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MC4R

Official Full Name
melanocortin 4 receptor
Background
The protein encoded by this gene is a membrane-bound receptor and member of the melanocortin receptor family. The encoded protein interacts with adrenocorticotropic and MSH hormones and is mediated by G proteins. This is an intronless gene. Defects in this gene are a cause of autosomal dominant obesity.
Synonyms
MC4R; melanocortin 4 receptor; melanocortin receptor 4; MC4-R; MGC126851; MGC138197; melanocortin 4-receptor; zMC4; si:dkey-151m6.62

MC4R (melanocortin-4 receptor) is a class of peptides secreted by the ventromedial nucleus of the hypothalamus and is one of the five subtypes (MC1-5R) of the melanocortin receptor family. MC4R binds to the natural endogenous ligand α-melanocyte stimulating hormone (α-MSH) secreted by the brain, inhibiting the increase in body weight.

The Role of MC4R

MC4R is abundantly present in various regions of the animal's central nervous system, including the cerebral cortex, thalamus, hypothalamus, brainstem, and notochord. In mammals, MC4R has the function of mediating leptin and is an important signal molecule that regulates energy balance and energy homeostasis. MC4R can be combined with its endogenous ligand melanocortin (MC) or agouti protein (agouti protein) and agouti related protein (AGRP) to control appetite and body weight. It plays a key role in steady state.

MC4R.png

Figure 1. The hypothalamic melanocortin system. (Girardet, et al. 2014)

The central nervous system's body weight regulation function of MC4R is mainly to inhibit food intake, resulting in lower blood sugar, insulin and leptin levels, thereby reducing body fat and reducing body weight. Therefore, MC4R has received much attention as an important regulatory factor in human obesity studies. Recent studies have shown that there is a correlation between the G→A mutation at the 1232 site of MC4R and the thickness of the sheep's backfat, and the AG and AA models have higher backfat thickness than the GG model. Studies have shown that MC4R is a dominant receptor subtype in neural tissue, especially in the hypothalamus, and therefore it is thought to play a key role in appetite control in the hypothalamus.

MC4R Adjustment

Melanocortin (MC) is a generic term for α-MSH, β-MSH, γ-MSH and ACTH. The precursor substance, which is produced by hydrolysis of proopiomelanocortin (POMC). Injecting α-MSH and its congener MT-II into the lateral ventricle of mice (a strong agonist of MC3R and MC4R) can inhibit the increase in food intake in mice during normal fasting and neuropeptide Y (NPY) stimulation. It also inhibits the overexpression of agouti (rat eggs) and ob/ob (lack of leptin) in obese mice. In mice that knocked out the MC4R gene, there was no response to the appetite-suppressing agonist MT-II, confirming that the regulation of endogenous MSH on food intake was achieved by MC4R. Studies have shown that antagonizing the binding of αMSH to MC4R in the hypothalamic feeding center increases the food intake of mice by 10% to 36% compared with the control group, reduces the heat production, increases the utilization rate of calories, and gradually becomes obese, and the body length is also increase.

MC4R and Obesity

MC4R is the first target site found to be associated with human dominant genetic disease obesity. The importance of MC4R in human energy and body weight regulation was gradually revealed after Yeo et al. and Vaisse et al first discovered MC4R gene translocation mutations in two patients with early-onset obesity. It is estimated that 1% to 4% of the extremely obese people with a BMI greater than 40 are due to mutations in the MC4R gene. Studies have shown that mice that knocked out the MC4R gene (MC4R-/-) developed genetic obesity and showed symptoms such as polyphagia, obesity, and excessive insulin secretion.

In humans, obesity caused by mutations in the MC4R gene has a variety of phenotypes, and is not accompanied by other endocrine and metabolic abnormalities other than polyphagia and obesity. The thyroid, adrenal gland, and reproductive function are normal, unlike other types of single-gene mutational obesity. In addition, the polymorphism of MC4R may also be related to body fat distribution and lipid metabolism. The obesity caused by body defect MC4R is adolescent, and the severity of women is higher than that of men. Most of them have a feminine tendency to distribute body fat.

References:

  1. Girardet, C. , & Butler, A. A. . (2014). Neural melanocortin receptors in obesity and related metabolic disorders. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1842(3), 482-494.
  2. Juliana Pereira Lopes Gonçalves, Palmer, D. , & Meldal, M. . (2018). Mc4r agonists: structural overview on antiobesity therapeutics. Trends in Pharmacological Sciences.
  3. Siljee, J. E. , Wang, Y. , Bernard, A. A. , Ersoy, B. A. , Zhang, S. , & Marley, A. , et al. (2018). Subcellular localization of mc4r with adcy3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nature Genetics.

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