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DOI: 10.1080/01926230500311222
Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction
1 Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA Correspondence: Address correspondence to: Laura A. Gumprecht, Merck Research Labs, Dept. Safety Assessment, WP-81-403, Sumneytown Pike, West Point, PA 19486; e-mail: lauragumprecht{at}merck.com
This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of a metabolic syndrome of diabesity comprised of age-related degenerative diseases and obesity in a outbred stock of Sprague–Dawley (SD) rats [Crl:CD (SD) IGS BR]. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72–79% of AL (group 2), DR at 68–72% of AL (group 3) or DR at 47–48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights, carcass analysis, in-life data including estrous cyclicity, and histopathology were determined. At 6–7 weeks of age SD rats had 6% body fat. AL-feeding resulted in hypertriglyceridemia, hypercholesterolemia, and dietary-induced obesity (DIO) by study week 14, with 25% body fat that progressed to 36–42% body fat by 106 weeks. As early as 14 weeks, key biomarkers developed for spontaneous nephropathy, cardiomyopathy, and degenerative changes in multiple organ systems. Early endocrine disruption was indicated by changes in metabolic and endocrine profiles and the early development and progression of lesions in the pituitary, pancreatic islets, adrenals, thyroids, parathyroids, liver, kidneys, and other tissues. Reproductive senescence was seen by 9 months with declines in estrous cyclicity and pathological changes in the reproductive organs of both sexes fed AL or moderate DR, but not marked DR. The diabesity syndrome in AL-fed, DIO SD rats was readily modulated or prevented by moderate to marked DR. Moderate DR of balanced diets resulted in a better toxicology model by significantly improving survival, controlling adult body weight and obesity, reducing the onset, severity, and morbidity of age-related renal, endocrine, metabolic, and cardiac diseases. Moderate DR feeding reduces study-to-study variability, increases treatment exposure time, and increases the ability to distinguish true treatment effects from spontaneous aging. The structural and metabolic differences between the phenotypes of DIO and DR SD rats indicated changes of polygenic expression over time in this outbred stock. AL-overfeeding of SD rats produces a needed model of DIO and diabesity that needs further study of its patterns of polygenic expression and phenotype.
Key Words: Dietary restriction • aging • type 2 diabetes • dietary induced obesity • reproductive senescence • metabolic syndrome "X."
It is well established that moderate caloric or dietary restriction (DR) significantly improves 2-year survival, controls adult body weight, and delays the onset of diet- and age-related spontaneous diseases and tumors. This results in a better experimental toxicity model by reducing the "noise" of background diseases while allowing an increased duration of exposure to test substances for the evaluation of the potential carcinogenicity and toxicity in long-term studies. The adverse effects of ad libitum (AL)-overfeeding on the early development of many spontaneous tumors and degenerative diseases of this SD outbred stock (Gumprecht et al., 1993; Keenan et al., 1994a, 1994b, 1995a, 1995b, 1996, 1999, 2000a, 2000b; Dixit et al., 1996; Keenan et al., 1997; Hubert et al., 1997; Laroque et al., 1997; Hoe et al., 1998; Vermorel et al., 1998; Hubert et al., 2000; Kemi et al., 2000; Molon-Noblot et al., 2003) and other aged rat strains (McCay et al., 1935; Burek, 1978; Tucker, 1979; Ross et al., 1983; Kritchevsky et al., 1984; Maeda et al., 1985; Berry, 1986; Masoro et al., 1989; Laganiere and Yu, 1989a, 1989b; Yu et al., 1989; Mietes, 1990; Chapin et al., 1993; Grasl-Kraupp et al., 1994; Merry and Holehan, 1994; Sonntag and Yu 1994; Roe et al., 1995; Masoro et al., 1996; Masoro and Austad, 1996; McShane and Wise, 1996; Seki et al., 1997; Kritchevsky, 1999; Sonntag, 1999; Duffy et al., 2001; Haseman et al., 2003; Wan et al., 2003) have been reported. However, the role of AL-overfeeding in the pathogenesis of dietary-induced obesity (DIO) and the metabolic syndrome (syndrome X) associated with adult-onset diabetes, or "diabesity" (Levin et al., 1997; Leiter, 2002; Reifsnyder and Leiter, 2002; Axen et al., 2003) in SD rats has not been fully investigated or exploited as a model of the polygenic diabesity syndrome which is common in heterozygous human populations worldwide (Klinger et al., 1996; Weindruch and Sohal, 1997; Brunner et al., 2001; Eckel et al., 2002; Pasquale et al., 2003). This paper describes the temporal, clinical, and pathological features of the "diabesity