Abstract
Despite considerable effort, the identification of genes that regulate complex multigenic traits such as obesity has proven difficult with conventional methodologies. The use of a chromosome substitution strain-based mapping strategy based on deep congenic analysis overcame many of the difficulties associated with gene discovery and led to the finding that the juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity. The effects of a mild Cntnap2 mutation on body weight were highly dependent on genetic background, as both obesity-promoting and obesity-resistant effects of Cntnap2 were observed on different genetic backgrounds. The more severe effect of complete TAG1 deficiency, by decreasing food intake, completely prevented the weight gain normally associated with high-fat-diet feeding. Together, these studies implicate two novel proteins in the regulation of diet-induced obesity. Moreover, as juxtaparanodal proteins have previously been implicated in various neurological disorders, our results suggest a potential genetic and molecular link between obesity and diseases such as autism and epilepsy.
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References
Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH et al (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159
Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH et al (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160–164
Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB et al (2011) Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res 21:1213–1222
Bagnasco M, Dube MG, Katz A, Kalra PS, Kalra SP (2003) Leptin expression in hypothalamic PVN reverses dietary obesity and hyperinsulinemia but stimulates ghrelin. Obes Res 11:1463–1470
Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K, Klin A, Ercan-Sencicek AG, Stillman AA et al (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82:165–173
Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, Litt M (1994) Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 8:136–140
Chen AY, Kim SE, Houtrow AJ, Newacheck PW (2010) Prevalence of obesity among children with chronic conditions. Obesity (Silver Spring) 18:210–213
Coleman DL (1973) Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9:294–298
Cordell HJ (2009) Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet 10:392–404
Curtin C, Anderson SE, Must A, Bandini L (2010) The prevalence of obesity in children with autism: a secondary data analysis using nationally representative data from the National Survey of Children’s Health. BMC Pediatr 10:11
Daniels ZS, Nick TG, Liu C, Cassedy A, Glauser TA (2009) Obesity is a common comorbidity for pediatric patients with untreated, newly diagnosed epilepsy. Neurology 73:658–664
Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11:446–450
Emily M, Mailund T, Hein J, Schauser L, Schierup MH (2009) Using biological networks to search for interacting loci in genome-wide association studies. Eur J Hum Genet 17:1231–1240
Everitt B, Hothorn T (2006) A handbook of statistical analyses using R. Chapman & Hall/CRC, Boca Raton, FL
Farooqi IS (2011) Genetic, molecular and physiological insights into human obesity. Eur J Clin Invest 41:451–455
Ghelardini C, Galeotti N, Pecori Vettori A, Capaccioli S, Quattrone A, Bartolini A (1997) Effect of K+ channel modulation on mouse feeding behaviour. Eur J Pharmacol 329:1–8
Gilbert-Diamond D, Moore JH (2011) Analysis of gene-gene interactions. Curr Protoc Hum Genet Chapter 1:Unit1.14
Hill-Baskin AE, Markiewski MM, Buchner DA, Shao H, DeSantis D, Hsiao G, Subramaniam S, Berger NA, Croniger C, Lambris JD et al (2009) Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum Mol Genet 18:2975–2988
Hofker M, Wijmenga C (2009) A supersized list of obesity genes. Nat Genet 41:139–140
Jandacek RJ, Heubi JE, Tso P (2004) A novel, noninvasive method for the measurement of intestinal fat absorption. Gastroenterology 127:139–144
Jensen-Seaman MI, Furey TS, Payseur BA, Lu Y, Roskin KM, Chen C-F, Thomas MA, Haussler D, Jacob HJ (2004) Comparative recombination rates in the rat, mouse, and human genomes. Genome Res 14:528–538
Kaiyala KJ, Schwartz MW (2011) Toward a more complete (and less controversial) understanding of energy expenditure and its role in obesity pathogenesis. Diabetes 60:17–23
Kaiyala KJ, Morton GJ, Leroux BG, Ogimoto K, Wisse B, Schwartz MW (2010) Identification of body fat mass as a major determinant of metabolic rate in mice. Diabetes 59:1657–1666
Klein BS, Himmelbauer H, Zechner U, Riemann M, Liptay S, Hameister H, Schmid RM (2000) Assignment of the mouse Rbpsuh gene to chromosome 5 and one processed pseudogene Rbpsuh-rs3 to chromosome 6. Cytogenet Cell Genet 88:218–220
Konno H, Fukunishi Y, Shibata K, Itoh M, Carninci P, Sugahara Y, Hayashizaki Y (2001) Computer-based methods for the mouse full-length cDNA encyclopedia: real-time sequence clustering for construction of a nonredundant cDNA library. Genome Res 11:281–289
Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081
Law CO, Kirby RJ, Aghamohammadzadeh S, Furley AJW (2008) The neural adhesion molecule TAG-1 modulates responses of sensory axons to diffusible guidance signals. Development 135:2361–2371
Liu Y, Xu H, Chen S, Chen X, Zhang Z, Zhu Z, Qin X, Hu L, Zhu J, Zhao G-P et al (2011) Genome-wide interaction-based association analysis identified multiple new susceptibility loci for common diseases. PLoS Genet 7:e1001338
