RT Journal Article
SR Electronic
T1 Loss and gain of function experiments implicate TMEM18 as a mediator of the strong association between genetic variants at human Chromosome 2p25.3 and obesity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 122853
DO 10.1101/122853
A1 Rachel Larder
A1 M. F. Michelle Sim
A1 Pawan Gulati
A1 Robin Antrobus
A1 Y.C. Loraine Tung
A1 Debra Rimmington
A1 Eduard Ayuso
A1 Joseph Polex-Wolf
A1 Brian Y.H. Lam
A1 Cristina Dias
A1 Darren W. Logan
A1 Sam Virtue
A1 Fatima Bosch
A1 Giles S.H. Yeo
A1 Vladimir Saudek
A1 Stephen O’Rahilly
A1 Anthony P. Coll
YR 2017
UL http://biorxiv.org/content/early/2017/03/31/122853.abstract
AB An intergenic region of human Chromosome 2 (2p25.3) harbours genetic variants which are among those most strongly and reproducibly associated with obesity. The molecular mechanisms mediating these effects remain entirely unknown. The gene closest to these variants is TMEM18, encoding a transmembrane protein localised to the nuclear membrane. The expression of Tmem18 within the murine hypothalamic paraventricular nucleus was altered by changes in nutritional state, with no significant change seen in three other closest genes. 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 confirmed the nuclear membrane localisation of TMEM18 but provide new evidence that it is 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.