Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation.
Rachel LarderM F Michelle SimPawan GulatiRobin AntrobusY C Loraine TungDebra RimmingtonEduard AyusoJoseph Polex-WolfBrian Y H LamCristina DiasDarren W LoganSam VirtueFatima BoschGiles S H YeoVladimir SaudekStephen I O'RahillyAnthony P CollPublished in: Proceedings of the National Academy of Sciences of the United States of America (2017)
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.
Keyphrases
- body weight
- insulin resistance
- high fat diet
- high fat diet induced
- wild type
- copy number
- endothelial cells
- metabolic syndrome
- weight loss
- adipose tissue
- type diabetes
- genome wide
- poor prognosis
- weight gain
- cell proliferation
- electronic health record
- induced pluripotent stem cells
- dna methylation
- oxidative stress
- physical activity
- dna damage
- artificial intelligence
- genome wide analysis