MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort

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.

Associations of MC4R, LEP, and LEPR Polymorphisms with Obesity-Related Parameters in Childhood and Adulthood

“…Evidence suggests that this gene is involved in appetite regulation and energy expenditure [ 29 ]. The MC4R rs17782313 variant was associated with the obesity-related proteins ghrelin and visfatin in the Arabic population [ 30 ]. Previous studies showed strong associations of the MC4R rs17782313 variant with higher energy and fat intake and lower carbohydrate and protein intake [ 31 , 32 ].…”

Association and interaction of the MC4R rs17782313 polymorphism with plasma ghrelin, GLP-1, cortisol, food intake and eating behaviors in overweight/obese Iranian adults

“…Ghrelin has a well-established role in the hypothalamic regulation of appetite. This hormone reduces appetite by decreasing Pro-opiomelanocortin (POMC) neuronal activity and increasing AgRP neuronal activity [ 1 ]. GLP-1 suppresses hunger by activating the glucagon-like peptide 1 receptor (GLP-1R) in the peripheral and central nervous systems, resulting in weight loss [ 52 ].…”

“…However, the results of some studies were consistent and some were not consistent with the results of this study. The results of a cohort study showed higher ghrelin levels in carriers of C-allele compared to T-allele carriers [ 1 ]. Magno et al .…”

“…Obesity has become a worldwide epidemic and still rising at an alarming rate. It can dramatically affect the quality of life and increase the risk of metabolic disorders including diabetes, hypertension, and cardiovascular complications [ 1 ]. Obesity is highly heritable and arises from the interactions of multiple genes, environmental and behavioral factors.…”

Effect of Sleeve Gastrectomy on Glycometabolism via Forkhead Box O1 (FoxO1)/Lipocalin-2 (LCN2) Pathway

“…In the present study, we found that the binding rate of LCN2 and MC4R in the hypothalamus was significantly increased after SG. It is generally believed that the pathogenesis of obesity and related diseases (such as diabetes and hypertension) is closely related to the regulatory role of the central nervous system [ 43 – 45 ]. The central melanocortin signaling pathway plays a key role, mainly by acting on MC4R.…”