The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children.
BACKGROUND
TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.


METHODS
The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).


RESULTS
TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).


CONCLUSIONS
We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.
Almén
Markus Sällman
MS
Department of Neuroscience, Functional Pharmacology, Uppsala University, BMC, Uppsala SE 75124, Sweden.
Jacobsson
Josefin A
JA
Shaik
Jafar H A
JH
Olszewski
Pawel K
PK
Cedernaes
Jonathan
J
Alsiö
Johan
J
Sreedharan
Smitha
S
Levine
Allen S
AS
Fredriksson
Robert
R
Marcus
Claude
C
Schiöth
Helgi B
HB
D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D015992:Body Mass Index; D001835:Body Weight; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D016415:Sequence Alignment; D014018:Tissue Distribution; D055815:Young Adult
D008565:Membrane Proteins; C530715:TMEM18 protein, human