The Rat Corpulent zyx (cp) Mutation Maps to the Same Interval on (Pgrnl-Glutl) Rat Chromosome 5 as the Fatty (fa) Mutation E. zyxwvutsrqpo Bowie Kahle, zyxwvuts * Kenneth G. Butz, * Streamson C. Chua, ** Erin E. Kershaw, ** Rudolph L. Leibel, ** Terry W. Fenger, * Carl T. Hansen, Otho E. Michaelis$§ Abstract SON C CHUA, ERIN E KERSHAW, RUDOLPH L LEIBEL, TERRY W FENGER, CARL T HANSEN, OTHO E MICHAELIS. The rat corpulent (cp) mutation maps to the same interval on (Pgml-Glutl) rat chromo- some 5 as the fatty (fa) mutation. Obes. Res. 1997;5:142- 145. The autosomal recessive obesity mutations fatty (fa) and corpulent (cp) arose in separate rat strains, 13M and Koletsky, respectively. By complementation analysis, the two mutations appear to be in the same gene. The some- what different phenotypes of zyxwvut falfa and cplcp animals probably reflect the fact that the mutations are segre- gating on different rat strains. The fa mutation has been mapped to the interval between Pgml and Glutl on rat Chr 5, but cp has not been mapped genetically. We mapped cp in 30 obese progeny of a LAIN-BN cpl+ in- tercross using microsatellite markers for these flanking genes. Cp maps to the same genetic interval as rat fa and mouse db. Cp is flanked by Glutl and Pgml: KAHLE, E BOWIE, KENNETH G BUTZ, STREAM- Pgml________ cp ________ Glutl map distance (cM) 1.67 6.67 Thus, cp and fa map to the same -8 cM interval of the rat genome. In conjunction with the complementation Submitted zyxwvutsrqponm for publication May 23, 1996. Accepted for publication July 22, 1996. From the *Departments of Biology and Microbiology, Marshall University, Hunting- ton, WV, **Laboratory of Human Behavior and Metabolism, The Rockefeller Uni- versity, New York, NY, tAnimal Genetic Resources, Division of Research Services, the National Institutes of Health, Bethesda, MD, tBeltsville Human Nutrition Re- search Center, Beltsville, MD. $Deceased date of death May 27, 1995. Reprint requests to E. Bowie Kahle, Ph.D., Department of Biology, Marshall Uni- versity, Huntington, WV 25755. Copyright zyxwvutsrqponm 0 1997 NAASO. studies alluded to above, these findings indicate that cp and fa are mutations in the same gene (Lepr). Key words: inherited, single-gene, obesity, genes Introduction Obese rodents are the most studied experimental mod- els for human genetic obesity. Six genetically and pheno- typically distinct single-gene obesity mutations have been identified in mice, diabetes (db), obese (ob), fat wit), agouti (A" and Ay), adipose (Ad), and tubby (tub) (7,8,10). The physiology of obesity has been intensively studied in two autosomal recessive mutations in the rat, fatty (fa) (32) and corpulent (cp) (12,19). Thefu mutation in the rat arose spontaneously in 1961 and showed strong phenotypic similarities to the db and ob mouse mutations (32). It has been shown thatfu and db are mutations in the leptin receptor (Lepr) (4,5,5a,13,20,23,26). Studies showed that the Zucker fatty is hyperinsulinemic with normal blood glucose levels (33) and develops adipo- cyte hypertrophy and hyperplasia (15). During the interven- ing quarter century thefu animal was among the most stud- ied experimental models for human obesities. The cp mu- tation arose spontaneously in Koletsky's hypertensive rat strain (19) and the mutation was introgressed into the LAB and SHR/N strains developed at National Institutes of Health (NIH) (12). Rat strains carrying the cp mutation served as useful experimental models for disorders of car- bohydrate utilization (9,17,21). The obese LAIN-cp rat ex- hibited metabolic characteristics associated with type IV hyperlipoproteinemia (carbohydrate sensitivity) in humans (24,25), including normoglycemia or mild hyperglycemia and basal hyperinsulinemia. Breeding of Zucker rats segregating forfu mutation and Koletsky rats segregating for cp mutation have produced obese F, progeny in a 3:l lean/obese ratio (31). In recent complemention studies, we also have produced obese, ap- 142 OBESITY RESEARCH zyxwvutsr Vol. zyxwvuts 5 No. 2 Mar. 1997