syndrome" as observed in AL-overfed SD rats and demonstrates the beneficial effects of moderate or marked DR in modulating the many co-morbidities associated with this syndrome. The SD rat stock used in this study is officially designated as the Charles River CD rat, and should not be confused with other "Sprague–Dawley" rat stocks that breeders have developed with very different phenotypes under similar housing and feeding conditions. We refer to the animals in our study as "SD," but the breeder uses the designation of CD IGS or Crl:CD (SD) IGS BR to identify their albino outbred SD stock from others. This stock originated in 1925 at the University of Wisconsin through the efforts of Robert W. Dawley (the stock’s name was derived from his wife’s maiden name and his own). A docile, large hybrid hooded male was mated to female Wistar (albino) rats, and after 7 generations the rats were outbred. Obtained by the Charles River Company in 1950, the stock was rederived in 1955 and in 1991 the breeder selected 8 lines of this stock to form the "IGS" foundation colony that was rederived in isolators in 1997. This stock is very docile, with high fecundity and rapid growth when AL-fed commercial diets. It is considered one of the best outbred SD rat stocks and is commonly used in behavioral, nutritional, reproductive, teratological, toxicological, and carcinogenicity testing worldwide. Adult-onset human or animal type 2 diabetes associated with obesity (diabesity) is induced by a complex set of genetic, dietary and environmental interactions (Weindruch and Walford, 1988; Klinger et al., 1996; Brunner et al., 2001; Eckel et al., 2002; Bray, 2002). For example, monogenic obesity mutations in rodents such as those in the leptin gene (Lepob, ob/ob mice) or its receptor gene (Leprdb, db/db mice, Leprfa fa/fa Zucker rats or Leprcp cplcpJCR rats) have been extremely useful in the study of these processes and useful in efficacy testing of anti-obesity and anti-diabetic drugs (Harrison and Archer, 1987; Lee and Yu, 1990; Lu et al., 1991; Leiter, 2002; Inui et al., 2004; Park and Prolla, 2005). However, the monogenic basis of these mutated inbred rodent models does not reflect the more common forms of human obesity and adult-onset type 2 diabetes (diabesity) which are known to be a polygenic syndrome in heterozygous human populations (Klinger et al., 1996; Whitaker et al., 1997; Eckel et al., 2002; Hursting et al., 2003; Konstantinov, 2003; Rauser et al., 2003; Park and Prolla, 2005). Thus, there is a need for a polygenic outbred obesity rodent model in which disease trait loci interact with each other and can be modulated by the diet and environment to elicit DIO syndromes that are potentially diabetic and will better represent the most common human syndromes. While inbred and transgenic rats and mice with well-known quantitative trait loci for obesity and/or diabetes have been helpful in understanding the genetics of these processes, many diabetes-prone strains with different combinations of disease-associated loci do not develop obesity and conversely many strains that develop genetically driven obesity syndromes are not diabetes-prone (Leiter, 2002). Inbred strains with null mutations in specific genes are not truly representative of the human polygenic syndrome of obesity-driven type 2 diabetes or diabesity. For this reason, more polygenic outbred obesity rodent models are needed to determine the quantitative trait loci that interact with each other and could be modified by new therapeutic means. When overfed, the Charles River outbred SD rat stock has been shown to develop a phenotype of DIO that progresses to an adult-onset type-II diabetic syndrome. This syndrome, characterized by the development of hyperlipidemia, hyperinsulinemia, changes in glucose metabolism and the many other co-morbidities that model a polygenic adult-onset, obesity-induced diabetes (diabesity) in humans (Keenan, 1994a, 1994b, 1996, 1997, 1999, 2000a, 2000b; Levin et al., 1997; Molon-Noblot et al., 2001, 2003). This SD rat stock’s phenotype is reminiscent of the syndrome described in hybrid mice in which different quantitative trait loci are combined, leading to obesity and diabetes syndromes (Leiter, 2002; Reifsnyder and Leiter, 2002; Park and Prolla, 2005). This cross-sectional and longitudinal study describes the pathologic features of DIO adult-onset diabesity in SD rats induced by simple ad libitum overfeeding of a commercial rodent diet and the modulation of this syndrome by different degrees of moderate to marked dietary restriction. These data demonstrate the untapped potential of this outbred SD stock as a more appropriate model of the human polygenic adult-onset type 2 diabetes syndrome that is driven by dietary-induced obesity.
