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New animal models reveal that coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8) are candidate genes for the onset of type 2 diabetes associated with obesity in rats

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Abstract

Obesity is a major risk factor for the onset of type 2 diabetes; however, little is known about the gene(s) involved. Therefore, we developed new animal models of obesity to search for diabetogenic genes associated with obesity. We generated double congenic rat strains with a hyperglycaemic quantitative trait locus (QTL) derived from the Otsuka Long-Evans Tokushima Fatty rat and a fa/fa (Lepr −/−) locus derived from the Zucker Fatty rat; phenotypic analysis for plasma glucose and insulin levels and RNA and protein levels were determined using reverse transcription quantitative PCR and Western blotting analyses, respectively. The double congenic strain F344-fa-nidd2 (Lepr −/− and Nidd2/of) exhibited significantly higher glucose levels and significantly lower hypoglycaemic response to insulin than the obese control strain F344-fa (Lepr −/−). These phenotypes were clearly observed in the obese strains but not in the lean strains. These results indicate that the Nidd2/of locus harbours a diabetogenic gene associated with obesity. We measured the expression of 60 genes in the Nidd2/of QTL region between the strains and found that the mRNA expression levels of five genes were significantly different between the strains under the condition of obesity. However, three of the five genes were differentially expressed in both obese and lean rats, indicating that these genes are not specific for the condition of obesity. Conversely, the other two genes, coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8), were differentially expressed only in the obese rats, suggesting that these two genes are candidates for the onset of type 2 diabetes associated with obesity in rats.

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References

  • Aitman TJ, Critser JK, Cuppen E, Dominiczak A, Fernandez-Suarez XM, Flint J, Gauguier D, Geurts AM, Gould M, Harris PC, Holmdahl R, Hubner N, Izsvak Z, Jacob HJ, Kuramoto T, Kwitek AE, Marrone A, Mashimo T, Moreno C, Mullins J, Mullins L, Olsson T, Pravenec M, Riley L, Saar K, Serikawa T, Shull JD, Szpirer C, Twigger SN, Voigt B, Worley K (2008) Progress and prospects in rat genetics: a community view. Nat Genet 40:516–522

    Article  CAS  PubMed  Google Scholar 

  • Amin MM, Asaad GF, Abdel Salam RM, El-Abhar HS, Arbid MS (2014) Novel CoQ10 antidiabetic mechanisms underlie its positive effect: modulation of insulin and adiponectine receptors, Tyrosine kinase, PI3 K, glucose transporters, sRAGE and visfatin in insulin resistant/diabetic rats. PLoS ONE 9:e89169

    Article  PubMed Central  PubMed  Google Scholar 

  • Collaboration TM-SAR (2013) Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med 369:233–244

    Article  Google Scholar 

  • Dupuis J, Siegmund D (1999) Statistical methods for mapping quantitative trait loci from a dense set of markers. Genetics 151:373–386

    PubMed Central  CAS  PubMed  Google Scholar 

  • Forsgren M, Attersand A, Lake S, Grunler J, Swiezewska E, Dallner G, Climent I (2004) Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ. Biochem J 382:519–526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Galaviz-Hernandez C, Stagg C, de Ridder G, Tanaka TS, Ko MS, Schlessinger D, Nagaraja R (2003) Plac8 and Plac9, novel placental-enriched genes identified through microarray analysis. Gene 309:81–89

    Article  CAS  PubMed  Google Scholar 

  • Grarup N, Sandholt CH, Hansen T, Pedersen O (2014) Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia 57:1528–1541

    Article  CAS  PubMed  Google Scholar 

  • Hertel JK, Johansson S, Raeder H, Midthjell K, Lyssenko V, Groop L, Molven A, Njolstad PR (2008) Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT study). Diabetologia 51:971–977

    Article  CAS  PubMed  Google Scholar 

  • Ishida K, Mizuno A, Murakami T, Shima K (1996) Obesity is necessary but not sufficient for the development of diabetes mellitus. Metabolism 45:1288–1295

