Genetic Linkage to Childhood Obesity Saeed Mahmood Mentor: Dr. Akintola Odutola Medical University of theAmericas 3439 Richmond Rd Staten Island,NY 10306 (917) 349-5543s.mahmood@mua.
edAbstractHypothesis – Defectin leptin and its receptor gene is linked to childhood obesity because of dysregulationof production of leptin and its receptors. Methods: Articles for this literature review analysis were selected using PubMed, Nature Journals, Oxford Journals, and New England Journal of Medicine. Keywords used to search were “lepr”, “leptin role”, “childhood obesity”, “leptin receptor gene”, “leptin receptor”, “leptin structure”, “leptin receptor structure”, “leptin gene”, and “lepr chromosome”.
Studies used evaluated the role of leptin hormone on childhood obesity. All studies to be relatively recent within a ten-year period. Exclude all studies before 2006 and those not written in English. Focus on studies that involve large number of populations, which includes humans, mice, and animals. All studies to be relatively recent within a ten-year period. Results Several studies reported that the environment, behavior is a major contribute to childhood obesity however there is also a genetic linkage with childhood obesity, specifically defect in leptin hormone or its receptor gene leads to deficiency and dysregulation of leptin hormone and its receptor and it leads to hyperphagia and severe, early-onset obesity. Conclusions Identification of genetic linkage with childhood obesity is a critical issue, because it can help us develop medication to target this problem or even maybe a gene therapy in the future.
Currently there is still lot of research going to necessarily confirm or reject this conclusion that the leptin hormone gene and its receptor gene dysregulation cause childhood obesity. Word count – 240 KeywordsLepr, Lep gene, leptin role, leptin hormone,childhood obesity, leptin receptor gene, leptin receptor, leptin structure,childhood obesity. Introduction Obesity is defined as excess fat mass. Body Mass Index (BMI) is a measurement of the amount of fat person has. Obesity is defined as BMI > 25 kg/m².
Childhood obesity prevenelnece has been increasing. Childhood obesity is linked with numerous health complications and is a major problem in the United States presently. According to the Childhood Obesity Foundation, in 2013 around 43 million infants and children were obese and the numbers are expected to rise.
According to Centers of Disease Control and Prevention childhood obesity affect 12.5 million teens and children in the United States. High BMI leads to cardiovascular dieses (Freedman et al., 2009). Although several socioeconomic factors of various types have been linked causally with childhood obesity, not much is known about genetic linkage of this problem. Childhood obesity mode of inheritance is categorized in two groups either polygenic or monogenic.
In the vast majority of obese children, no syndromal or monogenic cause for the obese state can be diagnosed and therefore a polygenic cause is suggested (Funcke, 2014). Of all monogenic forms of obesity, leptin defeincy caouse by mutation in leptin gene is the only one that is curable (Paz-Filho, 2011). There is some evidence linking defects in several genes (LEP and LEPR genes) responsible for producing leptin and its receptors throughout the body with childhood obesity. The gene defect in LEP gene lead to defect in the protein therefore there is very low amount of hormone in individuals with gene defect (Farooqi, 2014). Several polymorphisms of both leptin and leptin receptor genes were studied in diverse populations for its probable relationship with obesity and the related complications (Khosropur, 2016). Leptin producing gene is located on chromosome 7q31.
3 (Alvarez, 2013). Leptin receptors producing gene is located on chromosome 1.p31.3 (Dias, 2010).
Leptin is a neuroendocrine hormone that is produced and released by adipocyte (Klok, 2007). It increases with amount on adipocytes a an individual as. An obese invidual has a higher amount of leptin produced and realsed by adipocyte compare to lean indivaual given that an obese person has more number of apidyctce. Lepttin with helps control the hunger and increases the energy expindentuure. An increase in leptin has a disadvantage for an obese invidial because it increases the chance of causing a phrmonma known as “leptin resistance”. It circulates in lean individuals at the level of 5 – 15 ng/mL (Khosropour, 2016). Leptin is responsible for regulation of satiety.