Animals Three hundred-eighty male and 380 female Sprague–Dawley [Crl:CD (SD) IGS BR] rats were obtained from Charles River Laboratories, Raleigh, NC. The animals were 7 weeks old at the initiation of the study and weighed 172–266 g for males and 134–213 g for females. The rats were individually housed in stainless steel cages in an environmentally controlled room with a 12-hour light cycle (lights on at 0700 hours and off at 1900 hours). They were individually identified with implantable microchip identification devices (BioMedic Data Systems) and allocated to cages by a randomized columnar allocation scheme. The animals were assigned to 4 different treatment groups using a balanced random allocation scheme based on body weight. Each group consisted of 95 males and 95 females with 15 animals/sex/group allocated for the 13-, 26-, and 53-week interim necropsy, and with 50 animals/sex/group allocated to the 106-week final necropsy. The Institutional Animal Care and Use Committee at Merck Research Laboratories, West Point, PA reviewed and approved all procedures used in this study.
Diet and Dietary Regimen
Clinical Evaluations
Osmotic Minipump Implantation
Necropsy, Carcass Analysis, and Histopathology
Stereology For hepatocyte number, the numerical density was calculated from direct measurements to determine the number of hepatocyte nuclei per cubic centimeter of liver. To determine the volume of liver, the density of liver (0.93 cm3/gm) was multiplied by the weight (gm) of the liver. The corrected liver volume was calculated by multiplying the volume of liver by a measured shrinkage factor (0.118). The number of hepatocyte nuclei per liver was determined by multiplying the corrected liver volume by the number of hepatocyte nuclei per cubic centimeter of liver. The total number of BrdU labeled hepatocyte nuclei per liver was determined by multiplying the total number of nuclei per liver by the BrdU labeling index (%LI).
Hepatocyte BrdU Labeling Index (LI%)
Myocardial Fibrotic Index (MFI%)
Statistical Analysis
Mortality and Survival For both sexes survival was proportional to the degree of DR. In groups 1, 2, 3, and 4, 106-week survival rates were 18, 40, 56, and 82% in females, and 18, 44, 68, and 78% in males, respectively. The group 4 animals had the highest percentage and average weeks of survival on the study, and the AL-fed group 1 animals had the lowest values (approximately 18% survival for both sexes and 81 to 83 average weeks on study). Interestingly, there was a difference in survival that was significant between the two moderate DR-fed groups 2 and 3, in both sexes, by trend test. The average survival and weeks on study were statistically different between groups by both trend tests and pair-wise comparisons as shown in Table 1. The most common cause of death in both sexes of all groups was pituitary adenomas. The next most common cause of death in the AL-fed males was chronic nephropathy, followed by cardiomyopathy, and in AL-fed females it was mammary gland tumors. The tumor data will be presented in more detail in a separate paper.
Food and Water Consumption The mean food consumption in the AL-fed group 1 over the course of the study ranged in females from 19.8 to 29.8 grams per day (mean value 23.6 grams per day) and in males from 26.4 to 33.3 grams per day (mean value 30.4 grams per day) (Figure 1). The mean measured food consumption was approximately equivalent to their daily allotment of ration of 17, 16, and 11 grams per day for females and 24, 22, and 14.5 grams per day for males in groups 2, 3, and 4, respectively., Females in groups 2, 3, and 4 consumed 72, 68 and 47% of AL intake and males in the same groups consumed 78, 72, and 48% of AL intake respectively. The absolute food intake corrected for food wastage was approximately 6 to 12% in all groups. There were no significant differences in food wastage between any of the 4 treatment groups over the course of the study. While absolute food intake was significantly different between the 4 groups, the mean relative food consumption per gram body weight was similar in all groups. These data indicate total body growth is proportional to the total amount of food provided or consumed in all groups. However, when the body weights were expressed as percent lean body weight, the percent food intake was not proportional to the lean body weight. As they aged the AL-fed animals partitioned more of their intake into body fat rather than lean body mass (Figure 9). The calculated intake of nutrients, including metabolizable energy, showed similar trends throughout the study, with absolute and percent lean body weight, nutritive and energy intake proportional to the total body weights achieved. However, relative food intake expressed as a percent of total body weight was remarkably similar across groups (Figures 2 and 3). These data indicate a significant portion of the food consumed by the AL groups was converted and stored as body fat.
