Narrative Literature Review on MC4R rs17782313 Gene-Nutrient Interaction and Obesity Risk

Authors

  • Monica H.S. Otline Yocku Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia
  • Adriyan Pramono Faculty of Medicine, Universitas Diponegoro, Semarang, Indonesia

DOI:

https://doi.org/10.26630/jk.v16i1.4893

Keywords:

Gene-Nutrition interaction, Metabolic disorders, Observational studies

Abstract

The Melanocortin 4 Receptor (MC4R) gene plays a critical role in appetite regulation and energy balance. The single nucleotide polymorphism (SNP) rs17782313, located near the MC4R gene, has been widely associated with an increased risk of obesity, primarily through its influence on appetite control and energy homeostasis. Understanding how this genetic variant interacts with dietary intake can offer valuable insights into the pathophysiology of obesity and inform personalized nutritional strategies. This study aims to investigate the role of SNP rs17782313 in dietary factors and obesity risk, with a particular focus on the underlying molecular mechanisms. A narrative literature review was conducted, synthesizing findings from molecular, genetic, and epidemiological studies. The review highlights how rs17782313 may influence MC4R function and how macronutrient intake, particularly carbohydrates, proteins, and fats, modulates this effect. Evidence suggests that nutritional factors can affect gene expression or interact directly with the MC4R pathway, influencing energy intake, metabolic responses, and body weight regulation. Observational studies in various populations confirm the global relevance of these gene-diet interactions. The findings highlight the need for an integrative approach that combines genetics and nutrition to develop individualized interventions for obesity prevention and treatment. Understanding these interactions may contribute to more effective management of obesity and related metabolic disorders by tailoring dietary recommendations to genetic profiles.

References

Adamska-Patruno, E., Goscik, J., Czajkowski, P., Maliszewska, K., Ciborowski, M., Golonko, A., Wawrusiewicz-Kurylonek, N., Citko, A., Waszczeniuk, M., Kretowski, A., & Gorska, M. (2019). The MC4R Genetic Variants Are Associated With Lower Visceral Fat Accumulation And Higher Postprandial Relative Increase In Carbohydrate Utilization In Humans. European Journal of Nutrition, 58(7), 2929–2941. https://doi.org/10.1007/s00394-019-01955-0

Adamska-Patruno, E., Bauer, W., Bielska, D., Fiedorczuk, J., Moroz, M., Krasowska, U., Czajkowski, P., Wielogorska, M., Maliszewska, K., Puckowska, S., Szczerbinski, L., Lipinska, D., Gorska, M., & Kretowski, A. (2021). An Association between Diet and MC4R Genetic Polymorphism, in Relation to Obesity and Metabolic Parameters—A Cross-Sectional Population-Based Study. International Journal of Molecular Sciences, 22(21), 12044. https://doi.org/10.3390/ijms222112044

Alizadeh, S., Pooyan, S., Mirzababaei, A., Arghavani, H., Hasani, H., & Mirzaei, K. (2022). Interaction Of MC4R Rs17782313 Variants And Dietary Carbohydrate Quantity And Quality On Basal Metabolic Rate And General And Central Obesity In Overweight/Obese Women: A Cross-Sectional Study. BMC Endocrine Disorders, 22(1), 121. https://doi.org/10.1186/s12902-022-01023-5

Álvarez-Martín, C., Caballero, F. F., de la Iglesia, R., & Alonso-Aperte, E. (2024). Association of MC4R rs17782313 Genotype With Energy Intake and Appetite: A Systematic Review and Meta-analysis. Nutrition Reviews. https://doi.org/10.1093/nutrit/nuae075

Brouwers, B., de Oliveira, E. M., Marti-Solano, M., Monteiro, F. B. F., Laurin, S.-A., Keogh, J. M., Henning, E., Bounds, R., Daly, C. A., Houston, S., Ayinampudi, V., Wasiluk, N., Clarke, D., Plouffe, B., Bouvier, M., Babu, M. M., Farooqi, I. S., & Mokrosiński, J. (2021). Human MC4R Variants Affect Endocytosis, Trafficking And Dimerization Revealing Multiple Cellular Mechanisms Involved In Weight Regulation. Cell Reports, 34(12), 108862. https://doi.org/10.1016/j.celrep.2021.108862

Carrasco-Luna, J., Navarro-Solera, M., Gombert, M., Martín-Carbonell, V., Carrasco-García, Á., Del Castillo-Villaescusa, C., García-Pérez, M. Á., & Codoñer-Franch, P. (2023). Association of the rs17782313, rs17773430, and rs34114122 Polymorphisms of/near MC4R Gene with Obesity-Related Biomarkers in a Spanish Pediatric Cohort. Children, 10(7), 1221. https://doi.org/10.3390/children10071221

