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

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

Zucker (fa/fa) Rat
Ruth Kava, M. R. C. Greenwood, and P. R. Johnson

Ruth Kava is assistant director, Obesity Research Center Animal Model Laboratory, Department of Biology, Vassar College, Poughkeepsie, New York. M. R. C. Greenwood is professor, Department of Nutrition, University of California, Davis. P. R. Johnson is professor and chair, Department of Biology, Vassar College.

Introduction

The Zucker (fa/fa) rat is the best-known and most widely used rat model of genetic obesity. In a recent extensive review of obesity research, Bray et al. (1989) cited over 700 references, 100 of which referred to experimental work using the Zucker fa/fa rat. To a much lesser extent, the Zucker rat has been used for investigations of obesity-associated NIDDM (non-insulin-dependent diabetes mellitus).

The fa mutation was discovered by Zucker and Zucker (1961, 1963) in crosses between Sherman and Merck stock M rats (13M strain). Animals homozygous for the fa allele became noticeably obese by 3 to 5 weeks of age, and by 14 weeks of age their body composition was over 40 percent lipid (Zucker and Antoniades, 1972). The obesity is inherited as a Mendelian recessive trait. Affected animals are hyperlipemic, hypercholesterolemic (Zucker and Zucker, 1962, 1963), and hyperinsulinemic (Zucker and Antoniades, 1972), and develop adipocyte hypertrophy and hyperplasia (Johnson et al., 1971).

During the late 1960s and early 1970s, Zucker rats derived from the original lineage maintained at the Harriet G. Bird Memorial Laboratory in Stow, Massachusetts, were provided to a number of laboratories in the United States, Europe, and Japan; in some cases secondary distributions were made to investigators at other institutions. For example, colonies of Zucker rats were established at Hoffman-LaRoche, Inc. (Triscari et al., 1981), University of California at Davis (Wickler et al., 1986), University of Geneva (Ionescu et al., 1985), Institut National de la Sante et de la Recherche Medicale (Planche et al., 1988), University of New Mexico (Hayek and Woodside, 1979), Pennsylvania State University (Martin et al., 1979), Rutgers University (Smith and Kaplan, 1980), and Vassar College. Breeding regimens are not known for most of these colonies; indeed, some colonies are no longer in existence. This review will focus on the colony at Vassar College, which has been the source of experimental animals for obesity researchers at a number of other laboratories. Also, since 1985, the Vassar facility has been the designated Animal Model Core Laboratory of the National Institutes of Health-supported Obesity Research Center. As such, it has supplied Zucker rats to over 50 investigators in the United States and Canada.

Vassar College Zucker Rat Colony

The Vassar colony was established by Patricia R. Johnson in 1974 from six pairs of heterozygous breeders supplied by the late Lois Zucker from the Bird Memorial Laboratory colony. Litters were produced by random pairings, with new breeders (+/?) being test crossed to known heterozygotes (+/fa) for identification of genotype. Initial attempts to breed obese (fa/fa) males met with limited success. However, it was found that many obese males, if food-restricted and given testosterone propionate injections, exhibited a greater propensity for mating and success at litter production (Hemmes et al., 1978). This treatment regimen was used from 1976-1978 on an ad hoc basis to increase the number of fa/fa males capable of breeding. Obese male breeders were thus selected on the basis of responsiveness to this treatment. By 1978, the restriction-injection regimen was discontinued, and obese male breeders were selected preferentially. At present, approximately 70 percent of obese males tested in this colony are willing breeders. Since 1988 all obese rats in the Vassar colony have been produced by breeding obese (fa/fa) males with heterozygous (+/fa) lean females. The two advantages of this system are (1) an increase in the theoretical percentage of obese animals in any litter and (2) the ability to identify positively all lean rats from such litters as heterozygotes without test matings. In all, over 7,500 litters have been produced in this colony since its inception.

Vassar Homozygous Lean (+/+) Zucker Colony

In 1978, in order to allow experiments to test gene dosage effects of the fa allele, Johnson and collaborators established a colony of homozygous lean (+/+) Zucker rats. Lean male and female rats of unknown genotype (+/ ?) were testcrossed with known lean heterozygotes (+/ fa). If two such matings resulted in litters with no obese offspring, then that test animal was presumed to be homozygous lean and was used for the lean colony. This colony has been maintained completely independently of the obese colony since its establishment; to date, over 2,300 litters have been produced. Thus, the Vassar facility is able to provide Zucker rats of both phenotypes and all three genotypes: homozygous obese (fa/fa), homozygous lean (+/+), and heterozygous lean (+/fa).