    Article  CAS  PubMed  Google Scholar 

  • Jimenez-Preitner M, Berney X, Uldry M, Vitali A, Cinti S, Ledford JG, Thorens B (2011) Plac8 is an inducer of C/EBPbeta required for brown fat differentiation, thermoregulation, and control of body weight. Cell Metab 14:658–670

    Article  CAS  PubMed  Google Scholar 

  • Jimenez-Preitner M, Berney X, Thorens B (2012) Plac8 is required for white adipocyte differentiation in vitro and cell number control in vivo. PLoS ONE 7:e48767

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T (1992) Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41:1422–1428

    Article  CAS  PubMed  Google Scholar 

  • Kimber CH, Doney AS, Pearson ER, McCarthy MI, Hattersley AT, Leese GP, Morris AD, Palmer CN (2007) TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels. Diabetologia 50:1186–1191

    Article  CAS  PubMed  Google Scholar 

  • Kondrashov AS, Shabalina SA (2002) Classification of common conserved sequences in mammalian intergenic regions. Hum Mol Genet 11:669–674

    Article  CAS  PubMed  Google Scholar 

  • Kopelman PG (2000) Obesity as a medical problem. Nature 404:635–643

    CAS  PubMed  Google Scholar 

  • Kose H, Moralejo DH, Ogino T, Mizuno A, Yamada T, Matsumoto K (2002) Examination of OLETF-derived non-insulin-dependent diabetes mellitus QTL by construction of a series of congenic rats. Mamm Genome 13:558–562

    Article  CAS  PubMed  Google Scholar 

  • Kose H, Yamada T, Matsumoto K (2012) Single diabetic QTL derived from OLETF rat is a sufficient agent for severe diabetic phenotype in combination with leptin-signaling deficiency. Exp Diabetes Res 2012:858121

    Article  PubMed Central  PubMed  Google Scholar 

  • Kunitomo M, Yamaguchi Y, Kagota S, Otsubo K (2008) Beneficial effect of coenzyme Q10 on increased oxidative and nitrative stress and inflammation and individual metabolic components developing in a rat model of metabolic syndrome. J. Pharmacol. Sci. 107:128–137

    Article  CAS  PubMed  Google Scholar 

  • Ledford JG, Kovarova M, Koller BH (2007) Impaired host defense in mice lacking ONZIN. J. Immunol. 178:5132–5143

    Article  CAS  PubMed  Google Scholar 

  • Lopez-Martin JM, Salviati L, Trevisson E, Montini G, DiMauro S, Quinzii C, Hirano M, Rodriguez-Hernandez A, Cordero MD, Sanchez-Alcazar JA, Santos-Ocana C, Navas P (2007) Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet 16:1091–1097

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Moralejo DH, Wei S, Wei K, Weksler-Zangen S, Koike G, Jacob HJ, Hirashima T, Kawano K, Sugiura K, Sasaki Y, Ogino T, Yamada T, Matsumoto K (1998) Identification of quantitative trait loci for non-insulin-dependent diabetes mellitus that interact with body weight in the Otsuka Long-Evans Tokushima Fatty rat. Proc Assoc Am Physicians 110:545–558

    CAS  PubMed  Google Scholar 

  • Ohlsson R, Renkawitz R, Lobanenkov V (2001) CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet 17:520–527

    Article  CAS  PubMed  Google Scholar 

  • Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CJ, Hess JF (1996) Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 13:18–19

    Article  CAS  PubMed  Google Scholar 

  • Quinzii C, Naini A, Salviati L, Trevisson E, Navas P, Dimauro S, Hirano M (2006) A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 78:345–349

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rogulski K, Li Y, Rothermund K, Pu L, Watkins S, Yi F, Prochownik EV (2005) Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt-Mdm2-p53 pathway. Oncogene 24:7524–7541

    Article  CAS  PubMed  Google Scholar 

  • Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson Bostrom K, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336

    Article  CAS  PubMed  Google Scholar 

  • Singh RB, Niaz MA, Rastogi SS, Shukla PK, Thakur AS (1999) Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens 13:203–208

