Genetic background (DDD/Sgn versus C57BL/6J) strongly influences postnatal growth of male mice carrying the Ay allele at the agouti locus: identification of quantitative trait loci associated with diabetes and body weight loss

BMC Genetics

Kunio Satou¹  Jun-ichi Suto² 

[1]Viral Disease and Epidemiology Research Division, National Institute of Animal Health, Tsukuba, Ibaraki 305-0856, Japan

[2]Agrogenomics Research Center, National Institute of Agrobiological Sciences, Tsukuba, Ibaraki 305-8634, Japan

关键词: Quantitative trait locus (QTL);    Growth analysis;    Diabetes mellitus;    DDD mice;    Body weight loss;    A^y allele;   

Others  :  1087166
DOI  :  10.1186/1471-2156-14-35

 received in 2012-11-16, accepted in 2013-04-23,  发布年份 2013

【 摘 要 】

Background

Mice carrying the A^y allele at the agouti locus become obese and are heavier than their non-A^y littermates. However, this does not hold true for the genetic background of the DDD mouse strain. At 22 weeks of age, DDD.Cg-A^y females are heavier than DDD females, whereas DDD.Cg-A^y males are lighter than DDD males. This study aimed to determine the possible cause and identify the genes responsible for the lower body weight of DDD.Cg-A^y males.

Results

Growth curves of DDD.Cg-A^y mice were analyzed and compared with those of B6.Cg-A^y mice from 5 to 25 weeks. In DDD.Cg-A^y males, body weight gain stopped between 16 and 17 weeks and the body weight gradually decreased; thus, the lower body weight was a consequence of body weight loss. Quantitative trait locus (QTL) mapping was performed in backcrossed (BC) males of DDD × (B6 × DDD.Cg-A^y) F₁-A^y mice. For the body weight at 25 weeks, significant QTLs were identified on chromosomes 1 and 4. The DDD allele was associated with a lower body weight at both loci. In particular, the QTL on chromosome 4 interacted with the A^y allele. Furthermore, suggestive QTLs for plasma glucose and high molecular weight adiponectin levels were coincidentally mapped to chromosome 4. The DDD allele was associated with increased glucose and decreased adiponectin levels. When the body weight at 25 weeks and plasma glucose levels were considered as dependent and independent variables, respectively, BC A^y males were classified into two groups according to statistical analysis using the partition method. Mice of one group had significantly higher glucose and lower adiponectin levels than those of the other group and exhibited body weight loss as observed with DDD-A^y males.

Conclusions

The lower body weight of DDD.Cg-A^y male mice was a consequence of body weight loss. Diabetes mellitus has been suggested to be a possible contributory factor causing body weight loss. The QTL on distal chromosome 4 contained the major responsible genes. This QTL interacted with the A^y allele, implying the reason why body weight loss occurs in DDD.Cg-A^y but not in DDD males.

【 授权许可】

   
2013 Suto and Satou; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 11.

Figure 12.

Figure 13.

Figure 14.

Figure 1.

