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The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity

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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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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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Author notes

  1. David A. Buchner

    Present address: Life Sciences Institute, University of Michigan, 210 Washtenaw Ave, Ann Arbor, MI, 48109, USA

  2. Jon M. Geisinger

    Present address: Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA

  3. Sabrina H. Spiezio & Joseph H. Nadeau

    Present address: Institute for Systems Biology, 401 Terry Ave. North, Seattle, WA, 98109, USA

Authors and Affiliations

  1. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    David A. Buchner, Jon M. Geisinger, Michael G. Morgan, Sabrina H. Spiezio & Joseph H. Nadeau

  2. Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Colleen M. Croniger

  3. Rammelkamp Center for Education and Research, MetroHealth Campus of Case Western Reserve University, Cleveland, OH, 44109, USA

    Patricia A. Glazebrook & Diana L. Kunze

  4. Department of Dentistry, University of Washington, Seattle, WA, 98109, USA

    Karl J. Kaiyala

  5. Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA, 98109, USA

    Michael W. Schwartz

  6. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Takeshi Sakurai

  7. Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK

    Andrew J. Furley

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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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