    Article  CAS  PubMed  Google Scholar 

  • Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS, Nica A, Wheeler E, Chen H, Voight BF, Taneera J, Kanoni S, Peden JF, Turrini F, Gustafsson S, Zabena C, Almgren P, Barker DJ, Barnes D, Dennison EM, Eriksson JG, Eriksson P, Eury E, Folkersen L, Fox CS, Frayling TM, Goel A, Gu HF, Horikoshi M, Isomaa B, Jackson AU, Jameson KA, Kajantie E, Kerr-Conte J, Kuulasmaa T, Kuusisto J, Loos RJ, Luan J, Makrilakis K, Manning AK, Martinez-Larrad MT, Narisu N, Nastase Mannila M, Ohrvik J, Osmond C, Pascoe L, Payne F, Sayer AA, Sennblad B, Silveira A, Stancakova A, Stirrups K, Swift AJ, Syvanen AC, Tuomi T, van ‘t Hooft FM, Walker M, Weedon MN, Xie W, Zethelius B, Ongen H, Malarstig A, Hopewell JC, Saleheen D, Chambers J, Parish S, Danesh J, Kooner J, Ostenson CG, Lind L, Cooper CC, Serrano-Rios M, Ferrannini E, Forsen TJ, Clarke R, Franzosi MG, Seedorf U, Watkins H, Froguel P, Johnson P, Deloukas P, Collins FS, Laakso M, Dermitzakis ET, Boehnke M, McCarthy MI, Wareham NJ, Groop L, Pattou F, Gloyn AL, Dedoussis GV, Lyssenko V, Meigs JB, Barroso I, Watanabe RM, Ingelsson E, Langenberg C, Hamsten A, Florez JC, (2011) Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes 60:2624–2634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sugiura K, Miyake T, Taniguchi Y, Yamada T, Moralejo DH, Wei S, Wei K, Sasaki Y, Matsumoto K (1999) Identification of novel non-insulin-dependent diabetes mellitus susceptibility loci in the Otsuka Long-Evans Tokushima fatty rat by MQM-mapping method. Mamm Genome 10:1126–1131

    Article  CAS  PubMed  Google Scholar 

  • Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc. Natl. Acad. Sci. U. S. A. 76:4350–4354

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Nojima K, Babaya N, Yamada K, Shibata M, Yamato E, Ogihara T (2000) Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse. Diabetologia 43:932–938

    Article  CAS  PubMed  Google Scholar 

  • Walley AJ, Jacobson P, Falchi M, Bottolo L, Andersson JC, Petretto E, Bonnefond A, Vaillant E, Lecoeur C, Vatin V, Jernas M, Balding D, Petteni M, Park YS, Aitman T, Richardson S, Sjostrom L, Carlsson LM, Froguel P (2012) Differential coexpression analysis of obesity-associated networks in human subcutaneous adipose tissue. Int. J. Obes. (Lond.) 36:137–147

    Article  CAS  Google Scholar 

  • Wei S, Wei K, Moralejo DH, Ogino T, Koike G, Jacob HJ, Sugiura K, Sasaki Y, Yamada T, Matsumoto K (1999) Mapping and characterization of quantitative trait loci for non-insulin-dependent diabetes mellitus with an improved genetic map in the Otsuka Long-Evans Tokushima fatty rat. Mamm Genome 10:249–258

    Article  CAS  PubMed  Google Scholar 

  • Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to thank Drs. Jyunichi Takahashi and Takakazu Kaneko (Faculty of Life Sciences, Kyoto Sangyo University) for helpful suggestions regarding DNA sequence techniques and rat genome informatics, respectively.

Author contribution

DS and KM designed the study, performed experiments, analysed data and the first draft of the manuscript. JK and RW performed the experiments or analysis and interpretation of data. KM is responsible for the integrity of the work as a whole.

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  1. Department of Animal Medical Sciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan

    Daiki Sasaki, Jun Kotoh, Risa Watadani & Kozo Matsumoto

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  1. Daiki Sasaki
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Correspondence to Kozo Matsumoto.

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Sasaki, D., Kotoh, J., Watadani, R. et al. New animal models reveal that coenzyme Q2 (Coq2) and placenta-specific 8 (Plac8) are candidate genes for the onset of type 2 diabetes associated with obesity in rats. Mamm Genome 26, 619–629 (2015). https://doi.org/10.1007/s00335-015-9597-4

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