Water consumption, measured throughout the study as an absolute value and a relative value adjusted for body weight, indicated absolute intake was proportional to body size. However, when expressed as ml. water per kg. body weight, the DR-fed males in groups 2 and 3 had approximately a 30% increase in relative water consumption and the females in the same groups had approximately 20 to 40% increase in relative water consumption compared to their AL-fed counterparts. Males in group 4, the marked DR-fed group, had approximately a 70% increase in water consumption, and females had 10 to 15% increase in water consumption compared to the average water intake per gram body weight in the AL-fed groups (Figures 4 and 5).
Glucose, Insulin, Triglyceride, and Cholesterol Levels Fasting blood glucose and insulin data have been previously reported (Molon-Noblot et al., 2001). In summary, the mean insulin values were higher in AL-fed animals than other groups over the course of the study. In fasted rats, glucose values from vena cava samples were generally similar across groups, but group 4 had the lowest mean values. Blood glucose was also determined at intervals via tail stick methods on unfasted animals over the course of the day. In male rats, glucose values were generally comparable across groups in the morning prior to feeding when AL-fed rats’ glucose was higher than those of the restricted groups. In females, mean blood glucose values were generally higher in groups 1 and 2 than in groups 3 and 4 (Molon-Noblot et al., 2001). The AL-fed animals had higher serum levels of insulin, IGF-1 and glucose than the DR-fed animals as previously reported (Molon-Noblot et al., 2001, 2003). Plasma total cholesterol levels were consistently higher in AL-fed animals of both sexes and the lowest in the Group 4 marked DR-fed rats throughout the study. By study weeks 25 through 51, cholesterol levels in the Group 1 AL-fed animals increased significantly above any of the food restricted groups (Figure 6). Serum triglycerides showed an even more dramatic pattern of change in the AL-fed animals so that by 24 weeks, a significant increase in triglycerides was seen in the AL-fed animals of both sexes. A proportional decrease in tryglyceride levels relative to food intake was observed in the 3 food restricted groups. These differences in lipid profiles were most evident in the females at the latter portions of the study (Figure 7).
Growth Curves and Body Weights at Interim and Terminal Necropsies Differences in the total food intake resulted in not only proportional and increasing rates of body weight gain, but terminal body weights that were different between the groups as early as the first few weeks of the study. For the AL-fed and 2 moderate DR-fed groups, body weight gain and terminal body weights increased proportionally up to 1 year and then leveled off for the males, but increased in AL-fed females through 106 weeks. In the group 4 females, there was a slight decrement in body weight during the first 8 weeks of the study at which point this group began to gain body weight and maintained its average weight over the course of the study (Figure 8). Individual rats, particularly the AL-fed rats developed a terminal senescent body weight loss as they developed tumors, and cardiac or endocrine disease as noted by others (Black et al., 2003). These events and the early deaths of the largest rats tended to lower the average body weights of most groups from study week 80 onward (Figure 8 and Table 1).
Carcass Analysis at Interim and Terminal Necropsies The whole body carcass analysis for percentages of protein, fat, moisture and ash content were determined on 10–15 rats/sex/group from each interim necropsy and the final necropsy. In addition, carcass analysis was performed on 10 rats/sex at 6 weeks of age to establish baseline values on AL-fed animals at the study initiation. The mean percent whole body carcass analysis values for AL-fed, 6-week-old male and female SD rats were: 72.4 and 72.3% moisture, 17.7 and 17.3% protein, 6.14 and 5.84% fat, 2.50 and 2.53% ash and 27.6 and 27.7% dry matter respectively. Therefore, 6-week old, AL-fed SD rats are typically lean animals at the study onset, with only 6% whole body fat. Differences in carcass composition between adult study groups generally reflected differences in total food consumption and their resultant body weight gains and terminal body weights. The AL-fed rats of both sexes rapidly developed DIO with the largest body fat content that became a significant portion of their total body weight from 6 months onward. On gross examination much of this body fat was white adipose tissue that was centrally located in the abdominal cavity and the subcutaneous tissues of the abdomen and lower thoracic area (Figure 10). The group 4 (50% DR) rats had the smallest body weight fat content. For both females and males a clear dose response pattern was noted for all components of body composition. Furthermore, the AL-fed groups were statistically significantly different in carcass composition from both the moderate and the marked DR-fed groups 2, 3, and 4 (Table 2). Thus, the AL-fed animals had the greatest gain in central body fat with age, the greatest percent of body fat, the greatest grams of body fat per animal, and when expressed as relative values of percent of body weight or brain weight, a clear dose-related increase in body fat was observed in the AL-fed animals relative to the three other measured-fed groups (Figure 9). Conversely, the highest percentage of carcass protein, ash and moisture content was seen in the marked DR-fed group 4 which was largely a reflection of their proportional decrease of total body fat content throughout the study. The moderate DR-fed groups were not lean and gained body fat with age, with males and females developing averages of 13 and 25% body fat, respectively, from 1 year onward (Figure 9 and Table 2).
Organ Weights at Interim and Terminal Necropsies The AL-fed group 1 animals had the largest percent of body weight gain, largest terminal body weights and largest internal organs, compared to the other three DR-fed groups (Tables 3a, b, c). These changes reflected growth patterns similar to those observed in central body fat increases and somatic growth of non-fat tissues. These differences appear to reflect the effects of higher levels of energy intake and correlated with increased levels of growth promoting hormones (Growth hormone, IGF-1, prolactin, insulin) that were reported previously (Molon-Noblot et al., 2001, 2003). This resulted in a greater central body fat content, larger musculoskeletal growth and greater thoracic and abdominal organ sizes in the AL-fed animals. In contrast, no significant differences were seen between all the groups in the growth and absolute brain and testes weights of the AL-fed and moderately DR-fed animals. However, the 50% DR-fed group 4 animals did have slightly smaller brain and testes weights and growth than the other three groups. These observations indicate that the moderate measured feeding regimens (Groups 2 and 3) do not interfere with gross brain growth and development, but marked DR of group 4 does affect all organs’ growth (Tables 3a, b, c, 5, 6).
Compared to the AL-fed group, the absolute and relative weights of spleen, thymus, heart, kidneys, liver, adrenals, thyroids, ovaries, prostate, pituitary and pancreas were generally smaller and frequently statistically so by trend and pairwise statistical comparisons in the measured groups in a food intake or dose-proportional manner (Tables 3a, b, c, 5, 6). The degree of these differences between each group appeared generally proportional to their total food intake. Group 4 (50% DR) were the smallest animals and had the smallest organ weights. In most cases the lower thoracic and abdominal organ weights seen in the moderate and marked DR-fed groups correlated with a relative decreased incidence and/or severity of degenerative lesions in these animals. Because of differences in body size, central obesity and thoracic and abdominal organ size observed across the groups, additional analyses were done on the relative organ weights expressed as a percent of body weights. Relative to the AL-fed animals, the measured groups had proportionally significant increases in the relative size of their hearts, kidneys, adrenals, livers, and other endocrine organ weights as a percent of body weights (data not shown). These changes generally reflected differences in metabolic and physiological stresses placed on these organs, the rate of body-weight gain and the differences in their carcass composition. As mentioned previously, differences in the absolute and relative sizes of brains and testes were not significantly different in the moderately DR-fed and AL-fed groups, but were lower in the 50% DR-fed group. However, these organs expressed as a percent of body weight were relatively increased in size proportional to the absolute size of their bodies and growth (data not shown).
Estrous Cyclicity
The onset of reproductive senescence in these unmated females was characterized by irregular estrous cyclicity in the AL-fed and moderate DR-fed groups, but was delayed in group 4 females under marked DR. The difference between cyclicity patterns in the 50% DR-fed group and those seen in the AL-fed and 2 moderate DR-fed groups was clearly established by 9 months of age, at which time regular estrous cyclicity was still evident in 70% of the marked DR-fed group 4 females compared with approximately 36% of the females in groups 1, 2, and 3. By 12 months of age this difference in regular estrous cycles was 43% in group 4 compared to approximately 12% in the other three groups. At 18, 21 and 24 months, approximately 25% of the females in group 4 still exhibited regular estrous cyclicity. None or very few of the females in the group 1 AL-fed animals or the group 2 and 3 moderate DR-fed females had regular estrous cycles at these ages. Throughout the 106 week study, the percentage of surviving females exhibiting patterns of regular estrous cyclicity in the AL-fed and moderate food restricted groups 2 and 3 were comparable (Table 4 and Figure 11).
Gross and Microscopic Degenerative Changes
Morphologic Pathology
The qualitative and quantitative changes observed in the pituitaries over time have been separately reported (Molon-Noblot et al., 2003). In summary, the AL-fed animals had the largest pituitaries, highest levels of prolactin and growth hormone secretion, and the highest incidence of focal hyperplasia and tumors of the anterior and intermediate lobes. The age-adjusted incidence of these tumors was statistically significantly decreased in the animals of each of the measured-fed groups. Pituitary tumors were the most common cause of death in all groups and both sexes.
Mammary Glands
Pancreas
Adrenals
Heart
Kidneys
Liver While no differences were seen in liver tumor incidence between the different dietary groups compared to the AL-fed group (to be reported separately), degenerative changes, such as hepatocellular periportal vacuolation and telangiectasis were most evident and severe in the AL-fed groups compared to the DR-fed groups, although most of the DR-fed animals lived for a significantly longer time than their AL-fed counterparts. In animals with hepatocellular periportal vacuolation, particularly females, there was a relative increase in BrdU nuclear labeling of hepatocytes in that region, but not in the total BrdU labeling index. Other proliferative changes, such as bile duct hyperplasia, occurred at a similar incidence in the AL-fed and DR-fed groups but were of greater severity in the AL-fed animals. Basophilic and eosinophilic altered hepatocellular foci were seen in all groups with a similar incidence and grade in the AL-fed and moderate DR-fed groups, but a lower incidence and grade in the marked DR-fed group 4. These data were consistent with previously reported morphological studies and measures of metabolic and oxidative stress (Laganiere and Yu, 1989a, 1989b; Yu et al., 1989; Grasl-Kraupp et al., 1994; Keenan et al., 1995b; Hikita et al., 1999).
Male Reproductive Tract No difference was seen in the incidence of testicular tumors (to be reported separately), but the incidence of focal interstitial cell (Leydig cell) hyperplasia in AL-fed males was similar to each of the DR-fed groups, even though the DR-fed males lived for a considerably longer time. While there were no differences in testes weight among the groups, the weight of the prostate glands was significantly decreased by trend and pairwise comparisons at each interim and at the final necropsies in all the DR-fed groups. In the AL-fed males the incidence of chronic prostatitis was higher and graded as more severe. The incidence and grades of epithelial hyperplasia in either the dorsolateral lobe or the ventral lobes of the prostate were of similar incidence across the AL-fed and DR-fed groups. However, the one adenoma of the dorsolateral lobes of the prostate was seen in this study. The other male accessory sex glands (seminal vesicles, coagulating glands and bulbourethral glands, etc.) were generally observed as being much larger in the AL-fed males with a higher incidence of inflammatory or degenerative changes observed compared to the DR-fed male groups. These accessory sex glands in the moderate and marked DR males, while smaller, were not atrophic and had very few lesions.
