The Effects of Ad Libitum Overfeeding and Moderate and Marked Dietary Restriction on Age-Related Spontaneous Pituitary Gland Pathology in Sprague—Dawley Rats

Abstract

This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of aged-related pituitary gland changes in Sprague-Dawley (SD) rats. 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 and insulin-like growth factor 1 (IGF-1) serum levels were measured at interim and final necropsies. Serum levels of prolactin (PRL), progesterone, estradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured at 53 and/or 106 weeks. In addition to the routine histopathologic examination, determination of 7 stereologic parameters after pituitary immunohistochemistry of PRL, growth hormone (GH) and BrdU was done in both sexes at 13, 26, and 53 weeks. Body and pituitary weights were proportional to the food intake. In AL-fed rats, hyperplastic and neoplastic changes developed early and progressed with age, affecting almost all animals by 106 weeks. These changes were associated with high PRL serum levels. Pituitary adenomas were the most common cause of death in both sexes. In DR rats, a delayed onset and a decreased incidence of pituitary tumors were observed in association with decreased serum IGF-1, PRL, estradiol, and LH levels. The results of the stereological analysis demonstrated that, compared to AL-fed rats, pituitary glands from DR rats contained lower PRL and GH secreting cell volumes, and a lower epithelial cell BrdU labeling index, which correlated with a lower incidence of pituitary tumors at study termination. Moderate and marked degrees of DR delayed the onset of pituitary tumors in a temporal- and dose-related manner. In contrast to marked DR, which dramatically reduced the incidence of hyperplastic and neoplastic pituitary gland changes, moderate DR delayed the onset but did not prevent the development of pituitary tumors.

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

“…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).…”

“…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;…”

“…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).…”

Endocrine Glands

“…81,82 The reason for predisposition of laboratory rats to the development of pituitary adenomas with advancing age is uncertain. 86,87 Wistar rats fed a low protein diet ad libitum also developed fewer pituitary adenomas than their counterparts fed a more protein-rich diet. 83 The higher incidence of pituitary adenomas in females suggests that estrogen is involved, either by a direct effect on pituitary cells or inhibition of dopamine.…”

“…83 The higher incidence of pituitary adenomas in females suggests that estrogen is involved, either by a direct effect on pituitary cells or inhibition of dopamine. 87 Repeated breeding also delays the appearance of pituitary adenomas in female rats. Following treatment of Wistar rats with tamoxifen for two years both males and females showed a dramatic reduction in the number of pituitary adenomas and adenoma-related deaths in all treated groups compared with control rats over the period of the study.…”