ILAR Journal Online, Volume 32(3) 1990: New Rat Models of Obesity and Type Ii Diabetes

Online Issues

<< All Back-issues

<< This Issue's Table of Contents

ILAR Journal V32(3) 1990
New Rat Models of Obesity and Type II Diabetes

Development of Fatty and Corpulent Rat Strains
Dorothy D. Greenhouse, Carl T. Hansen, and Otho E. Michaelis

Dorothy D. Greenhouse is a senior program officer, Institute of Laboratory Animal Resources, National Research Council, Washington, D.C. Carl T. Hansen is a geneticist, Veterinary Resources Program, National Center for Research Resources, National Institutes of Health, Bethesda, Maryland. Otho E. Michaelis is a research biologist, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Maryland, and is also adjunct associate professor, Division of Renal Diseases, Department of Medicine, George Washington University, Washington, D.C.

Much of what we know about normal physiologic and pathologic processes has been learned by studying animal models, which provide systems in which basic cause-and-effect relationships can be explored. One effective model is an animal in which normal function has been altered by mutation, a spontaneous heritable change that results in some measurable change in the structure or function of an organism. The study of mutations can be enhanced by using breeding techniques designed to transfer a restricted region of the genome to different inbred strains (Green, 1966; NRC, 1989). The resulting congenic strains can then be used to examine the interaction between the mutant gene and its genetic background.

The papers that follow deal with two autosomal recessive mutations that cause obesity in the rat: fatty (fa) and corpulent (cp). Both mutations occurred spontaneously in outbred stocks and were subsequently backcrossed onto inbred strains. During this process, animals were distributed to the scientific community, often before backcrossing was completed. Although this has produced some interesting models, there is considerable confusion about the appropriate nomenclature. This paper briefly describes the development of these models and provides terminology that distinguishes between animals with similar origins but different characteristics. These names have been coordinated with the strains' developers and have been selected to fit with the developers' previously published work, as well as with the internationally accepted rules of standardized nomenclature for inbred (Greenhouse et al., in press) and outbred (Festing et al., 1972) rats. Figure 1 illustrates the development of each of these models.

Fatty

The mutation fatty (fa) arose spontaneously in an out-bred stock of rats designated 13M at the Laboratory of Comparative Pathology, Stow, Massachusetts (Zucker and Zucker, 1961). The fa gene was backcrossed onto out-bred Wistar stock obtained from Kyoto University by Dr. Hitoshi Ikeda, Takeda Chemical Industries, Ltd., Osaka, Japan (R. G. Peterson, Diabetes Research and Training Center, Indiana University School of Medicine, Indianapolis, personal communication). Following a combination of inbreeding and backcrossing, the stock was designated WDF/Ta-fa. Animals of this strain were sent to Indiana University Medical Center, Indianapolis, where an additional seven generations of inbreeding was completed before the WDF/TaDrt-fa colony was lost. Two other models were developed at Indiana using the fa gene (Peterson, personal communication). The gene was backcrossed onto WKY/N, and at N10F7, the model was sent to the National Institutes of Health (NIH). Inbreeding of "Zucker fatty rats" has also begun (F12), and the resulting partially inbred strain has been designated ZDF/Drt-fa.

Corpulent

The mutation corpulent (cp) arose spontaneously after several generations of selective inbreeding in a stock derived from an SHR/N female crossed with a male, normotensive SD (Sprague-Dawley®)¹ rat (Koletsky, 1973). Breeding stock of this model was eventually transferred to the NIH, where the mutation was backcrossed onto three strains: SHR, WKY, and LA.

The SHR rat was developed at Kyoto University from an outbred Wistar male with spontaneous hypertension and a female with slightly higher than normal blood pressure. Subsequent brother × sister pairs were selected for the presence of hypertension (Okamoto, 1969). At the thirteenth generation of inbreeding (Fl3), breeding stock was supplied to NIH (Hansen et al., 1982). The separation of this stock from the parental stock before F20 (the generation number at which inbreeding is considered complete) means a high probability of genetic differences between the two stocks. Since the offshoot retained the name SHR, it is critical that the substrain code N, which denotes the NIH, be used to distinguish it from other SHR sublines.

