2. Academic Validation
  3. Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation

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

  • Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):9421-9426. doi: 10.1073/pnas.1707310114.
Rachel Larder 1,  M F Michelle Sim 1,  Pawan Gulati 1,  Robin Antrobus 2,  Y C Loraine Tung 1,  Debra Rimmington 1,  Eduard Ayuso 3,  Joseph Polex-Wolf 1,  Brian Y H Lam 1,  Cristina Dias 4,  Darren W Logan 4,  Sam Virtue 1,  Fatima Bosch 3,  Giles S H Yeo 1,  Vladimir Saudek 1,  Stephen O'Rahilly 5,  Anthony P Coll 5
Affiliations

Affiliations

  • 1 University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
  • 2 Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
  • 3 Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08193 Bellaterra, Spain.
  • 4 Wellcome Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.
  • 5 University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom; so104@medschl.cam.ac.uk apc36@cam.ac.uk.
PMID: 28811369 DOI: 10.1073/pnas.1707310114
Abstract

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.

Keywords

GWAS; TMEM18; hypothalamus; obesity.

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