Obesity-associated gene <i>TMEM18</i> has a role in the central control of appetite and body weight regulation.

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 <i>TMEM18</i>, although the molecular mechanisms mediating these effects remain entirely unknown. <i>Tmem18</i> expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of <i>Tmem18</i> in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of <i>Tmem18</i> 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 <i>TMEM18</i> itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity.