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ILAR Journal V32(3) 1990
New Rat Models of Obesity and Type II Diabetes
Orien L. Tulp
| Orien L. Tulp is professor of nutrition science, Department of Nutrition and Food Sciences, College of Science, Drexel University. |
Introduction
Obesity is prevalent in Westernized society, typically affecting more than one-fourth of the adult population. It is generally recognized that obesity may develop in mammalian species as a result of increased energy intake, decreased energy expenditure, genetic factors, or some combination of these factors (Bouchard, 1989; Sims, 1989; Stunkard, 1988).
Obesity occurs in the LA/N-cp (cp/cp) and related corpulent strains as a result of an autosomal recessive trait (cp) originally derived from the Koletsky rat and becomes visibly evident in approximately one-fourth of the offspring of heterozygous breeding pairs by 5 to 6 weeks of age (Hansen, 1988). Although the biochemical mechanisms that cause obesity in corpulent rats are unclear, these rats exhibit impairments in thyroidal and neuronal components of energy expenditure early in life similar to those thought to occur in humans (Bessard et al., 1983; Danforth, 1985; Danforth et al., 1979; Ravussin et al., 1985; Schutz et al., 1984; Sims, 1989; Trayburn, 1989; Tulp, 1984; Tulp et al., 1986, 1989). In addition to marked adiposity, the obese phenotype exhibits hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia, insulin resistance, and an impaired glucose tolerance when compared to their lean littermates (Michaelis et al., 1983, 1986). In the SHR/N-cp and WKY/N-cp strains, the impaired glucose tolerance progresses to non-insulin-dependent diabetes mellitus, while LA/N-cp rats remain moderately glucose intolerant but nondiabetic throughout life (Michaelis et al., 1989). The obese phenotypes of all three strains are hyperphagic from an early age. However, this may not be true hyperphagia because the food intake is only moderately elevated when expressed as a function of body weight (Carswell et al., 1989).
The purpose of this paper is to summarize our studies on the parameters of energy expenditure, obesity, and longevity in the LA/N-cp rat. These studies provide an insight into the biochemical and physiologic mechanisms of obesity in this rat model.
The LA/N//Tul-cp rat strain maintained at Drexel University was obtained in 1981 from the twelfth back-cross of original breeding stock provided by C. T. Hansen, Veterinary Resources Branch, National Institutes of Health, and has been maintained under conditions of geographic isolation as a closed outbred, pathogen-free strain in the Department of Nutrition Laboratories, Drexel University. Under these conditions, both lean and obese LA/N-cp rats typically survive for over 2 years (Figure 1) when fed ad libitum.
Growth, Body Weights, and Longevity of Corpulent Rats
When fed normally, obese LA/N-cp rats of both sexes gain weight approximately twice as rapidly as their lean (+/+; +/cp) littermates after weaning, and they remain twice as heavy throughout life (Figure 1). Maximum body weight of both sexes occurs late in the first year of life and remains relatively stable in obese males until 18 months of age and in obese females until 24 months of age, after which it declines gradually in both sexes. Lean females attain stable weights by 6 months of age, remain weight stable until 24 months of age, when many increase in weight gradually to 300 g or more. In contrast, lean males attain maximum stable weights by 9 months of age and remain weight stable until 30 months of age, at which time they begin gradually to lose weight.
Michaelis and coworkers (1983, 1986) have shown that weight gain may be further exaggerated in the obese phenotype of this strain when the animals are fed semipurified diets containing greater proportions of sucrose and total fat. Tulp et al. (1984) and Tulp and Sheilds (1984) reported that the weight gain of obese LA/N-cp rats over a 4-month period was significantly exaggerated following a high-energy mixed cafeteria diet. In those studies, the total weight gains of the cafeteria-fed animals averaged four times that gained by their normally fed lean litter-mates and were twice that gained by their cafeteria-fed lean littermates during the same period. More recently, when carbohydrate overnutrition was induced in lean and obese LA/N-cp rats from 8 weeks of age with supplements of sucrose or partially hydrolyzed cornstarch in the drinking water, obese rats gained rapidly (O. L. Tulp, N. L. Young, and P. McClellan, Drexel University, unpublished data, 1990). Excessive gain in lean animals was minimal or absent despite large (> 25 percent) increases in caloric intake in both phenotypes with both regimens. Thus, it would appear that the macronutrient composition of the diet is an important contributor to excess weight gain in corpulent rats. The obese phenotype gained weight more efficiently when overfed both mixed and carbohydrate-enriched diets, while the lean phenotype of this strain is considerably more resistant to excess weight gain with either dietary regimen.
Although the capacity to lay down body fat efficiently has been considered a survival attribute in some species, the development of severe obesity, as occurs in the corpulent rat, appears to decrease longevity. There are limited data regarding survival or longevity of the obese phenotype of the LA/N-cp strain beyond 2 years of age, since only one-fourth of the offspring become obese, and because virtually all of the obese offspring from this colony have been assigned to experimental studies by 6 weeks of age. Rats of the corpulent phenotype of the LA/N-cp strain lived 2.5-3 years, while rats of the lean phenotype lived 3-3.5 years.
Adipose Cellularity, Lipoprotein Lipase, and Body Composition of Corpulent Rats
Greenwood and Hirsch (1974) first demonstrated that in normally fed SD rats most adipocyte proliferation occurred prior to and in the early weeks following weaning, while lipid filling of mature adipocytes could continue well into adulthood. Early caloric restriction resulted in a delay in the formation and lipid filling of adipocytes, and refeeding resulted in a partial recovery of adipocyte number and full recovery of adipocyte size (Tulp et al., 1979a; Tulp and Horton, 1981). In obese LA/N-cp rats, adipocyte proliferation would appear to continue well into adulthood, resulting in marked increases in adipocyte number in all principal depots in adult animals by 15 weeks of age (Tables 1 and 2). Adipocyte lipid content increased significantly with increasing age in all depots, attaining maximal cell sizes of approximately 1mg of lipid per cell for most rats in most adipose depots (Table 2).
Adipose tissue lipoprotein lipase activity (LPL) of 4-month-old rats (Table 2) was greater in obese than in lean animals in dorsal adipose depots and modestly greater in epididymal depots. In contrast, LPL activity of 9-month-old weight-stable rats was similar in both depots studied in both phenotypes.
Carcass composition differed markedly between the lean and obese phenotype (Table 3). Carcass fat content of adult LA/N-cp rats was significantly greater in the obese than in the lean phenotype whether expressed as a percentage of body weight or as grams of lipid per carcass. Lean tissue mass of obese LA/N-cp rats was also greater than that of their lean littermates, while linear dimensions were similar in both phenotypes.
Energy Expenditure in Corpulent Rats
The development and expression of nonshivering thermogenesis requires autonomic, thyroidal, and insulinogenic actions and is a normal component of the adaptive responses to diet and environment (Diamond and LeBlanc, 1987; Himms-Hagen, 1985; Rothwell and Stock, 1979; Sims, 1989; Tulp et al., 1979b, 1982). The capacity for nonshivering thermogenesis is decreased in both obese humans (Schutz et al., 1984) and obese animals (Bray, 1969; Thurlby and Trayhurn, 1979; Young et al., 1980). Measures of resting thermogenesis were made via indirect calorimetry (Stock, 1975) in groups of lean and corpulent rats under a variety of experimental conditions. Resting oxygen consumption under conditions of thermal neutrality (30° C) was consistently greater in lean than in obese rats at a variety of ages encompassing much of adulthood (Figure 2A). Moreover, factors of sympathomimetic challenge with norepinephrine and isoproterenol (Figure 2B), feeding of chow and carbohydrate meals (Figure 2C), and of the thermic exposure to a cold challenge (Figure 2D) also produced significantly greater responses in lean than in obese animals, which is consistent with an impairment in the capacity for expression of nonshivering thermogenesis. In contrast, thermogenically maximal doses of ephedrine and caffeine (Figure 2B) resulted in similar responses in both phenotypes, which suggests that a functional defect in the thermogenic mechanism of brown adipocytes may be located proximal to the biochemical thermogenic component of the end-organ system (Tulp and Buck, 1987; Tulp et al., 1989).
The conversion of thyroxine to the thermogenically and physiologically more active hormone triiodothyronine via thyroxine (T4) 5'-deiodinase (EC 3.8.1.4) in peripheral tissues is a fundamental component of the normal adaptive response to diet and environment, where it is an essential element of the metabolic adaptation. The enzyme occurs in at least two forms in different tissues, one of which is at least partially dependent upon insulin for its activity (Gavin et al., 1981). The T3 generated via extrathyroidal deiodination exerts numerous calorigenic actions in peripheral tissues, including effects on glucose uptake and metabolism and on protein synthesis and degradation.
Measures of circulating T3 were greater in lean than in obese animals (Figure 3), and failed to increase in obese rats following cafeteria feeding or the feeding of protein-restricted diets (Tulp, 1988). The decreases in circulating T3 are presumed to be at least partially reflective of a decreased capacity for the generation of T3 from T4 in peripheral tissues. The activity of hepatic T4-5'-deiodinase activity has been reported to show a reciprocal relationship to an animal's predisposition toward the development of obesity, being greater in lean than in obese rats (McIntosh et al., 1989). Deiodinase activity tended to be greater in lean than in six-week-old pre-obese rats in liver, kidney, and gastrocnemius muscle, but basal deiodinase activity in 6-week-old pre-obese rats was greater in interscapular brown adipose tissue (Figure 3). Brown adipose tissue is the only tissue of homeotherms whose primary function is the generation of heat (Hahn and Novak, 1975) and has been identified as the primary tissue responsible for much of the extra heat production following dietary and environmental (cold) stimuli (Hahn and Novak, 1975; Rothwell and Stock, 1979). Obese LA/N-cp rats had greater amounts of brown adipose tissue of relatively normal morphology (Table 1; Tulp et al., 1989), and basal deiodinase activity was markedly elevated in that tissue, which suggests that the greater deiodinase activity may have been a compensatory response to the lower deiodinase activity of other tissues. Sundin (1981) has proposed that the sympathetic and thyroidal components of thermogenesis generally exert complementary and often reciprocal actions on the capacity for energy expenditure. Thus, the total heat production of an organism may fall within a physiologic range compatible with survival under normal conditions of diet and environment, and may be inadequate only during periods of acute thermogenic stress. Because of the calorigenic actions of T3 on tissues, diminished deiodinase activity in peripheral tissues is likely to result in decreased energy requirements and may thereby contribute to the greater efficiency of energy conservation and fat accretion in the obese phenotype.
Several authors (Glick et al., 1985; Trayhurn, 1989) have reported increases in deiodinase activity of brown adipose tissue in normally lean animals following both acute and chronic carbohydrate feeding (Tulp et al., 1988a). Kates and Himms-Hagen (1985) have shown that 14 hours of 4° C acute cold exposure results in marked stimulation of IBAT T4-5'-deiodinase activity in lean but not in obese (ob/ob) mice. Although the character of deiodinase activity of peripheral tissues of LA/N-cp rats during conditions of acute thermogenic stress has not been determined, it is presumed to be compromised in the obese phenotype, since circulating T3 concentrations do not increase following the feeding of cafeteria diets or protein-restricted, high-carbohydrate diets (Tulp, 1988) and following 3 hours of acute cold exposure (Byar and Tulp, 1988). The alterations in basal deiodinase activity would appear to be at least in part secondary to insulin resistance (Tulp et al., 1988b). The resting metabolic rates (RMRs), serum T3 concentrations, and T4-5'-deiodinase activity of gastrocnemius muscle and IBAT of obese LA/N-cp rats were normalized following bilateral adrenalectomy (McKee and Tulp, 1986; Tulp et al., 1988b). Adrenalectomized pre-obese LA/N-cp rats maintained normal weight gain and adiposity when fed a stock diet, but gained weight more rapidly than their lean littermates when fed a cafeteria diet (Tulp et al., 1988b).
In terms of energy expenditure, protein synthesis (at 29.2 kcals/mole of peptide bonds) in the lean tissues of an animal may represent the most biochemically expensive process mammalian cells undertake (Waterlow et al., 1981). In mammalian organisms, numerous hormonal and metabolic factors affect the rates and efficiency of protein synthesis and degradation. Intracellularly, excess T3 and glucocorticoids contribute to proteolysis and thus augment the intracellular free amino acid pool generated by the degradative processes. The hormonal actions therefore influence the intracellular availability of limiting amino acids for processes of protein synthesis and resynthesis. In contrast, insulin may promote both amino acid uptake and protein synthesis, thus countering the hormonally mediated proteolytic actions and helping to preserve nitrogen balance. These hormonal actions on protein metabolism can make a significant contribution to the economy of amino nitrogen balance in the organism, with a corresponding economy of energy requirements.
Protein synthesis was measured in vitro via incorporation of 14C-phenylalanine into muscle tissue, and proteolysis via the simultaneous release of tyrosine from the same muscle preparation (Fulks et al., 1975). Protein synthesis and degradation in 6-week-old pre-obese male rats averaged 20 percent less than in their lean littermates (Figure 4), which could result in a significant decrease in maintenance energy requirements and allow a greater proportion of available energy for lipid deposition and storage. Thus, the excess energy deposition in the obese phenotype of this strain may be at least in part a consequence of energy conservation from decreased protein turnover. When protein-restricted diets were fed to obese Zucker and corpulent rats, growth occurred normally, while growth of similarly fed lean littermates was stunted, a finding consistent with the decreased rates of protein turnover observed in this and other studies of obese rats (Durbin-Nalchayan et al., 1983; Tulp, 1988; Young et al., 1980). The extent to which insulin resistance may contribute to decreased protein requirements is unclear, but it is likely to be implicated in the process because of the role of insulin in the intracellular regulation of T4-5'-deiodinase activity and of intracellular T3 generation and proteolysis, in concert with other factors.
On the basis of available data, the LA/N-cp rat is an excellent model for the study of obesity. The animals are available as a congenic, pathogen-free model with an apparent longevity that is substantially greater than has been reported with other obese rat models. Obese rats of both sexes have survived more than 3 years in the Drexel colony, and lean animals have lived to nearly 4 years of age without special treatments or precautions, other than an isolated, climate-controlled environment. Moreover, the characteristic parameters of obesity and energy expenditure are similar to those in obese humans. The obesity is characterized by marked increases in adipocyte lipid content and adipocyte number in all principal depots and in a significant elevation of total carcass fat. The obesity is associated with a preservation or modest hypertrophy of the lean body mass. As in obese humans, the obesity occurs in association with elevations in serum lipids (Michaelis et al., 1983; Tulp et al., 1984), impaired glucose tolerance (Michaelis et al., 1986), abnormalities in peripheral thyroid hormone metabolism (Tulp and McKee, 1986), and an impaired capacity for nonshivering thermogenesis (Tulp, 1984). Reversal of the insulin-resistant state via bilateral adrenalectomy results in a return toward normal of most parameters of obesity, but does not eliminate the causative trait (McKee and Tulp, 1986; Tulp et al., 1988b).
Although longevity in the obese phenotype needs to be more fully characterized, the presence of obesity in the cp/cp genotype of this strain appears to decrease longevity. In very long-term studies, some considerations in experimental design and data interpretation may be necessary to allow for this factor. The major limitation of the model is that it is difficult to propagate because obese animals typically do not mate or reproduce. This makes colony maintenance labor intensive and limits the number of obese offspring to one-fourth of the animals. Additionally, although obese animals are homozygous for the corpulent trait (cp/cp), two-thirds of the lean animals are heterozygous for the trait (cp/+), and only one-third are homozygous normal (+/+). Should there be differences in the genetic predisposition for secondary traits associated with the lean phenotype, they are likely to be more variable among the lean animals than among the obese. Thus, although this model offers many advantages for the study of mechanisms of obesity and energy metabolism, additional investigation of reproductive endocrinology and of gene dosing effects on a variety of metabolic parameters is needed.
Acknowledgments
The author wishes to acknowledge the institutional assistance of Colby College, Waterville, Maine, where the colony was housed from 1981-1983, and of the Department of Nutrition and Food Sciences, Drexel University, where the colony has been housed since 1983, and numerous students from the two institutions who have participated in various aspects of these studies. The studies cited and included in this manuscript were supported in part by grants-in-aid and support-in-kind from numerous organizations, including the American Heart Association; Miles Laboratories; Best Foods, a Division of CPC International; Wyeth Laboratories; the Agricultural Research Service of the U.S. Department of Agriculture; and the Veterinary Resources Branch, National Institutes of Health.
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TABLE 1 Fat Pad Weights of Corpulent Rats
| Grams/Depot | |||||
| Phenotype | Dorsal | Epididymal | Retroperitoneal | IBATa | IBAT:BW x 10-2b |
| Lean | 0.55 ± 0.12 | 0.21 ± 0.04 | 0.44 ± 0.06 | 0.29 ± 0.03 | 1.84 ± 0.19 |
| Corpulent | 3.40 ± 0.37 | 1.32 ± 0.13 | 1.25 ± 0.15 | 0.69 ± 0.04 | 3.09 ± 0.03 |
| p = | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 |
| Lean | 0.70 ± 0.10 | 3.3 ± 0.20 | 2.5 ± 0.02 | 0.46 ± 0.02 | 1.44 ± 0.10 |
| Corpulent | 14.60 ± 1.1 | 16.6 ± 0.60 | 19.1 ± 1.1 | 1.40 ± 0.22 | 2.47 ± 0.02 |
| p = | <0.001 | <0.001 | <0.001 | <0.001 | <0.05 |
| Lean | --- | 2.80 ± 0.28 | 4.32 ± 0.67 | 0.60 ± 0.06 | 0.18 ± 0.01 |
| Corpulent | --- | 21.01 ± 0.72 | 65.32 ± 11.41 | 1.54 ± 0.09 | 1.24 ± 0.01 |
| p = | --- | <0.05 | <0.001 | <0.05 | <0.01 |
NOTE: Data are mean ± 1 SEM, N = 6 male rats per group; p determined by unpaired t-test.
aIBAT, interscapular brown adipose tissue.
bBW, body weight.
SOURCE: Data were obtained from LA/N-cp rats fed Purina Chow #5001 from weaning to 1.5 months of age, and a semipurified diet thereafter (Michaelis et al., 1986).
TABLE 2 Adipose Cellularity and Lipoprotein Lipase Activity of Corpulent Rats
| Dorsal Depot | Epididymal Depot | Retroperitoneal Depot | ||||
| Phenotype | Cells/Depot | mg Lipid/Cell | Cells/Depot | mg Lipid/Cell | Cells/Depot | mg Lipid/Cell |
| Lean | 2.8 ± 0.6 | 0.164 ± 0.052 | 4.0 ± 0.6 | 0.013 ± 0.010 | 1.8 ± 0.1 | 0.126 ± 0.062 |
| Corpulent | 8.9 ± 0.4 | 0.235 ± 0.014 | 4.7 ± 0.4 | 0.195 ± 0.013 | 4.2 ± 0.6 | 0.319 ± 0.060 |
| p = | N.S. | N.S. | <0.05 | <0.05 | <0.05 | <0.05 |
| Age 3.5 months | ||||||
| Lean | 2.8 ± 0.4 | 0.156 ± 0.012 | 7.5 ± 1.0 | 0.343 ± 0.018 | 7.5 ± 0.9 | 0.259 ± 0.021 |
| Corpulent | 10.5 ± 2.4 | 0.553 ± 0.050 | 13.9 ± 3.2 | 0.570 ± 0.101 | 13.9 ± 2.7 | 0.629 ± 0.048 |
| p = | <0.01 | <0.05 | <0.05 | <0.05 | <0.05 | <0.05 |
| Age 10.5 months | ||||||
| Lean | --- | 0.120 ± 0.015 | 9.1 ± 0.8 | 0.248 ± 0.030 | 9.1 ± 0.9 | 0.508 ± 0.10 |
| Obese | --- | 0.631 ± 0.055 | 19.3 ± 0.5 | 0.789 ± 0.075 | 48.5 ± 1.3 | 1.155 ± 0.03 |
| p = | <0.05 | <0.05 | N.S. | <0.01 | <0.05 | |
| Lean | 2.58 ± 1.06 | 7.07 ± 0.82 | ||||
| Corpulent | 10.02 ± 2.42 | 9.02 ± 0.65 | ||||
| p = | <0.01 | <0.10 | ||||
| Lean | 3.81 ± 0.6 | 2.35 ± 0.52 | ||||
| Obese | 2.52 ± 0.4 | 1.94 ± 0.50 | ||||
| p = | N.S. | N.S. | ||||
NOTE: Data are mean ± 1 SEM, N = 6 male rats per group; p determined by unpaired t-test. Data were condensed from several experiments. LPL activity was determined in SHR/N-cp rats; all other data determined in LA/N-cp rats. Rats were fed Purina Chow #5001 from weaning to 1.5 months of age and a semipurified diet thereafter (Michaelis et al., 1986). Adipose cellularity was determined with the method of Hirsch and Gallian (1968) as modified by Tulp et al. (1982). N.S. = Not significant.