Chermon, D., & Birk, R. (2023). Predisposition of the Common MC4R rs17782313 Female Carriers to Elevated Obesity and Interaction with Eating Habits. Genes, 14(11), 1996. https://doi.org/10.3390/genes14111996

Fairbrother, U., Kidd, E., Malagamuwa, T., & Walley, A. (2018). Genetics of Severe Obesity. Current Diabetes Reports, 18(10), 85. https://doi.org/10.1007/s11892-018-1053-x

Fontaine, T., Busch, A., Laeremans, T., De Cesco, S., Liang, Y.-L., Jaakola, V.-P., Sands, Z., Triest, S., Masiulis, S., Dekeyzer, L., Samyn, N., Loeys, N., Perneel, L., Debaere, M., Martini, M., Vantieghem, C., Virmani, R., Skieterska, K., Staelens, S., … Menet, C. (2024). Structure Elucidation Of A Human Melanocortin-4 Receptor Specific Orthosteric Nanobody Agonist. Nature Communications, 15(1), 7029. https://doi.org/10.1038/s41467-024-50827-7

Hainer, V., Aldhoon Hainerová, I., Kunešová, M., Taxová Braunerová, R., Zamrazilová, H., & Bendlová, B. (2020). Melanocortin Pathways: Suppressed And Stimulated Melanocortin-4 Receptor (MC4R). Physiological Research, S245–S254. https://doi.org/10.33549/physiolres.934512

Hammad, M. M., Abu-Farha, M., Hebbar, P., Cherian, P., Al Khairi, I., Melhem, M., Alkayal, F., Alsmadi, O., Thanaraj, T. A., Al-Mulla, F., & Abubaker, J. (2020). MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort. Frontiers in Endocrinology, 11. https://doi.org/10.3389/fendo.2020.00437

Heyder, N., Kleinau, G., Szczepek, M., Kwiatkowski, D., Speck, D., Soletto, L., Cerdá-Reverter, J. M., Krude, H., Kühnen, P., Biebermann, H., & Scheerer, P. (2019). Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00515

Heyder, N. A., Kleinau, G., Speck, D., Schmidt, A., Paisdzior, S., Szczepek, M., Bauer, B., Koch, A., Gallandi, M., Kwiatkowski, D., Bürger, J., Mielke, T., Beck-Sickinger, A. G., Hildebrand, P. W., Spahn, C. M. T., Hilger, D., Schacherl, M., Biebermann, H., Hilal, T., … Scheerer, P. (2021). Structures Of Active Melanocortin-4 Receptor–Gs-Protein Complexes With NDP-Α-MSH And Setmelanotide. Cell Research, 31(11), 1176–1189. https://doi.org/10.1038/s41422-021-00569-8

Huang, T., Zheng, Y., Hruby, A., Williamson, D. A., Bray, G. A., Shen, Y., Sacks, F. M., & Qi, L. (2017). Dietary Protein Modifies the Effect of the MC4R Genotype on 2-Year Changes in Appetite and Food Craving: The POUNDS Lost Trial. The Journal of Nutrition, jn242958. https://doi.org/10.3945/jn.116.242958

Kalinderi, K., Goula, V., Sapountzi, E., Tsinopoulou, V. R., & Fidani, L. (2024). Syndromic and Monogenic Obesity: New Opportunities Due to Genetic-Based Pharmacological Treatment. Children, 11(2), 153. https://doi.org/10.3390/children11020153

Katsuura-Kamano, S., Uemura, H., Arisawa, K., Yamaguchi, M., Hamajima, N., Wakai, K., Okada, R., Suzuki, S., Taguchi, N., Kita, Y., Ohnaka, K., Kairupan, T. S., Matsui, D., Oze, I., Mikami, H., Kubo, M., & Tanaka, H. (2014). A Polymorphism Near MC4R Gene (Rs17782313) Is Associated With Serum Triglyceride Levels In The General Japanese Population: The J-MICC Study. Endocrine, 47(1), 81–89. https://doi.org/10.1007/s12020-014-0306-y

Khalilitehrani, A., Qorbani, M., Hosseini, S., & Pishva, H. (2015). The Association Of MC4R Rs17782313 Polymorphism With Dietary Intake In Iranian Adults. Gene, 563(2), 125–129. https://doi.org/10.1016/j.gene.2015.03.013

Koochakpoor, G., Daneshpour, M. S., Mirmiran, P., Hosseini, S. A., Hosseini-Esfahani, F., Sedaghatikhayat, B., & Azizi, F. (2016). The Effect Of Interaction Between Melanocortin-4 Receptor Polymorphism And Dietary Factors On The Risk Of Metabolic Syndrome. Nutrition & Metabolism, 13(1), 35. https://doi.org/10.1186/s12986-016-0092-z

Liu, Z., & Hruby, V. J. (2022). MC4R Biased Signalling And The Conformational Basis Of Biological Function Selections. Journal of Cellular and Molecular Medicine, 26(15), 4125–4136. https://doi.org/10.1111/jcmm.17441

