Surgical caloric restriction ameliorates mitochondrial electron transport dysfunction in obese females.

BACKGROUND: The authors examine the mitochondrial electron transport system (ETS) with regard to caloric restriction and body size in humans. METHODS: The study population included 59 morbidly obese (MO) female subjects with mean body mass index (BMI) 49.6 +/- 1.7 and 40 age-matched previously morbidly obese patients with surgically-induced caloric restriction (SCR) and mean BMI 28.9 +/- 1.1. ETS function in the 2 study groups were made by measuring their lymphocyte mitochondrial ETS complexes I-IV activities and complex III binding kinetics. Linear regression analyses were used to analyze the interactions between ETS function and BMI, energy intake, and metabolic status. RESULTS: The MO, as compared to SCR, subjects had significantly (P < 0.01) higher ETS complexes II-IV activities (complex II = 20.4 +/- 1.9 vs 15.3 +/- 1.1, complex III = 129.4 +/- 10.1 vs 72.3 +/- 4.9, complex IV = 3.1 +/- 0.3 vs 1.4 +/- 0.1 nmol/mg/min for the MO vs SCR, respectively). ETS complexes activities were positively and significantly correlated with subjects' BMI, carbohydrate caloric intake, and fasting plasma insulin levels. Michaelis-Menten kinetic analysis showed that the Km for ubiquinol-2 in complex III of MO patients was 2-fold greater than SCR values, reflecting an apparent reduction in substrate binding capacities producing a resistance to electron flow in the MO population. Caloric consumption, carbohydrate calories, insulin levels, and BMI were also each significantly (P < 0.05) and positively correlated with the Km of Complex III. CONCLUSIONS: ETS function and efficiency are compromised by increasing BMI and caloric consumption in morbidly obese women, and caloric restriction may reduce the potential for excessive oxidative free radical generation via the ETS.

Changes in expression level of genes as a function of time of day in the liver of rats.

Daily, rhythmic variation in various biochemical, physiological, and behavioral events is a fundamental property of biological organization. Here, we report analysis of relative levels of gene expression in the liver of 16 Fischer 344 rats as a function of time of day. Expression levels were determined for 3906 genes using high-density oligonucleotide microarrays. Of the 3906 genes, 1171 (30%) were clearly expressed while 2735 (70%) were not expressed or the expression was too low to distinguish from background levels. The maximum estimated changes observed for most genes (1029, 88%) were less than 1.5-fold. Analysis of variance and the Kruskal-Wallis tests were used to identify 67 genes whose expression was significantly altered as a function of time of day. These significantly altered genes were classified according to their functions and fall into key cellular pathways including drug metabolism, ion transport, signal transduction, DNA binding and regulation of transcription, and immune response.

Nonneoplastic pathology in male Sprague-Dawley rats fed the American Institute of Nutrition-93M purified diet at ad libitum and dietary-restricted intakes.

This study evaluates the effects of age and chronic dietary restriction (DR) on nonneoplastic diseases in rats that were fed the American Institute of Nutrition (AIN)-93M purified diet. Male Sprague-Dawley (SD) rats were divided into an ad libitum (AL) group and a DR group that was fed the AIN-93M diet with intake reduced by 31%. Nonneoplastic disease profiles were developed to clarify whether the AIN-93M diet fulfills long-term nutritional requirements of rats. Subsets of rats were killed at 58 and 114 weeks of age, and histopathology was performed. At 58 weeks of age, the 2 main types of nonneoplastic diseases in AL rats were liver vacuolization and cardiomyopathy. Dietary restriction reduced the severity and incidence of both lesions. At 114 weeks of age, the most common lesions in AL rats were cardiomyopathy, nephropathy, liver vacuolization, and degeneration with renal failure and genitourinary infections causing the greatest mortality. Dietary restriction reduced the incidence and severity of these lesions. Nonneoplastic diseases accounted for 28.9% and 0.0% of total mortalities in the AL and DR groups, respectively; however, there was a higher incidence of unknown deaths in the DR rats (52.6%) compared to AL rats (28.9%), which may have limited the success of DR to improve survival. Although the AIN-93M diet supported chronic rat growth, alterations in some dietary component concentrations may be required to lower body weight in chronic rodent and human studies. Factors such as diet composition and digestibility may alter nonneoplastic diseases and mortality in rats and humans in a similar fashion.

Neoplastic pathology in male Sprague-Dawley rats fed AIN-93M diet ad libitum or at restricted intakes.

