Title Effect of TMEM 18 on the central control of appetite

An intergenic region of human Chromosome 2 (2p25.3) harbours 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 new 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. Significance statement The growing size and sophistication of genome wide association studies has led to the identification of variants which are clearly and reliably associated with obesity. A strong association between increased BMI and a region of human chromosome 2, near to the gene TMEM18, has been repeatedly demonstrated in children and adults. The function of TMEM18 in the control of appetitive behaviour and body composition has been poorly characterised. In murine models, we show germline loss results in weight gain while adult onset hypothalamic overexpression results in weight loss, supporting the hypothesis that TMEM18 acting within the central nervous system can affect energy balance. We also report a novel structure and putative molecular function of TMEM18, challenging the current published model.