Lotta, L. A., Mokrosiński, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., Kaimakis, V., Hoult, D., Stewart, I. D., Wheeler, E., Day, F. R., Perry, J. R. B., Langenberg, C., Wareham, N. J., & Farooqi, I. S. (2019). Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell, 177(3), 597-607.e9. https://doi.org/10.1016/j.cell.2019.03.044

Lv, D., Zhang, D.-D., Wang, H., Zhang, Y., Liang, L., Fu, J.-F., Xiong, F., Liu, G.-L., Gong, C.-X., Luo, F.-H., Chen, S.-K., Li, Z.-L., & Zhu, Y.-M. (2015). Genetic Variations In SEC16B, MC4R, MAP2K5, And KCTD15 Were Associated With Childhood Obesity And Interacted With Dietary Behaviors In Chinese School-Age Population. Gene, 560 (2), 149–155. https://doi.org/10.1016/j.gene.2015.01.054

Meng, Y., Groth, S. W., & Li, D. (2018). Dietary Intake Modifies the Association between Obesity-Risk Genes and Gestational Weight Gain in African American Women. Journal of Nutrition and Metabolism, 2018, 1–7. https://doi.org/10.1155/2018/5080492

Metzger, P. J., Zhang, A., Carlson, B. A., Sun, H., Cui, Z., Li, Y., Jahnke, M. T., Layton, D. R., Gupta, M. B., Liu, N., Kostenis, E., Gavrilova, O., Chen, M., & Weinstein, L. S. (2024). A Human Obesity-Associated MC4R Mutation With Defective Gq/11α Signaling Leads To Hyperphagia In Mice. Journal of Clinical Investigation, 134(4). https://doi.org/10.1172/JCI165418

Mohammed, I., Selvaraj, S., Ahmed, W. S., Al-Barazenji, T., Hammad, A. S., Dauleh, H., Saraiva, L. R., Al-Shafai, M., & Hussain, K. (2023). Functional Characterization of Novel MC4R Variants Identified in Two Unrelated Patients with Morbid Obesity in Qatar. International Journal of Molecular Sciences, 24(22), 16361. https://doi.org/10.3390/ijms242216361

NCBI. (2024, July 8). MC4R melanocortin 4 receptor [ Homo sapiens (human) ]. NCBI. https://www.ncbi.nlm.nih.gov/gene/4160

Park, S., Daily, J. W., Zhang, X., Jin, H. S., Lee, H. J., & Lee, Y. H. (2016b). Interactions With The MC4R Rs17782313 Variant, Mental Stress And Energy Intake And The Risk Of Obesity In Genome Epidemiology Study. Nutrition & Metabolism, 13(1), 38. https://doi.org/10.1186/s12986-016-0096-8

Rahati, S., Qorbani, M., Naghavi, A., & Pishva, H. (2022). Association And Interaction Of The MC4R Rs17782313 Polymorphism With Plasma Ghrelin, GLP-1, Cortisol, Food Intake And Eating Behaviors In Overweight/Obese Iranian Adults. BMC Endocrine Disorders, 22(1), 234. https://doi.org/10.1186/s12902-022-01129-w

Rodríguez Rondón, A. V, Welling, M. S., van den Akker, E. L. T., van Rossum, E. F. C., Boon, E. M. J., van Haelst, M. M., Delhanty, P. J. D., & Visser, J. A. (2024). MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels. The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/clinem/dgae210

Sull, J. W., Kim, G., & Jee, S. H. (2020). Association Of MC4R (Rs17782313) With Diabetes And Cardiovascular Disease In Korean Men And Women. BMC Medical Genetics, 21(1), 160. https://doi.org/10.1186/s12881-020-01100-3

Vranceanu, M., Filip, L., Hegheș, S.-C., de Lorenzo, D., Cozma-Petruț, A., Ghitea, T. C., Stroia, C. M., Banc, R., Mîrza, O. M., Miere, D., Cozma, V., & Popa, D.-S. (2024). Genes Involved in Susceptibility to Obesity and Emotional Eating Behavior in a Romanian Population. Nutrients, 16(16), 2652. https://doi.org/10.3390/nu16162652

Walia, G. K., Saini, S., Vimal, P., Bhatia, K., Kumar, A., Singh, R., Prabhakaran, D., & Gupta, V. (2021). Association Of MC4R (Rs17782313) Gene Polymorphism With Obesity Measures In Western India. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 15(3), 661–665. https://doi.org/10.1016/j.dsx.2021.03.013

Yu, K., Li, L., Zhang, L., Guo, L., & Wang, C. (2020). Association Between MC4R Rs17782313 Genotype And Obesity: A Meta-Analysis. Gene, 733, 144372. https://doi.org/10.1016/j.gene.2020.144372

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Published

30-04-2025