【 参考文献 】

• [1]Leibel RL, Chung WK, Chua SC Jr: The molecular genetics of rodent single gene obesities. J Biol Chem 1997, 272:31937-31940.
• [2]Bultman SJ, Michaud EJ, Woychik RP: Molecular characterization of the mouse agouti locus. Cell 1992, 71:1195-1204.
• [3]Miller MW, Duhl DM, Vrieling H, Cordes SP, Ollmann MM, Winkes BM, Barsh GS: Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev 1993, 7:454-467.
• [4]Robbins LS, Nadeau JH, Johnson KR, Kelly MA, Roselli-Rehfuss L, Baack E, Mountjoy KG, Cone RD: Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 1993, 72:827-834.
• [5]Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RO, Wilkison WO, Cone RD: Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994, 371:799-802.
• [6]Duhl DM, Vrieling H, Miller KA, Wolff GL, Barsh GS: Neomorphic agouti mutations in obese yellow mice. Nat Genet 1994, 8:59-65.
• [7]Michaud EJ, Bultman SJ, Stubbs LJ, Woychik RP: The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dev 1993, 7:1203-1213.
• [8]Michaud EJ, Bultman SJ, Klebig ML, van Vugt MJ, Stubbs LJ, Russell LB, Woychik RP: A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. Proc Natl Acad Sci USA 1994, 91:2562-2566.
• [9]Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH: Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 2000, 26:97-102.
• [10]Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F: Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997, 88:131-141.
• [11]Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS: Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997, 278:135-138.
• [12]Suto J: The Ay allele at the agouti locus reduces the size and alters the shape of the mandible in mice. Proc Jpn Acad Ser B 2009, 85:248-257.
• [13]Suto J: Quantitative trait loci that control body weight and obesity in an F2 intercross between C57BL/6J and DDD.Cg-Ay mice. J Vet Med Sci 2011, 73:907-915.
• [14]Lindsey JK: Growth curves. In Statistical analysis of stochastic processes in time. Edited by Gill R, Ripley BD, Ross S, Silverman BW, Stein M. Cambridge, UK: Cambridge university press; 2004:268-284.
• [15]Nawata K, Matsubara M: Regression analysis for economical analysis. In Statistical methods for the social and behavioral sciences (Basic statistics II). Tokyo, Japan: University of Tokyo press; 1994:155-200. (in Japanese)
• [16]Broman KW, Sen Ś: A guide to QTL mapping with R/qtl. New York: Springer; 2009.
• [17]Broman KW, Wu H, Sen Ś, Churchill GA: R/qtl: QTL mapping in experimental crosses. Bioinformatics 2003, 19:889-890.
• [18]Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241-247.
• [19]Vogel H, Scherneck S, Kanzleiter T, Benz V, Kluge R, Stadion M, Kryvych S, Blüher M, Klöting N, Joost H-G, Schürmann A: Loss of function of Ifi202b by a microdeletion on chromosome 1 of C57BL/6J mice suppresses 11ß-hydroxysteroid dehydrogenase type 1 expression and development of obesity. Hum Mol Genet 2012, 21:3845-3857.
• [20]Scherneck S, Nestler M, Vogel H, Blüher M, Block MD, Diaz MB, Herzig S, Schulz N, Teichert M, Tischer S, Al-Hasani H, Kluge R, Schürmann A, Joost HG: Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL. PLoS Genet 2009, 5:e1000541.
• [21]Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001, 7:941-946.
• [22]Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated kinase. Nat Med 2008, 8:1288-1295.
• [23]Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Froguel P, Nagai R, Kimura S, Kadowaki T, Noda T: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002, 277:25863-25866.
• [24]Nakajima Y, Imamura K, Onodera T, Goto N: Hydronephrosis in the inbred mouse strain DDD. Lab Anim 1983, 17:143-147.
• [25]Goto N, Nakajima Y, Onodera T, Imamura K: Inheritance of hydronephrosis in the inbred mouse strain DDD. Lab Anim 1984, 18:22-25.
• [26]Vogel H, Nestler M, Rüschendorf F, Block M-D, Tischer S, Kluge R, Schürmann A, Joost H-G, Scherneck S: Characterization of Nob3, a major quantitative trait locus for obesity and hyperglycemia on mouse chromosome 1. Physiol Genomics 2009, 38:226-232.
• [27]Plum L, Kluge R, Giesen K, Altmüller J, Ortlepp JR, Joost HG: Type 2 diabetes-like hyperglycemia in a backcross model of NZO and SJL mice. Diabetes 2000, 49:1590-1596.
• [28]Scherneck S, Vogel H, Nestler M, Kluge R, Schürmann A, Joost HG: Role of zinc finger transcription factor Zfp69 in body fat storage and diabetes susceptibility of mice. Results Prob Cell Differ 2010, 52:57-68.
• [29]Córdoba-Chacón J, Gahete MD, Pozo-Salas AI, Martínez-Fuentes AJ, de Lecea L, Gracia-Navarro F, Kineman RD, Castaño JP, Luque RM: Cortistatin is not a somatostatin analogue but stimulates prolactin release and inhibits GH and ACTH in a gender-dependent fashion: potential role of ghrelin. Endocrinology 2011, 152:4800-4812.
• [30]Semjonous NM, Sherlock M, Jeyasuria P, Parker KL, Walker EA, Stewart PM, Lavery GG: Hexose-6-phosphate dehydrogenase contributes to skeletal muscle homeostasis independent of 11ß-hydroxysteroid dehydrogenase type 1. Endocrinology 2011, 152:93-102.
• [31]Hummel KP, Coleman DL, Lane PW: The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL/KsJ and C57BL/6J strains. Biochem Genet 1972, 7:1-13.
• [32]Coleman DL, Hummel KP: The influence of genetic background on the expression of the obese (ob) gene in the mouse. Diabetologia 1973, 9:287-293.
• [33]Coleman DL: Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978, 14:141-148.
• [34]Stoehr JP, Nadler ST, Schueler KL, Rabaglia ME, Yandell BS, Metz SA, Attie AD: Genetic obesity unmasks nonlinear interactions between murine type 2 diabetes susceptibility loci. Diabetes 2000, 49:1946-1954.
• [35]Qiu J, Ogus S, Mounzih K, Ewart-Toland A, Chehab FF: Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes. Endocrinology 2001, 142:3421-3425.
• [36]Haluzik M, Colombo C, Gavrilova O, Chua S, Wolf N, Chen M, Stannard B, Dietz KR, Le Roith D, Reitman ML: Genetic background (C57BL/6J Versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology 2004, 145:3258-3264.