leptin stimulates dorsomedial nucleus in the hypthalamus and inhibited lateral nucleus in the hypothalamus. Dorsomedial nucleus is linked with feeding, drinking and circadian rhythm. When the dorsomedial nucleus is stimulated in prevents the intake of the food. The lateral nucleus is also linked with feeding behavior, stimulation of this nucleus leads to intake of the food. In this paper, I will review recent evidence to test my hypothesis that defects in LEPR genes contribute to childhood obesity through mechanism of dysregulation of production of leptin hormone receptors. I chose this topic because it is very important to understand how genetic factors contribute to childhood obesity so as to identify areas where new treatment interventions may be directed in its management. Evidence Table First Author Date of publication Study Design Level of Evidence Study Population Exposure Outcome Results Olza, J.
August 2017 Case-control study 3 Spanish female Children with normal and high BMI. Leptin receptor gene defect Female children with leptin receptor gene variant rs11804081 had higher BMI. Zhao, Y. February 2014 Case control study 3 135 Chinese individual with normal and BMI Missense mutation in exon 3 of leptin gene Gene defect was found in ovbese invidals. Hasnain, Shaban April 2016 Case control 3 475 Pakistani children Leptin gene defect A child with mutation in p. N103K leptin gene had higher BMI than his siblings.
Colmers, W. March 2013 Animal experiment 0 Mouse with pradder-willi syndrome gene Leptin hormone Food intake didn’t not decrease in mouse with PWS gene after an injection with leptin hormone. Hinuy, H. March 2010 Case-control study 3 110 obese and 100 non-obese Individuals. 45 women and 65 men, aged 49 ± 14 years Leptin receptor gene defect Women with defect in leptin gene found to have higher BMI. But not the men. Bahrami, E. May 2014 Case-control study 3 486 adolescents (243 with high and equal number with normal BMI.
Insulin level and leptin levels were high in obese adolescents. Altawil, A. October 2016. Case series 4 Two and healf year old girl with weight gain and hyperhagia Franshit in exon 3 of leptin gene cause the girl to eat more and gain wight Wabitsch, M.
July, 2015. Case series 4 Obese 9 year-old girl, 6 year-old boy with normal weight at birth. Leptin receptor gene Congenital deficiency of leptin gene results in severe early-onset obesity.
Appendix Figure 1 Note: Reteive from Marie Pigeyre, Fereshteh T. Yazdi, Yuvreet Kaur, David Meyre. Recent progess in genstic, eptgentics and metagenomics enviels the pathophysiologhy of human obesity. Clinical Scinece. 2016 May 06.
References: 1. Bender N, Allemann N, Marek D, Vollenweider P, Waeber G, Mooser V, Egger M, Bochud M. Association between variants of the leptin receptor gene (LEPR) and overweight: a systematic review and an analysis of the CoLaus study.
PLoS One. 2011;6(10):e26157. doi: 10.1371/journal.pone.
0026157. Epub 2011 Oct 18. 2. Dubern B, Clement K. Leptin and leptin receptor-related monogenic obesity. Biochimie. 2012 Oct;94(10) Epub 2012 May 22 3. Friedlander Y, Li G, Fornage M, Williams OD, Lewis CE, et al.
(2010) Candidate molecular pathway genes related to appetite regulatory neural network, adipocyte homeostasis and obesity: results from the CARDIA Study. Ann Hum Genet 74: 387–398 4. Hollensted M, Ahluwalia TS, Have CT, Grarup N, Fonvig CE, Nielsen TR, Trier C, Paternoster L, Pedersen O, Holm JC, Sørensen TI, Hansen T.
Common variants in LEPR, IL6, AMD1, and NAMPT do not associate with risk of juvenile and childhood obesity in Danes: a case-control study. BMC Med Genet. 2015 Nov 11;16:105 5.
Kaewsutthi S, Santiprabhob J, Phonrat B, Tungtrongchitr A, Lertrit P Tungtrongchitr R. Exome sequencing in Thai patients with familial obesity. Genet Mol Res.
