Abstract
Objective:
The gene TSPAN8 was recently identified in a genome-wide association study as the most likely causal gene in a locus that was correlated with the risk of type 2 diabetes (T2D) in northern European individuals. To assess whether Tspan8 is the actual T2D-causal gene in this locus, we ablated its expression in mice and determined the consequences of this ablation on a multitude of metabolic traits.
Results:
We found that genetic ablation of Tspan8 in mice results in a reduction (−15.6%) in the body weight of males fed a normal chow diet and that this deficiency results in a resistance to body weight gain (−13.7%) upon feeding a high fat and high carbohydrate diet. The differences in body weight could only be detected in male mice and were the consequence of both a decrease in fat deposition, and a decrease in lean body mass (16.9 and 11%, respectively). In spite of the significant body weight difference, no changes in fasting insulin and glucose levels could be detected in Tspan8 knockout mice, nor could we identify changes in the clearance of glucose or sensitivity to insulin in oral glucose tolerance test and intraperitoneal insulin sensitivity test studies, respectively. In addition, male Tspan8 knockout mice showed significantly lower bone mineral density and phosphorus levels (6.2 and 16.6%, respectively). Expression of Tspan8 in mouse was highest in digestive tissues, but virtually absent from the pancreas. In contrast, expression of human TSPAN8 was substantial in digestive tissues, as well as pancreatic cells.
Conclusions:
Our results argue for a role for Tspan8 in body-weight regulation in males, but do not show differences in T2D-associated traits that were anticipated from previous human genome-wide association studies. Differences in Tspan8 expression levels in mouse and human tissues suggest that Tspan8 could fulfill different or additional physiological functions in these organisms.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007; 316: 1331–1336.
Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007; 316: 1336–1341.
Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007; 316: 1341–1345.
Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 2007; 39: 770–775.
Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007; 445: 881–885.
Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006; 38: 320–323.
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008; 40: 638–645.
Grarup N, Andersen G, Krarup NT, Albrechtsen A, Schmitz O, Jorgensen T et al. Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4516 glucose-tolerant middle-aged Danes. Diabetes 2008; 57: 2534–2540.
Staiger H, Machicao F, Kantartzis K, Schafer SA, Kirchhoff K, Guthoff M et al. Novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes. PLoS ONE 2008; 3: e3019.
Omori S, Tanaka Y, Horikoshi M, Takahashi A, Hara K, Hirose H et al. Replication study for the association of new meta-analysis-derived risk loci with susceptibility to type 2 diabetes in 6244 Japanese individuals. Diabetologia 2009; 52: 1554–1560.
Sanghera DK, Been L, Ortega L, Wander GS, Mehra NK, Aston CE et al. Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs. J Hum Genet 2009; 54: 162–168.
Tanese K, Fukuma M, Yamada T, Mori T, Yoshikawa T, Watanabe W et al. G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. Am J Pathol 2008; 173: 835–843.
Eswaran J, von Kries JP, Marsden B, Longman E, Debreczeni JE, Ugochukwu E et al. Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases. Biochem J 2006; 395: 483–491.
Hemler ME . Targeting of tetraspanin proteins--potential benefits and strategies. Nat Rev Drug Discov 2008; 7: 747–758.
Zoller M . Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer 2009; 9: 40–55.
Cohen JC, Boerwinkle E, Mosley Jr TH, Hobbs HH . Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354: 1264–1272.
Nagy TR, Clair AL . Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. Obes Res 2000; 8: 392–398.
van der Hoogt CC, de Haan W, Westerterp M, Hoekstra M, Dallinga-Thie GM, Romijn JA et al. Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression. J Lipid Res 2007; 48: 1763–1771.
Johnson JM, Castle J, Garrett-Engele P, Kan Z, Loerch PM, Armour CD et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 2003; 302: 2141–2144.
She X, Rohl CA, Castle JC, Kulkarni AV, Johnson JM, Chen R . Definition, conservation and epigenetics of housekeeping and tissue-enriched genes. BMC Genomics 2009; 10: 269.
Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401.
Wajchenberg BL . Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21: 697–738.
Lonnqvist F, Thorne A, Large V, Arner P . Sex differences in visceral fat lipolysis and metabolic complications of obesity. Arterioscler Thromb Vasc Biol 1997; 17: 1472–1480.
Pedersen SB, Kristensen K, Hermann PA, Katzenellenbogen JA, Richelsen B . Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J Clin Endocrinol Metab 2004; 89: 1869–1878.
Mayes JS, Watson GH . Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev 2004; 5: 197–216.
Matsumoto C, Inada M, Toda K, Miyaura C . Estrogen and androgen play distinct roles in bone turnover in male mice before and after reaching sexual maturity. Bone 2006; 38: 220–226.
Miyaura C, Toda K, Inada M, Ohshiba T, Matsumoto C, Okada T et al. Sex- and age-related response to aromatase deficiency in bone. Biochem Biophys Res Commun 2001; 280: 1062–1068.
Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K . Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80: 3689–3698.
Bilezikian JP, Morishima A, Bell J, Grumbach MM . Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998; 339: 599–603.
Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997; 337: 91–95.
Herlevsen M, Schmidt DS, Miyazaki K, Zoller M . The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation. J Cell Sci 2003; 116: 4373–4390.
Gesierich S, Paret C, Hildebrand D, Weitz J, Zgraggen K, Schmitz-Winnenthal FH et al. Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility. Clin Cancer Res 2005; 11: 2840–2852.
Kanetaka K, Sakamoto M, Yamamoto Y, Yamasaki S, Lanza F, Kanematsu T et al. Overexpression of tetraspanin CO-029 in hepatocellular carcinoma. J Hepatol 2001; 35: 637–642.
Choi DS, Lee JM, Park GW, Lim HW, Bang JY, Kim YK et al. Proteomic analysis of microvesicles derived from human colorectal cancer cells. J Proteome Res 2007; 6: 4646–4655.
Simpson RJ, Jensen SS, Lim JW . Proteomic profiling of exosomes: current perspectives. Proteomics 2008; 8: 4083–4099.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO . Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007; 9: 654–659.
Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 2010; 70: 1668–1678.
Todd SC, Lipps SG, Crisa L, Salomon DR, Tsoukas CD . CD81 expressed on human thymocytes mediates integrin activation and interleukin 2-dependent proliferation. J Exp Med 1996; 184: 2055–2060.
Cherukuri A, Shoham T, Sohn HW, Levy S, Brooks S, Carter R et al. The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts. J Immunol 2004; 172: 370–380.
Knobeloch KP, Wright MD, Ochsenbein AF, Liesenfeld O, Lohler J, Zinkernagel RM et al. Targeted inactivation of the tetraspanin CD37 impairs T-cell-dependent B-cell response under suboptimal costimulatory conditions. Mol Cell Biol 2000; 20: 5363–5369.
Le Naour F, Rubinstein E, Jasmin C, Prenant M, Boucheix C . Severely reduced female fertility in CD9-deficient mice. Science 2000; 287: 319–321.
Miyado K, Yamada G, Yamada S, Hasuwa H, Nakamura Y, Ryu F et al. Requirement of CD9 on the egg plasma membrane for fertilization. Science 2000; 287: 321–324.
Wright MD, Geary SM, Fitter S, Moseley GW, Lau LM, Sheng KC et al. Characterization of mice lacking the tetraspanin superfamily member CD151. Mol Cell Biol 2004; 24: 5978–5988.
Goschnick MW, Lau LM, Wee JL, Liu YS, Hogarth PM, Robb LM et al. Impaired ‘outside-in’ integrin alphaIIbbeta3 signaling and thrombus stability in TSSC6-deficient mice. Blood 2006; 108: 1911–1918.
Rubinstein E, Ziyyat A, Prenant M, Wrobel E, Wolf JP, Levy S et al. Reduced fertility of female mice lacking CD81. Dev Biol 2006; 290: 351–358.
Heikens MJ, Cao TM, Morita C, Dehart SL, Tsai S . Penumbra encodes a novel tetraspanin that is highly expressed in erythroid progenitors and promotes effective erythropoiesis. Blood 2007; 109: 3244–3252.
Takeda Y, Kazarov AR, Butterfield CE, Hopkins BD, Benjamin LE, Kaipainen A et al. Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro. Blood 2007; 109: 1524–1532.
van Spriel AB, Puls KL, Sofi M, Pouniotis D, Hochrein H, Orinska Z et al. A regulatory role for CD37 in T cell proliferation. J Immunol 2004; 172: 2953–2961.
Tarrant JM, Groom J, Metcalf D, Li R, Borobokas B, Wright MD et al. The absence of Tssc6, a member of the tetraspanin superfamily, does not affect lymphoid development but enhances in vitro T-cell proliferative responses. Mol Cell Biol 2002; 22: 5006–5018.
Miyazaki T, Muller U, Campbell KS . Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81. Embo J 1997; 16: 4217–4225.
Acknowledgements
We thank Liz Polizzi Somers, Neil Geoghagen, Jayne Chin, Zhu Chen, Jun Wang, Eric Muise, Danielle Greenawalt and John Mudgett for their help with reagent supply, data analysis and paper preparation and Drs Debraj GuhaThakurta, Kenny Wong and Brian Hubbard for their help and advice.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Champy, MF., Le Voci, L., Selloum, M. et al. Reduced body weight in male Tspan8-deficient mice. Int J Obes 35, 605–617 (2011). https://doi.org/10.1038/ijo.2010.165
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijo.2010.165
Keywords
This article is cited by
-
Tetraspanin-8 sequesters syntaxin-2 to control biphasic release propensity of mucin granules
Nature Communications (2023)
-
Genomic insights into body size evolution in Carnivora support Peto’s paradox
BMC Genomics (2021)
-
TMT-based proteomic and bioinformatic analyses of human granulosa cells from obese and normal-weight female subjects
Reproductive Biology and Endocrinology (2021)
-
Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells
Nature Communications (2021)
-
Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice
Diabetologia (2021)