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Obesity-Associated Gene TMEM18 Has a Role in the Central Control of Appetite and Body Weight Regulation

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Obesity-Associated Gene TMEM18 Has a Role in the Central Control of Appetite and Body Weight Regulation Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation Rachel Lardera, M. F. Michelle Sima, Pawan Gulatia, Robin Antrobusb, Y. C. Loraine Tunga, Debra Rimmingtona, Eduard Ayusoc, Joseph Polex-Wolfa, Brian Y. H. Lama, Cristina Diasd, Darren W. Logand, Sam Virtuea, Fatima Boschc, Giles S. H. Yeoa, Vladimir Saudeka, Stephen O’Rahillya,1, and Anthony P. Colla,1 aUniversity of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom; bCambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; cCenter of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08193 Bellaterra, Spain; and dWellcome Genome Campus, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom Contributed by Stephen O’Rahilly, July 17, 2017 (sent for review May 3, 2017; reviewed by Jens Bruning and Marcelo A. Nobrega) An intergenic region of human chromosome 2 (2p25.3) harbors three transmembrane domain (19) which may act as a DNA- genetic variants which are among those most strongly and re- binding protein (20). We have therefore undertaken a range of producibly associated with obesity. The gene closest to these studies to determine whether TMEM18 plays a role in the variants is TMEM18, although the molecular mechanisms mediating control of energy balance in mammals. these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by Results changes in nutritional state. Germline loss of Tmem18 in mice Tmem18 Is Expressed within Hypothalamic Paraventricular Nucleus. We resulted in increased body weight, which was exacerbated by high initially examined the expression pattern of Tmem18 in a range of fat diet and driven by increased food intake. Selective overexpres- murine tissues and two mouse hypothalamic cell lines (N-46 and sion of Tmem18 in the PVN of wild-type mice reduced food intake GT1-7). In keeping with previous reports (19), Tmem18 was widely and also increased energy expenditure. We provide evidence that expressed, with expression observed in several regions of the brain, TMEM18 has four, not three, transmembrane domains and that it in brown adipose tissue and in both hypothalamic cell lines physically interacts with key components of the nuclear pore com- (SI Appendix,Fig.S1). We undertook qPCR analysis on hypotha- MEDICAL SCIENCES plex. Our data support the hypothesis that TMEM18 itself, acting lamic tissue acquired by laser capture microscopy (LCM) from within the central nervous system, is a plausible mediator of the three groups of wild-type mice (ad libitum fed, 48 h fasted and impact of adjacent genetic variation on human adiposity. fasted for 48 h with leptin administered throughout the fast). Forty- eight-hour fasting decreased PVN Tmem18 expression by 70%, TMEM18 | GWAS | hypothalamus | obesity with leptin administration during the fast restoring expression back to fed levels (Fig. 1). To examine expression of Tmem18 in other he understanding of human obesity has benefited greatly hypothalamic nuclei and also to determine expression of the three Tfrom advances in molecular genetics. In addition to the identification of many mechanistically illuminating, highly pen- Significance etrant monogenic disorders, genome-wide association studies (GWAS) have identified multiple common genetic variants The growing size and sophistication of genome-wide association strongly associated with body mass index (BMI) (1–5). Many of studies have led to the identification of variants which are clearly these loci are within, or close to, genes which, to date, have not and reliably associated with obesity. A strong association between been recognized to encode proteins with a role in the control of increased BMI and a region of human chromosome 2, near to the energy homeostasis. Of note, these genes show a strong pre- gene TMEM18, has been repeatedly demonstrated in children and ponderance to being highly expressed in the central nervous adults. The function of TMEM18 in the control of appetitive be- system, a finding which is congruent with the fact that monogenic havior and body composition has been poorly characterized. In disorders leading to obesity largely exert their effects through a murine models, we show germline loss results in weight gain while disruption of the central control of appetite and energy balance adult onset hypothalamic overexpression results in weight loss, (6). Murine models have proven to be highly useful in bridging supporting the hypothesis that TMEM18 acting within the central the gap between the identification of a variant as being associ- nervous system can affect energy balance. We also report a struc- ated with an adiposity phenotype and the understanding of how ture and putative molecular function of TMEM18, challenging the that variant actually influences energy balance. For example, the current published model. robust correlation between BMI and polymorphisms in the first intron of the human fat mass and obesity-associated (FTO) gene Author contributions: R.L., M.F.M.S., R.A., Y.C.L.T., J.P.