Abstract
Melanocortin 4 receptor (MC4R), a notable component of the melanocortin system, regulates appetite, body weight, and energy homeostasis. Genome-wide association studies have identified several MC4R variants associated with adiposity; of these, rs17782313, which is associated with increased body mass index (BMI) and overeating behavior, is of particular interest. Another gene associated with increased adiposity in global genome-wide association studies is DNAJC27, a heat shock protein known to be elevated in obesity. The detailed mechanisms underlying the role of MC4R variants in the biological pathways underlying metabolic disorders are not well-understood. To address this, we assessed variations of rs17782313 in a cohort of 282 Arab individuals from Kuwait, who are deeply phenotyped for anthropometric and metabolic traits and various biomarkers, including DNAJC27. Association tests showed that the rs17782313_C allele was associated with BMI and DNAJC27 levels. Increased levels of DNAJC27 reduced the MC4R-mediated formation of cAMP in MC4R ACTOne stable cells. In conclusion, this study demonstrated an association between the rs17782313 variant near MC4R and increased BMI and DNAJC27 levels and established a link between increased DNAJC27 levels and lower cAMP levels. We propose that regulation of MC4R activity by DNAJC27 enhances appetite through its effect on cAMP, thereby regulating obesity.
Highlights
Obesity has become a global epidemic and is increasing at an alarming rate worldwide, especially in the Arabian Peninsula region
The results of this study showed that the rs17782313 variant near Melanocortin 4 receptor (MC4R) was associated with hypertension, obesity, and high plasma levels of ghrelin and visfatin in a cohort of Arabic participants
In an independent experiment using cell lines, we have tested the impact of increased DNAJC27 on MC4R. In this cell line model, we showed that the overexpression of DNAJC27 resulted in decreased cyclic adenosine monophosphate (cAMP) production by the in vitro activation of wild-type MC4R
Summary
Obesity has become a global epidemic and is increasing at an alarming rate worldwide, especially in the Arabian Peninsula region. Its action is mediated by DNAJC27 Regulates MC4R Activity melanocortins, a group of peptide hormones that include adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), and Agouti-related peptide (AgRP) [2,3,4]. The action of MC4R is mediated through two main populations of neurons that regulate feeding behavior: the anorexigenic pro-opiomelanocortin (POMC)/CART neurons and the orexigenic AgRP/neuropeptide Y (NPY) neurons These neurons are expressed in the arcuate nucleus of the hypothalamus and function in opposition to each other. POMC neurons project into the paraventricular hypothalamus (PVH) and release MSH, which in turn binds to and activates MC4R on the PVH neurons This activation results in blocking the appetite and reducing food intake. This results in the activation of appetite and an increase in food intake [1, 3, 8]
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