Obesity-associated gene TMEM18 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 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.T he understanding of human obesity has benefited greatly from advances in molecular genetics. In addition to the identification of many mechanistically illuminating, highly penetrant monogenic disorders, genome-wide association studies (GWAS) have identified multiple common genetic variants strongly associated with body mass index (BMI) (1-5). Many of these loci are within, or close to, genes which, to date, have not been recognized to encode proteins with a role in the control of energy homeostasis. Of note, these genes show a strong preponderance to being highly expressed in the central nervous system, a finding which is congruent with the fact that monogenic disorders leading to obesity largely exert their effects through a disruption of the central control of appetite and energy balance (6). Murine models have proven to be highly useful in bridging the gap between the identification of a variant as being associated with an adiposity phenotype and the understanding of how that variant actually influences energy balance. For example, the robust correlation between BMI and polymorphisms in the first intron of the human fat mass and obesity-associated (FTO) gene has been followed by loss and gain of function studies in genetically modified mice, supporting the notion that a number of neighboring genes including IRX3 (which is the gene most likely mediating the effect of the human SNP), RPGRIP1L, and FTO itself can all play a role in the control of energy balance and body composition (7-13). A strong association between increased BMI and a region of human chromosome 2, near to the gene TMEM18, has been repeatedly demonstrated in both adults and children (2, 14-18). Like the genes in the vicinity of FTO, TMEM18 had not been recognized as having a role in energy homeostasis before its identification by GWAS, and relatively little is known about its function, save that it is expressed in the brain and that it encodes a 140-aa protein reported to contain three transmembrane domain (19) which may act as a DNAbinding protein (20)...

The role and possible mechanism of lncRNA AC092159.2 in modulating adipocyte differentiation

“…It has been confirmed that the transcription of most lncRNAs are in coordination with transcription of proteincoding genes and over 2000 lncRNAs are bidirectionally transcribed within 2|kb of the transcription start sites of protein-coding genes (Sigova et al 2013). Our findings suggested that AC092159.2 exerted its effect possibly by impacting on its neighboring gene TMEM18 which has been confirmed as an obesity susceptibility gene (Den Hoed et al 2010, Jurvansuu & Goldman 2011, Berndt et al 2013, Locke et al 2015, Larder et al 2017.…”

“…TMEM18 is a transmembrane protein of 140 amino acids containing four transmembrane domains which could act as DNA-binding protein for other downstream genes (Jurvansuu & Goldman 2011) and plausible mediator of genetic variation on human adiposity (Larder et al 2017). In recent years, researches have confirmed that TMEM18 was an obesity-associated gene (Den Hoed et al 2010, Berndt et al 2013, Locke et al 2015, Larder et al 2017 and TMEM18 was identified to be crucial for adipogenesis (Bernhard et al 2013). Moreover, the methylation levels of TMEM18 promoter were possibly associated with parameters of obesity and fat distribution (Rohde et al 2014).…”

<b><i>TMEM18</i></b>: A Novel Prognostic Marker in Acute Myeloid Leukemia

“…They also showed evidence that it can inhibit transcription. A later study suggested that TMEM18 is unlikely to directly regulate transcription [12]. In this study, the authors showed that the N- and C-termini of TMEM18 are exposed to the cytoplasm of cells treated with TX-100 or digitonin using immunocytochemistry and TMEM18 interacts with nuclear pore proteins [12].…”

“…While TMEM18 localization to the nuclear membrane has been demonstrated by immunocytochemistry and Western blotting [11, 12], its physiological roles remain controversial. Jurvansuu and Goldman [11] showed that TMEM18 can bind to chromatin via a specific sequence and bring it close to the nuclear membrane.…”

“…TMEM18 is a small protein consisting of 140 amino acids found in the nuclear envelope [10-12] and has been suggested to have transmembrane helices containing nuclear localization signals [11]. Although TMEM18 is ubiquitously expressed throughout the body, its expression in the brain is in the hypothalamus in particular [13].…”