2016 Jul 14;15(2). 6. Masuo K, Straznicky NE, Lambert GW, Katsuya T, Sugimoto K, et al. (2008) Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population. Hypertension Research – Clinical & Experimental 31: 1093–1100.
7. Mizuta E, Kokubo Y, Yamanaka I, Miyamoto Y, Okayama A, Yoshimasa Y, et al. Leptin gene and leptin receptor gene polymorphisms are associated with sweet preference and obesity. Hypertens Res. 2008;31:1069-78. Natasha Favoretto Dias, ArianaEster Fernandes, Maria Edna de Melo; Heidi Lui Reinhardt, Cintia Cercato,Sandra Mara Ferreira Villares, Alfredo Halpern, Marcio C. Mancini. Lack of mutations in the leptin receptorgene in severely obese children.
Arq Bras EndocrinolMetab vol.56 no.3 São Paulo Apr.
2012.9. Riestra P, Garcia-Anguita A,Schoppen S, Lopez-Simon L, de OM, et al.
(2010) Sex-specific association between leptin receptor polymorphisms and leptinlevels and BMI in healthy adolescents. Acta Paediatr 99: 1527–153010. Tabassum, Rubina, et al. Common variants of IL6, LEPR, and PBEF1 areassociated with obesity in Indian children. Diabetes 61.3 2012: 626-631.11. JosuneOlza, Azahara I.
Rupérez, Mercedes Gil-Campos, Rosaura Leis, Ramón Cañete,Rafael Tojo, Ángel Gil, Concepción M. Aguilera. Leptin Receptor Gene Variant rs11804091 Is Associated with BMI andInsulin Resistance in Spanish female Obese Children: ACase-Control Study. Int.
J. Mol. Sci.
2017.12. HamiltonM. Hinuy, Mario H. Hirata, Marcelo F. Sampaio, DikranArmaganijan, Simone Sorkin Arazi, Luis A.
Salazar,Rosario D. C. Hirata. Relationshipbetween variants of the leptin gene and obesity and metabolic biomarkers inBrazilian individuals. Arq Bras EndocrinolMetab vol.54 no.3 São Paulo.
2010. 13. Klok MD, Jakobsdottir S, Drent ML.
The role of leptin and ghrelin in the regulation of food intake andbody weight in humans: a review. Obes Rev. 2007;8:21-34.14. AngelA. Alvarez, Markus Bredel, in Emery and Rimoin’s. Primary Tumors of the Nervous System.
Principlesand Practice of Medical Genetics, 2013. 15. Zuo H, Shi Z, Yuan B, Dai Y, Wu G, Hussain A. Association between serum leptin concentrationsand insulin resistance: A population-based study from China.
PLoSOne. 2013;8:e54615. 16.
Ashwaq Shukri Altawil, HoriaAhmad Mawlawi, Khalid Ateeq Alghamdi and Faten Fohaid Almijmaj. A Novel Homozygous Frameshift Mutation inExon 2 of LEP Gene Associated with Severe Obesity: A Case Report.October 06, 2016.17. Paolini B, Maltese PE, Del Ciondolo I, TavianD, Missaglia S, Ciuoli C, et al. Prevalence of mutations in LEP, LEPR, and MC4Rgenes in individuals with severe obesity. Genet Mol Res.
2016;15(3).18. Farooqi IS, Keogh JM, Kamath S, Jones S, GibsonWT, Trussell R, et al.
Partial leptin deficiency and human adiposity. Nature.2001;414(6859):34–5. pmid:11689931.
19. Meier JJ, Menge BA, Breuer TG, Muller CA,Tannapfel A, Uhl W, et al. Functional assessment of pancreatic beta-cell areain humans. Diabetes.
2009;58(7):1595–603. PubMed Central PMCID: PMCPMC2699865.pmid:19509022.20. Wabitsch M, Funcke JB, von Schnurbein J, DenzerF, Lahr G, Mazen I, et al.