Both obese and lean colonies were originally propagated by random matings, and no rats from other colonies have been introduced. Thus, since their inception, the colonies have been closed and outbred. Since 1987, matings have been controlled such that members of each mated pair have no grandparents in common. Both colonies have been maintained in conventional housing.

Zucker Rat as a Model of Obesity

The most valuable contribution of the Zucker rat has been as a model of human early-onset, hyperplastic-hypertrophic obesity. Many investigators have used this model to study the development, etiology, associated pathologies, possible treatments, and putative mechanisms of its severe genetic obesity. A complete summary of this work, extending as it has over nearly three decades, is beyond the scope of this paper; the interested reader is referred to more extensive reviews by Bray and York (1971, 1979) and by Bray et al. (1989). Instead, we shall briefly summarize the characteristics of several of the most intensively investigated aspects of the Zucker rat's obesity, emphasizing work done with animals from the Vassar College colonies.

Food Intake

The obese Zucker rat is significantly hyperphagic compared to lean littermates as early as 17 days of age (Stem and Johnson, 1977) and is so particularly during periods of rapid growth--for example, the first 16 weeks of life (Vasselli et al., 1980). Pharmacological and dietary manipulations--e.g., naloxone (Thornhill et al., 1982), d-amphetamine and fenfluramine (Grinker et al., 1980), acarbose (Vasselli et al., 1983), cholecystokinin (Maggio et al., 1988), and replacement of dietary long-chain with medium-chain triglycerides (Turkenkopf et al., 1982)-succeed to varying extents in reducing or obliterating obese rats' hyperphagia. Jejunoileal bypass surgery, a treatment producing both decreased food intake and malabsorption of ingested nutrients, results in smaller, lighter fa/fa rats (Greenwood et al., 1982). However, in those studies in which it was assessed, such treatments do not normalize the obese body composition. Indeed, even lifelong food restriction, while decreasing body weight, results in obese rats whose body composition is approximately 50 percent lipid as compared to under 20 percent in lean littermates (Cleary et al., 1980). Clearly, the obese Zucker rat's hyperphagia is not necessary for expression of the obese syndrome.

Lipoprotein Lipase

The resistance to treatment of obesity in the Zucker fa/fa rat led investigators to search for metabolic or other correlates of the obese condition that might be candidates for the primary lesion produced by the presence of the fa gene. One of the earliest such correlates is the enhanced activity of adipose tissue lipoprotein lipase activity (AT-LPL), which is significantly correlated with enhanced triglyceride uptake by adipose tissue (Maggio and Greenwood, 1982). The activity of this enzyme, which controls lipid filling of adipocytes, is elevated as early as 12 days of age--well before Zucker rats can be visually identified as obese (Gruen et al., 1978). This elevated AT-LPL thus precedes other correlates of the obese Zucker rat's obesity, such as enhanced liver lipogenesis and hyperinsulinemia (Turkenkopf et al., 1980). AT-LPL, like the excessive carcass lipid deposition of the obese Zucker rat, is refractory to dietary (Cleary et al., 1980), surgical (Greenwood et Al., 1982), or hormonal treatment (Gray and Greenwood, 1984). Such data led Greenwood and collaborators (Greenwood and Vasselli, 1981; Greenwood et al., 1981; Greenwood, 1985) to propose the "LPL hypothesis," which suggests that the enhanced AT-LPL of the obese Zucker rat potentiates the animal's hyperphagia, leading to its gross hyperplastic-hypertrophic obesity. Both synthesis and degradation of the LPL enzyme are increased in the enlarged adipocytes from Zucker obese rats. However, these obese-lean differences are proportional to the increased cytoplasmic mass of the fat cells of obese animals and do not seem to be due to specific defects in LPL turnover (Fried et al., 1990).

Molecular Biology

Spiegelman and collaborators (Cook et al., 1987; Flier e/t al., 1987) identified a protein, adipsin, that is present in the serum of lean but not genetically obese (ob/ob) mice. The obese Zucker rat also exhibits reduced levels of serum adipsin as well as of adipose tissue adipsin mRNA. Adrenalectomy of obese rats restores the levels of both the circulating protein and the mRNA close to that seen in lean controls (P. R. Johnson, unpublished data; Ree et al., in press). At present, the normal physiological function of adipsin and the significance of its deficiency are unknown. Recently, however, Rosen et al. (1989) have demonstrated that adipsin has structural homologies and enzymatic activity similar to that of human complement factor D, which may indicate a link between obesity and the immune system.