Melendez-Vasquez CV, Rios JC, Zanazzi G, Lambert S, Bretscher A, Salzer JL (2001) Nodes of Ranvier form in association with ezrin–radixin–moesin (ERM)-positive schwann cell processes. Proc Natl Acad Sci USA 98:1235–1240
Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24:221–225
Newbury DF, Monaco AP (2010) Genetic advances in the study of speech and language disorders. Neuron 68:309–320
O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C et al (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43:585–589
Paigen K, Petkov P (2010) Mammalian recombination hot spots: properties, control and evolution. Nat Rev Genet 11:221–233
Peñagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, Sonnenblick LI, Gruver R, Almajano J, Bragin A et al (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147:235–246
Poliak S, Gollan L, Martinez R, Custer A, Einheber S, Salzer JL, Trimmer JS, Shrager P, Peles E (1999) Caspr2, a new member of the neurexin superfamily, is localized at the juxtaparanodes of myelinated axons and associates with K+ channels. Neuron 24:1037–1047
Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu S-Y, Shrager P et al (2003) Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 162:1149–1160
Rasband MN (2010) Clustered K+ channel complexes in axons. Neurosci Lett 486:101–106
Rasband MN (2011) Composition, assembly, and maintenance of excitable membrane domains in myelinated axons. Semin Cell Dev Biol 22:178–184
Ren D, Li M, Duan C, Rui L (2005) Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab 2:95–104
Rimmer JH, Yamaki K, Lowry BMD, Wang E, Vogel LC (2010) Obesity and obesity-related secondary conditions in adolescents with intellectual/developmental disabilities. J Intellect Disabil Res 54:787–794
Savvaki M, Panagiotaropoulos T, Stamatakis A, Sargiannidou I, Karatzioula P, Watanabe K, Stylianopoulou F, Karagogeos D, Kleopa KA (2008) Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 39:478–490
Seidenberg M, Pulsipher DT, Hermann B (2009) Association of epilepsy and comorbid conditions. Future Neurol 4:663–668
Shao H, Burrage LC, Sinasac DS, Hill AE, Ernest SR, O’Brien W, Courtland H-W, Jepsen KJ, Kirby A, Kulbokas EJ et al (2008) Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis. Proc Natl Acad Sci USA 105:19910–19914
Shao H, Sinasac D, Burrage L, Hodges C, Supelak P, Palmert M, Moreno C, Cowley A, Jacob H, Nadeau J (2010) Analyzing complex traits with congenic strains. Mamm Genome 21:276–286
Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, Petukhova GV (2011) Genome-wide analysis reveals novel molecular features of mouse recombination hotspots. Nature 472:375–378
Spiegelman BM, Flier JS (2001) Obesity and the regulation of energy balance. Cell 104:531–543
Steinmetz LM, Sinha H, Richards DR, Spiegelman JI, Oefner PJ, McCusker JH, Davis RW (2002) Dissecting the architecture of a quantitative trait locus in yeast. Nature 416:326–330
Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354:1370–1377
Tinsley FC, Taicher GZ, Heiman ML (2004) Evaluation of a quantitative magnetic resonance method for mouse whole body composition analysis. Obesity 12:150–160
Traka M, Goutebroze L, Denisenko N, Bessa M, Nifli A, Havaki S, Iwakura Y, Fukamauchi F, Watanabe K, Soliven B et al (2003) Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol 162:1161–1172
Tucker K, Overton JM, Fadool DA (2008) Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice. Int J Obes 32:1222–1232
Tung Y-CL, Ma M, Piper S, Coll A, O’Rahilly S, Yeo GSH (2008) Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J Neurosci 28:12419–12426
Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH et al (2008) A functional genetic link between distinct developmental language disorders. N Engl J Med 359:2337–2345
Walters RG, Jacquemont S, Valsesia A, de Smith AJ, Martinet D, Andersson J, Falchi M, Chen F, Andrieux J, Lobbens S et al (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463:671–675
Xu J, Koni PA, Wang P, Li G, Kaczmarek L, Wu Y, Li Y, Flavell RA, Desir GV (2003) The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight. Hum Mol Genet 12:551–559
Xu J, Wang P, Li Y, Li G, Kaczmarek LK, Wu Y, Koni PA, Flavell RA, Desir GV (2004) The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proc Natl Acad Sci USA 101:3112–3117
Yazbek SN, Spiezio SH, Nadeau JH, Buchner DA (2010) Ancestral paternal genotype controls body weight and food intake for multiple generations. Hum Mol Genet 19:4134–4144
Yazbek SN, Buchner DA, Geisinger JM, Burrage LC, Spiezio SH, Zentner GE, Hsieh C-WW, Scacheri PC, Croniger CM, Nadeau JH (2011) Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis. Genome Res 21:1065–1073
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432
Zuk O, Hechter E, Sunyaev SR, Lander ES (2012) The mystery of missing heritability: genetic interactions create phantom heritability. Proc Natl Acad Sci USA 109:1193–1198
Acknowledgments
This research was supported by the NIH NCRR grant RR12305, NIH NCI Transdisciplinary Research on Energetics and Cancer (TREC) grant U54 CA116867, and the NIH NIDDK grants DK76174 (CWRU MMPC), DK052989 and K01 DK084079.
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Buchner, D.A., Geisinger, J.M., Glazebrook, P.A. et al. The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity. Mamm Genome 23, 431–442 (2012). https://doi.org/10.1007/s00335-012-9400-8
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DOI: https://doi.org/10.1007/s00335-012-9400-8