-W., C.D., V.S., S.O., and A.P.C. designed research; R.L., M.F.M.S., P.G., R.A., Y.C.L.T., D.R., J.P.-W., B.Y.H.L., C.D., and has been followed by loss and gain of function studies in ge- A.P.C. performed research; E.A., D.W.L., and F.B. contributed new reagents/analytic tools; netically modified mice, supporting the notion that a number of R.L., M.F.M.S., P.G., Y.-C.L.T., J.P.-W., B.Y.H.L., C.D., D.W.L., S.V., G.S.H.Y., V.S., S.O., and neighboring genes including IRX3 (which is the gene most likely A.P.C. analyzed data; and R.L., V.S., S.O., and A.P.C. wrote the paper. mediating the effect of the human SNP), RPGRIP1L, and FTO Reviewers: J.B., Max Planck Institute for Metabolism Research Cologne; and M.A.N., The itself can all play a role in the control of energy balance and body University of Chicago. composition (7–13). A strong association between increased The authors declare no conflict of interest. BMI and a region of human chromosome 2, near to the gene Freely available online through the PNAS open access option. TMEM18, has been repeatedly demonstrated in both adults and Data deposition: The data reported in this paper have been deposited in the Gene Expression – Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE96627), and children (2, 14 18). Like the genes in the vicinity of FTO, the European Nucleotide Archive, www.ebi.ac.uk/ena (accession no. PRJEB13884). TMEM18 had not been recognized as having a role in energy 1To whom correspondence may be addressed. Email: [email protected] or homeostasis before its identification by GWAS, and relatively [email protected]. little is known about its function, save that it is expressed in the This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. brain and that it encodes a 140-aa protein reported to contain 1073/pnas.1707310114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1707310114 PNAS Early Edition | 1of6 Downloaded by guest on September 25, 2021 genes vicinal to Tmem18 (Sh3yl1, Snth2,andAcp1), in a further set A B of wild-type animals (either ad libitum fed or fasted for 24 h), we undertook RNA-Seq analysis of LCM-acquired tissue from four hypothalamic nuclei (arcuate, ventral medial, paraventricular, and dorsal medial nuclei) (GEO accession no. GSE96627; SI Appendix, Fig. S2). Tmem18 expression was observed in all nuclei examined. (SI Appendix,Fig.S3). Of note, in this dataset of 24-h fasting vs. fed, none of the changes in expression of Tmem18, Sh3yl1, Snth2, or Acp1 reached statistical significance in any of the four nuclei studied (SI Appendix,Fig.S4). Loss of Tmem18 Expression Results in an Increase in Body Mass. Knockout mice carrying mutant allele Tmem18tm1a(EUCOMM)Wtsi (abbreviated to “Tmem18tm1a”) were generated on a C57BL/6 CD genetic background as part of the European Conditional Mouse Mutagenesis Program (EUCOMM) (21). The introduction of the allele results in targeted disruption of exon 2 of Tmem18. qRT-PCR analysis revealed a very low level of residual Tmem18 transcript within the hypothalamus of homozygous mice (2.1% ±1.4), while heterozygous mice demonstrated a 50% de- + + crease in transcript expression compared with Tmem18 / (49 ± 9%)(SI Appendix, Fig. S5A). Tmem18 was the only transcript at that locus to be altered by introduction of the allele (SI Appendix, Fig. S5B), suggesting that there were no local “off target” effects. The mice were viable with expected homozygous mutant off- tm1a Fig. 2. Germline loss of Tmem18 results in increased body weight in male spring born from heterozygous crosses. Female Tmem18 wt/wt tm1a/tm1a homozygotes showed no differences in body weight or body mice. Body weights of Tmem18 (WT) and Tmem18 (HOM) male mice on normal chow from weaning (WT, n = 23; HOM, n = 23) (A)orHFD composition compared with wild-type littermates (SI Appendix, = = Fig. S6 A, C, and E). Male Tmem18tm1a homozygotes, on normal (B) from 8 wk of age (WT, n 15; HOM, n 20). Body composition analyses chow, had significantly increased body weight by 14 wk of age showing total, lean, or fat mass of 14-wk old WT and HOM male mice on normal chow (WT, n = 16; HOM, n = 16) (C) or HFD from 8 wk of age (WT, (Fig.
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