Genetic mutations of MC4R are considered as the most frequent cause of rare monogenic forms of human obesity. In the hypothalamus, leptin stimulates pro-opiomelanocortin (POMC) neurons of the arcuate nucleus, resulting in the release of alpha-melanocyte stimulating hormone (alpha-MSH), a cleavage product of POMC, which binds MC4R in in second order neurons of the paraventricular nucleus generating an anorexigenic response. In contrast, the Agouti-Related Protein (AGRP) is an inverse agonist of MC4R that induces an orexigenic response. MC4R expressed in other different brain areas seems to be related to different aspects of eating behaviour such as meal choice and termination. On the other hand, it has been described that MC4R reciprocally regulate preganglionic sympathetic and parasympathetic cholinergic neurons controlling energy expenditure, heart rate, blood pressure, fuel partitioning, as well as glucose and lipid metabolism. Active research is being carried out in order to identify the useof safe MC4R agonists that act in the central nervous system for the treatment of obesity, without having undesirable side effects such as increases in heart rate or blood pressure...

Melanocortin 4 receptor and children obesity / 国际儿科学杂志

Mutations in the melanocortin 4 receptor (MC4R) represent the most common known cause of monogenic human obesity.MC4R is a family of the five melanocortin receptors.It is an exon lying on chromosome 18.Studies have proved that there is a closed relationship between MC4R and weight regulation.MC4R mutation can result in severer adolescent obesity.

Gene Mutation Screening of Melanocortin 4 Receptor of Simple Obese Children in Nanjing City / 实用儿科临床杂志

Objective To screen melanocortin 4 receptor (Mc4R) gene mutation by direct DNA sequencing in order to explore the mutation situation of Mc4R gene in simple obese children in Nanjing.Methods One hundred and five simple obese children(obesity group) and 127 healthy children(healthy control group) were examined for mutations of Mc4R gene.Body mass index(BMI)cutoff points for overweight and obesity adopted Chinese children and adolescents,recommended by China Working Group of Obesity,and all children had no other hereditary and metabolic abnormality.Touch-down PCR was performed to amplify the full length Mc4R gene,then direct DNA sequencing was used to analyze the Mc4R gene.The differences of biochemical index levels between obesity group and healthy control group were analyzed ,including alanine transaminase,aspartate transaminas,total protein,albumin,globulin,albumin/globulin,triglyceride,cholesterol,high density lipoprotein,cortisol,insulin and C peptide.Results There were significant differences of biochemical index levels between obesity group and healthy control group,including triglyceride,insulin level after dining 2 h,C peptide and BMI(Pa