CNS Involvement

Data suggest that the obese Zucker rat has profoundly abnormal brain neuropeptide physiology and that these abnormalities may show a fa gene-dosage effect. For example, both obese (fa/fa) and heterozygous lean (+/fa) Zucker rats have lower than normal brain insulin content when compared to homozygous lean (+/+) animals, particularly in the olfactory bulb (Baskin et al., 1985). Because insulin infusion into the third ventricle of the brain reduces food intake and body weight in +/fa Zucker rats, but not in the obese animals (Ikeda et al., 1986), it is possible that the obese rats are less sensitive to central insulin levels than are lean animals. Indeed, Latteman (1989) has reported reduced in vitro insulin sensitivity in the hippocampus of fa/fa and +/fa Zucker rats compared to that of +/+ animals.

Cell Culture

The Zucker fa/fa rat's obesity is, of course, expressed at the cellular as well as the organismal level, and alterations in growth and metabolism have been described in cell culture systems. Goldstein and collaborators (1980, 1981) found that lipogenesis and protein synthesis are depressed as is insulin responsiveness in primary cultures of fetal hepatocytes from obese compared to lean Zucker rats. Adipoblast cultures from obese Zucker rats also demonstrated decreased synthetic capacity and underwent a slower, more prolonged period of proliferation than did cultures from homozygous lean Zucker rats (Bourgeois et al., 1983; Goldstein et al., 1985). Turkenkopf et al. (1988) found that lean Zucker rat-derived stromal-vascular cells from the epididymal fat pad differentiated earlier than those from obese animals. In contrast, there was not a significant genotype effect on cells derived from the inguinal depot, thus suggesting regional specificity in the altered development conferred by the fa gene.

Zucker Rat as a Model of NIDDM

The Zucker rat has not been as extensively used as a model of human NIDDM as for genetic obesity. Most likely this is because, unlike the best-known genetically obese mice (the db/db and ob/ob mutants), most investigators have found that the Zucker fa/fa rat is relatively normoglycemic or shows only slightly elevated hyperglycemia (Bryce et al., 1977; Ionescu et al., 1985; Muller and Cleary, 1988; Stern et al., 1972; Zucker and Zucker, 1961). Only one laboratory has reported severe hyperglycemia in the Zucker rat (Clark et al., 1983), and these rats have been maintained as a separate substrain (Peterson et al., 1990). Although most investigators have reported abnormal glucose tolerance in the obese Zucker rat (e.g., Ionescu et al., 1985; Kava et al., 1989), Amy et al. (1988)--using animals from the University of British Columbia--found normal (compared to lean littermates) responses in plasma glucose after an oral glucose load in obese rats. However, obesity-associated pathologies reminiscent of those seen in human NIDDM are present in the obese Zucker and have been studied by several laboratories. Obese Zucker rats are hyperinsulinemic, both in the fed state and in response to oral glucose (Ionescu et al., 1985; Kava et al., 1989; Stern et al., 1972; York et al., 1972). Skeletal muscle of the Zucker fa/fa rat is highly insulin resistant (Smith and Czech, 1983), with depressed basal and insulin-stimulated glucose transport (Sherman et al., 1988). In addition, in vivo the obese Zucker rat exhibits severe hepatic as well as peripheral insulin resistance (Terretaz et al., 1986a,b).

Only recently have investigators examined the obese Zucker rat for diabetes-associated pathologies such as peripheral vascular disease. Lash et al. (1989) found moderate diabetes-like microvascular changes consisting of decreased plantar muscle capillary density and increased basement membrane thickness in obese compared to lean Zucker rats.

Summary

The Zucker fa/fa rat has proved to be an invaluable and extensively used resource for the investigation of numerous aspects of genetic obesity. Our knowledge and understanding of the etiology, pathology, and correlates of intractable obesity have benefited enormously during the last three decades from experimentation using this rat model of human obesity. Clearly, the Zucker fa/fa rat has been and is a model of great heuristic importance in this area of biomedical research.

The utility of the Zucker fa/fa rat as a model for human NIDDM is not as clear as its utility for obesity research. Although many of the obesity-associated pathologies of human NIDDM are also present in the obese Zucker rat, the variation in reported occurrence and levels of hyperglycemia and glucose intolerance may be problematic. For these reasons, it behooves the investigator to be aware of the important differences among various Zucker colonies. However, because human NIDDM is a diverse and progressive disorder, the Zucker fa/fa rat may well prove to be as valuable a model for human NIDDM as it has been for human genetic obesity.

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