Two different models were developed from backcrossing the cp mutation onto the SHR/N strain. One of these was sent to Dr. Sylvia McCune, Ohio State University, Columbus, at backcross seven, and it developed several characteristics that are distinctly different from the true congenic strain SHR/N-cp (currently at N 18). Dr. McCune's model has been given the strain name SHHF/Mcc-cp (formerly called SHR/Mcc-cp).

Strain WKY/N (currently at FS0) was developed from outbred Wistar stock obtained in 1971 from the Kyoto School of Medicine, where it was used as the control for SHR (Hansen et al., 1982). The cp gene has been back-crossed onto this strain and is currently at backcross generation 12 (N12).

The third strain to which cp has been transferred is LA/ N, which was developed at NIH from a cross between ALB/N and a hooded stock of unknown origin (Hansen et al., 1982). Like the SHR corpulent, there are two distinct models for the LA corpulent. At backcross generation five (N5), the stock was distributed to Dr. James C. Russell, University of Alberta, Edmonton, where it has been maintained as an outbred stock. This stock has some distinct differences from the true congenic strain; therefore, in accordance with the rules of standardized nomenclature for outbred stocks (Festing et al., 1972), the name Jcr:LA-cp is used. LA/N-cp is currently at backcross generation 18 (N18).

Use of Standardized Nomenclature

The above discussion illustrates how confusion can arise when different stocks of animals are derived from the same background. This confusion can be easily avoided by using standardized nomenclature, which makes clear what the genetic characteristics of an animal are and enables investigators in separate laboratories to compare their results. Investigators needing assistance with nomenclature can contact the Institute of Laboratory Animal Resources, 2101 Constitution Avenue, Washington, DC 20418 (Phone: 202-334-2590; Fax: 202-334-1639).

References

Festing, M., K. Kondo, R. Loosli, S. M. Poiley, and A. Spiegel. 1972. International standardized nomenclature for outbred stocks of laboratory animals. ICLA Bull. 30:4-17. (Available from ILAR, National Research Council, 2101 Constitution Avenue, Washington, DC 20418).

Green, E.L. 1966. Breeding systems. Pp. 11-22 in Biology of the Laboratory Mouse, 2d ed., E. L. Green, ed. New York: McGraw-Hill.

Greenhouse, D. D., M. F. W. Festing, S. Hasan, and A. L. Cohen. In press. Inbred strains of rats. In Genetic Monitoring of Inbred Strains of Rats. A Manual on Colony Management, Basic Monitoring Techniques, and Genetic Variants of the Laboratory Rat, H. J. Hedrich, ed. Stuttgart: Gustav Fischer Verlag.

Hansen, C. T., S. Potkay, W. T. Watson, and R. A. Whitney, Jr. 1982. NIH Rodents: 1980 Catalogue. NIH Pub. No. 83-606. Washington, D.C., U.S. Department of Health and Human Services.

Koletsky, S. 1973. Obese spontaneously hypertensive rats--A model for study of atherosclerosis. Exp. Mol. Pathol. 19:53-60.

NRC (National Research Council). 1989. Mating systems for mutants. Pp. 155-160 in Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use. A report of the Institute of Laboratory Animal Resources Committee on Immunologically Compromised Rodents. Washington, D.C.: National Academy Press.

Okamoto, K. 1969. Spontaneous hypertension in rats. Int. Rev. Exp. Pathol. 7:227-270.

Zucker, L. M., and T. F. Zucker. 1961. Fatty, a new mutation in the rat. J. Hered. 52:275-278.

¹Sprague-Dawley® is a registered trademark of Harlan Sprague Dawley, Inc., Indianapolis, Indiana.

Figure 1 Development of Fatty and Corpulent Rat Strains