Female Reproductive Tract
Eyes
Tails
Musculoskeletal System
Another clinical observation was that the aging, obese AL-fed rats were much less active during the daily observation periods and dosing and during random observation period during the dark 12-hour cycle. All the DR-fed animals had much greater spontaneous activity levels than the AL-fed animals during the light and dark cycles. Adult-onset Type 2 diabetes and obesity in humans is associated with a high incidence of plantar pressure ulcers and peripheral neuropathy. Therefore attention was given to changes in the feet and peripheral nerves that might have increased risk for plantar ulcers under the metatarsal bones due to increased pressure on insensitive skin on the wire cage floors. The incidence and severity of peripheral sciatic nerve degeneration were increased as they aged. However, if peripheral neuropathy was a factor in plantar ulcers, it was difficult to make a correlation due to the DR-fed rats’ longer life spans and the longer time they had contact with the wire cage bottoms. This resulted in differences between groups in lesion severity, but not in lesion incidence (Table 7). Plantar ulcerative granulomas and dermatitis were observed in both sexes in groups 1, 2, and 3 and in only a few rats in group 4. These foot lesions were generally not found until the rats had been housed in the wire bottom cages for more than one year, as noted by others (Peace et al., 2001). The incidence of these lesions in the moderate DR-fed males in groups 2 and 3 was twice that of the group 1 AL-fed males. The severity of these lesions in the AL-fed animals correlated with underlying osteoarthritis of the tarsal joints in most of the affected animals. The higher incidence of plantar granulomas in the group 2 and 3 males appeared to be a function of their improved survival and duration on study compared to the AL-fed group 1 males. However, this trend was not seen in the females of groups 2 and 3 or both sexes in group 4. In spite of a higher incidence all of the DR-fed groups had a much lower severity of plantar chronic or ulcerative dermatitis and the less severe osteoarthritis of the tarsal joints (Gefen, 2002; Mueller et al., 2003). In contrast, the highest incidence and/or severity of osteoarthritis of the stifle joints was seen in both sexes of group 1 AL-fed rats. Both sexes of groups 2, 3 and 4 had a reduced incidence and/or severity of stifle joint lesions, with group 4 having the mildest changes (Table 7). Therefore, a clear increased incidence and severity of osteoarthritis of the stifle joints of the male AL-fed rats was observed relative to all the DR-fed groups. This was likely to be biologically significant since the DR-fed groups had much longer life spans than the AL-fed animals, and thus were in contact with the wire bottom caging for the longest period.
The results of this study demonstrate that the Charles River outbred SD rat stock [Crl:CD(SD) IGS BR] when AL-fed a commercial balanced diet such as Purina Rodent Diet, develops a profile of degenerative diseases and a syndrome of adult-onset obesity that progresses to a metabolic syndrome similar to that seen with human, polygenic adult-onset type 2 diabetes and obesity (diabesity). This syndrome is characterized by the chronic development of hyperlipidemia, hyperinsulinemia, changes in glucose metabolism, the development of chronic renal disease, cardiovascular disease, and degenerative changes in the weight-bearing joints, liver, pancreas, adrenals, thyroids and other endocrine organs. The multiple co-morbidities observed in these animals were readily manipulated by controlled DR feeding, and thus provide an excellent model to study experimental modulations of the diabesity syndrome by control of caloric intake in a manner similar to that observed in human beings undergoing dietary therapy for obesity and type 2 diabetes (Whitaker et al., 1997; Bray, 2002; Konstantinov, 2003). A World Health Organization (WHO) 2002 report identified the main global risks affecting human disease, disability, and death rates (Eckel et al., 2002; Konstantinov, 2003). The WHO found that among the top 10 risks accounting for 40% of the worldwide deaths, excessive weight and obesity were listed 10th, and hypertension, elevated cholesterol, and inactivity were numbered 3rd, 7th, and 14th respectively, and all these conditions are associated with diabesity. It is estimated that 1.1 billion people globally are overweight or obese. In the USA, adult obesity rates rose from 14% in 1978 to 31% of the population in 2002. In the UK, adult obesity rates rose from 6% in men and 8% in women in 1980 to 21% of men and 24% of women in 2002. The WHO 2002 World Health Report estimated over 2.2 million deaths per year worldwide were over weight-related, with 220,000 per year in Europe and over 300,000 per year in the USA. In addition, obesity related health risks among Asians have been rising with an estimate that a significant portion of the 3.6 billion Asian population already has an excessive body mass index (BMI). Thus obesity is prevalent in both developed and developing countries, and is also reaching epidemic proportions in the children of these populations. The current public health epidemic of diabesity is related to excessive food (caloric) intake, and is due to behavioral patterns including decreased physical activity and over-consumption of high fat, energy-dense foods. As with many species of animals, many humans become obese because of a biological predisposition to readily gain weight when food is available, in preparation for unfavorable environmental conditions when food is less available or energy needs are extreme. The worldwide prevalence of persistent obesity in developed countries has resulted in many serious sequelae in human beings, including type 2 diabetes, heart disease, hypertension, stroke, osteoarthritis of weight-bearing joints, many forms of cancer, a poor quality of life and an excess of premature deaths. In an extensive study of American men and women, both increased obesity and reduced exercise were shown to be strong and independent predictors of early death (Hu et al., 2004). The WHO predicts that the economic burden and medical complications of diabesity in human beings threaten to overwhelm health services, and the impact on morbidity and mortality in people soon m |
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Abstract
Introduction
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