TABLE 3 Body Composition and Biometry of Corpulent Rats
| Phenotype | Torso Length cm | Protein g/Carcass | Percent | Lipid g/Carcass | Percent | kcals/Carcass |
| Lean | 17.3 ± 0.2 | 63.5 ± 1.3 | 21.6 ± 1.3 | 21.7 ± 3.1 | 7.3 ± 1.0 | 561 ± 35 |
| Obese | 18.8 ± 0.3 | 78.6 ± 1.4 | 10.3 ± 0.4 | 354.8 ± 15.8 | 45.9 ± 1.0 | 3,745 ± 150 |
| p = | N.S. | <0.05 | <0.01 | <0.001 | <0.001 | <0.001
|
Figure 1 Body weights of LA/N//Tul-cp rats. Weights of 600 rats of various ages were determined in unfasted state with an Ohaus beam animal balance, N = 2-25 rats per individual data point. Most weights were collected during the same week. Each phenotype and sex gave a fifth order polynomial regression line.
Figure 2 Thermogenesis of LA/N-cp rats. Data are mean ± 1 SEM, N = 5-6 rats per group. * indicates that lean rats were different from obese rats of a corresponding age (p = < 0.05, unpaired t-test). All measurements were obtained with a Collins small animal spirmoter apparatus at 30°C and corrected to conditions of standard temperature, pressure, and density.
A. Resting metabolic rates. Rats were studied after an overnight (> 8 hr) fast. Lean were greater than obese at 6 and 12 weeks of age and at 14 months of age, and tended to be greater (p = < 0.10) at 8 months of age.
B. Effects of thermogenic drugs. Data are the percentage change from the RMR determined immediately before the drug challenge. All drugs were administered via subcutaneous injection immediately after obtaining an RMR as outlined above. NE = norepinephrine, equivalent to 200 mg NE base/kg body weight; ISO = isoproterenol, 200 mg per kg body weight; EPHED -- ephedrine, 200 mg/kg body weight.
C. Thermic effects of feeding. Measures were taken for 1-2 hr following gavage ingestion of the macronutrient source. CHOW-- Purina Chow #5001, 4 hours of ad libitum feeding; CAFE = cafeteria feeding, measures taken in fasted state after 4 weeks feeding of an ad libitum cafeteria diet; CHO = 10 kcals of a carbohydrate meal consisting of honey via gavage; OIL = 10 kcals of a lipid meal consisting of coconut oil via gavage. Animals were conditioned to gavage feeding for several weeks to minimize potential stressful effects on thermic responses to the feeding practice.
D. Thermic effects of cold. The temperature of the thermogenesis chamber was rapidly changed from 30°C to 4°C by immersion in an ice bath immediately following the RMR determination. The thermic responses to cold were obtained in fasted adult male rats aged 14 months after 25 min of cold exposure.
Figure 3 Serum T3 and T4-5' deiodinase activity of pre-obese male rats. Data are mean + 1 SEM, N = 6 rats per group, aged 6 weeks. Animals studied were biological littermates. Serum T3 was determined by radioimmunoassay; deiodinase activity was determined as outlined by Tulp and McKee (1986) and expressed as ng T3 formed/mg T4 incubated in a 15-min incubation.
Figure 4 Protein synthesis of pre-obese male rats. Data are mean, /V = 5-6 rats per group, aged 6 weeks. Animals studied were biological littermates. SYN = synthesis as computed by incorporation of 14C-phenalanine; DEC; = degradation as measured by the simultaneous efflux of unlabeled tyrosine from the same muscle preparation, as outlined by Fulks et al. (1975); QD = quarter diaphragm; AA = auricular appendage; DL = extensor digitorum Iongus muscle. SEM averaged 10 percent or less for all measures. * indicates p = < 0.05 compared to corresponding group.
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