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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.

SUBMITTER: Larder R

PROVIDER: S-EPMC5584443 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Larder Rachel R Sim M F Michelle MFM Gulati Pawan P Antrobus Robin R Tung Y C Loraine YCL Rimmington Debra D Ayuso Eduard E Polex-Wolf Joseph J Lam Brian Y H BYH Dias Cristina C Logan Darren W DW Virtue Sam S Bosch Fatima F Yeo Giles S H GSH Saudek Vladimir V O'Rahilly Stephen S Coll Anthony P AP

Proceedings of the National Academy of Sciences of the United States of America 20170815 35

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 wa ...[more]

PMID: 28811369

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Project description:BackgroundObesity is rising at an alarming rate globally. Different fermentable carbohydrates have been shown to reduce obesity. The aim of the present study was to investigate if two different fermentable carbohydrates (inulin and ?-glucan) exert similar effects on body composition and central appetite regulation in high fat fed mice.Methodology/principal findingsThirty six C57BL/6 male mice were randomized and maintained for 8 weeks on a high fat diet containing 0% (w/w) fermentable carbohydrate, 10% (w/w) inulin or 10% (w/w) ?-glucan individually. Fecal and cecal microbial changes were measured using fluorescent in situ hybridization, fecal metabolic profiling was obtained by proton nuclear magnetic resonance ((1)H NMR), colonic short chain fatty acids were measured by gas chromatography, body composition and hypothalamic neuronal activation were measured using magnetic resonance imaging (MRI) and manganese enhanced MRI (MEMRI), respectively, PYY (peptide YY) concentration was determined by radioimmunoassay, adipocyte cell size and number were also measured. Both inulin and ?-glucan fed groups revealed significantly lower cumulative body weight gain compared with high fat controls. Energy intake was significantly lower in ?-glucan than inulin fed mice, with the latter having the greatest effect on total adipose tissue content. Both groups also showed an increase in the numbers of Bifidobacterium and Lactobacillus-Enterococcus in cecal contents as well as feces. ?-Glucan appeared to have marked effects on suppressing MEMRI associated neuronal signals in the arcuate nucleus, ventromedial hypothalamus, paraventricular nucleus, periventricular nucleus and the nucleus of the tractus solitarius, suggesting a satiated state.Conclusions/significanceAlthough both fermentable carbohydrates are protective against increased body weight gain, the lower body fat content induced by inulin may be metabolically advantageous. ?-Glucan appears to suppress neuronal activity in the hypothalamic appetite centers. Differential effects of fermentable carbohydrates open new possibilities for nutritionally targeting appetite regulation and body composition.

Dataset Information

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

Publications

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

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