Severe Early-Onset Obesity Due to Bioinactive LeptinCaused by a p.N103K Mutation in the Leptin Gene. J Clin Endocrinol Metab.2015;100(9):3227–30. PubMed Central PMCID: PMCPMC4570156.
pmid:26186301.21. Zhang L, Yuan LH, Xiao Y, Lu MY, Zhang LJ, WangY: Association of leptin gene -2548 G/A polymorphism with obesity: ameta-analysis. Ann Nutr Metab 2014;64:127-136.22. Ng ZY, Veerapen MK, Hon WM, Lim RL: Associationof leptin/receptor and TNF-? gene variants with adolescent obesity in Malaysia.
Pediatr Int 2014;56:689-697.23. Walters, R.G., Jacquemont, S.,Valsesia, A., de Smith, A.J.
, Martinet, D., Andersson, J., Falchi, M., Chen,F., Andrieux, J.
, Lobbens, S., et al. (2010). A new highly penetrant form ofobesity due to deletions on chromosome 16p11.2. Nature 463, 671–675. 24. Sebag, J.
A., Zhang, C., Hinkle, P.M.,Bradshaw, A.M., and Cone, R.
D. (2013). Developmental control of themelanocortin-4 receptor by MRAP2 proteins in zebrafish.
Science 341,278–281. 25. Hastuti P, Zukhrufia I, Padwaswari MH, NurainiA, Sadewa AH. Polymorphism in leptin receptor gene was associated with obesityin Yogyakarta, Indonesia. Egyptian J Med HumGenet. 2016;26.
Freedman, D.S. et al.,2009. Relation of body mass index and skinfold thicknesses to cardiovasculardisease risk factors in children: the Bogalusa Heart Study. Am. J. Clin.
Nutr.,90(1), pp.210–216.27. : Khosropour S, Shojaee M, Lotfi P.Obesity, Leptin and Leptin Receptors, Gene Cell Tissue. 2016 ;3(4):e39980.
28. HastutiP, Zukhrufia I, Padwaswari MH, Nuraini A, Sadewa AH. Polymorphism in leptinreceptor gene was associated with obesity in Yogyakarta, Indonesia. Egyptian J Med Hum Genet. 2016;29.
Funcke,J.-B., von Schnurbein, J., Lennerz, B., Lahr, G.
, Debatin, K.-M.,Fischer-Posovszky, P.
, & Wabitsch, M. (2014). Monogenic forms of childhoodobesity due to mutations in the leptin gene.
Molecular and CellularPediatrics, 1, 3. http://doi.org/10.1186/s40348-014-0003-130. Altawil AS, Mawlawi HA, Alghamdi KA, AlmijmajFF.
A Novel Homozygous Frameshift Mutation in Exon 2 of LEP GeneAssociated with Severe Obesity: A Case Report. Clinical Medicine Insights Pediatrics. 2016;10:115-118. doi:10.4137/CMPed.S40432.31.
Farooqi IS, O’Rahilly S. 20 years of leptin: human disorders of leptin action. J Endocrinol. 2014;223:T63–T70.32. John-Olov Jansson, VilborgPalsdottir, Daniel A. Hägg, Erik Schéle, SuzanneL. Dickson, Fredrik Anesten, Tina Bake, MikaelMontelius, Jakob Bellman, Maria E.
Johansson, Roger D. Cone, Daniel J. Drucker, JianyaoWu, Biljana Aleksic, Anna E. Törnqvist, Klara Sjögren, Jan-ÅkeGustafsson, Sara H. Windahl and Claes Ohlsson. Body weight homeostat that regulates fat mass independently ofleptin in rats and mice. Proceedings of theNational Academy of Sciences Jan2018, 115 (2) 427-432; DOI: 10.
1073/pnas.1715687114.33. Marie Pigeyre, Fereshteh T. Yazdi, Yuvreet Kaur, David Meyre. Recent progress in genetic, epigenetic andmetagenomics reveals the pathophysiology of human obesity.
Clinical Science. 2016May 06. 34. Paz-Filho G, Wong ML, Licinio J: Ten years of leptin replacement therapy.
Obes Rev 2011, 12(5):e315–323.doi:10.1111/j.1467–789X.2010.00840.x 10.1111/j.1467-789X.2010.00840.x
