Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation

Rachel Larder, M. F.Michelle Sim, Pawan Gulati, Robin Antrobus, Y. C.Loraine Tung, Debra Rimmington, Eduard Ayuso, Joseph Polex-Wolf, Brian Y.H. Lam, Cristina Dias, Darren W. Logan, Sam Virtue, Fatima Bosch, Giles S.H. Yeo, Vladimir Saudek, Stephen O’Rahilly, Anthony P. Coll

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    17 Citations (Scopus)

    Abstract

    © 2017, National Academy of Sciences. All rights reserved. An intergenic region of human chromosome 2 (2p25.3) harbors genetic variants which are among those most strongly and reproducibly associated with obesity. The gene closest to these variants is TMEM18, although the molecular mechanisms mediating these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.
    Original languageEnglish
    Pages (from-to)9421-9426
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume114
    Issue number35
    DOIs
    Publication statusPublished - 29 Aug 2017

    Keywords

    • GWAS
    • Hypothalamus
    • Obesity
    • TMEM18

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    Larder, R., Sim, M. F. M., Gulati, P., Antrobus, R., Tung, Y. C. L., Rimmington, D., Ayuso, E., Polex-Wolf, J., Lam, B. Y. H., Dias, C., Logan, D. W., Virtue, S., Bosch, F., Yeo, G. S. H., Saudek, V., O’Rahilly, S., & Coll, A. P. (2017). Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation. Proceedings of the National Academy of Sciences of the United States of America, 114(35), 9421-9426. https://doi.org/10.1073/pnas.1707310114