The primary purpose of this study was to evaluate the effects of age and long-term dietary reduction on neoplastic diseases in rats fed the AIN-93M purified diet. Second, pathologic profiles are critical to comprehensive dietary evaluation. Male Sprague-Dawley rats assigned to 2 groups, ad libitum (AL) and dietary restricted (DR), were fed the AIN-93M (casein protein) diet free choice and reduced in amount by 31%, respectively. At 58 weeks of age, the predominant types of lesions in AL and DR rats were pituitary and skin tumors. At 114 weeks of age, the most common lesions were pituitary, adrenal gland, skin, mammary, brain, and pancreatic tumors and mononuclear cell leukemia. However, DR had no significant effect on these lesions. Primary findings demonstrate that DR significantly reduced the total number of tumors per rat and incidence of benign and primary tumors (all organs) but did not reduce the incidence of malignant tumors (all organs). Dietary restriction increased the percentage of unknown deaths. These results may explain why survival rates for AL and DR rats were not significantly different at 114 weeks (43.3 vs 57.5%, respectively). These findings differ from previous studies using NIH-31 cereal diet (Aging Clin Exp Res 2001;13:263; J Nutr 2002;132:101; Aging Clin Exp Res 2003;16(6):68; Aging Clin Exp Res 2004;16:448) where neoplastic lesions rather than nonneoplastic lesions were linked to a significant increase in survival rate among cohorts of DR-fed rats (J Nutr 2002;132:101). Factors such as diet composition and digestibility, although not independent of body weight, may have contributed to differences in rat mortality and may affect humans in a similar manner.

Nutrient intake and growth characteristics of male Sprague-Dawley rats fed AIN-93M purified diet or NIH-31 natural-ingredient diet in a chronic two-year study.

BACKGROUND AND AIMS: Daily nutrient intake and growth of male Sprague-Dawley (SD) rats fed compositionally different diets were monitored over 114 weeks to determine whether rats fed ad libitum (AL) or diet restricted (DR) followed normal growth parameters. A second objective was to evaluate the usefulness of the American Institutes of Nutrition's AIN-93M (maintenance formulation) diet for aging and DR studies. METHODS: Rats were fed NIH-31 cereal-based diet AL, or a vitamin-fortified modification of the NIH-31 diet at 10, 25, or 40% DR. Other SD rats were fed AIN-93M diet AL or 31% DR; daily nutrient intake and growth response were reported. RESULTS: At all intervals up to 36 weeks of age, rats fed AL the NIH-31 diet consumed significantly (p<0.001) more than rats fed AL the AIN-93M diet, and required more diet per unit of gain than AIN-93M AL rats. However, body weight (BW) gain in rats AL-fed the AIN-93M diet demonstrated that energy components were more efficiently metabolized than in those fed the NIH-31 diet. Whereas diet restriction decreased BW, the rate of maturation, i.e., the rate of reaching a mature BW, increased as intake level decreased. Growth response showed all growth curves were normal, but intake level effects on mature BW and maturation rate differed significantly (p<0.001). Curves for rats AL- and DR-fed the AIN-93M diets were similar to those of rats AL- and DR-fed NIH-31 diet formulations, suggesting that diets adequately met growth requirements and supported normal growth parameters of male SD rats when fed AL or DR. CONCLUSIONS: A modification in the AIN-93M energy components to reduce total calories and an evaluation of other nutrient profiles could improve its usefulness as a maintenance and aging diet.

The effects of different levels of dietary restriction on neoplastic pathology in the male Sprague-Dawley rat.

BACKGROUND AND AIMS: The primary purpose of this study was to evaluate the effects of varied levels of dietary restriction (DR) on neoplastic pathologies in rodents at 58 and 110 weeks of age. METHODS: Male Sprague-Dawley (SD) rats were divided into four nutritional groups; an ad libitum (AL) control group, and three dietary restricted (DR) groups that were fed the NIH-31 diet reduced in amount by 10, 25, and 40%. RESULTS: At 110 weeks of age, compared to AL rats, the incidence of benign tumors was significantly lower in all DR groups while primary tumors were significantly lower in the 10 and 40% DR groups; no malignant tumors were detected in the 10% DR group. Most defined mortalities were caused by neoplastic lesions. All levels of DR reduced the percentage of tumor-bearing animals, the incidence of skin tumors (combined), and the total number of tumors. Pituitary, skin, and pancreatic tumors were the most prolific lesions; pituitary and skin tumors were the most fatal. Compared to AL rats, the time to onset of skin and pancreatic tumors was longer in all of the DR groups. CONCLUSION: In many cases, the incidences of neoplastic lesions were similar among the DR groups, clearly indicating that the DR effect is not linear and that even a very low level of DR (10%) can have a significant effect on many important neoplastic lesions and tumor burden. The main effect of DR was to decrease the incidence of some neoplastic lesions and to increase the time to onset and/or decrease the progression of tumors, thereby increasing the 110-week survival rate of DR rats.

The effects of different levels of dietary restriction on non-neoplastic diseases in male Sprague-Dawley rats.

BACKGROUND AND AIMS: The primary purpose of the present study was to investigate the effects of 10, 25, and 40% dietary restriction (DR) on non-neoplastic diseases in rodents at 58 and 110 weeks of age, and to determine whether low-level DR (10 and 25%) can increase the survival rate and decrease variability in chronic bioassay studies. METHODS: Male Sprague-Dawley (SD) rats (NCTR colony) were divided into four nutritional groups, consisting of an ad libitum (AL) group with unlimited access to the NIH-31 diet, and three dietary restricted (DR) groups given the NIH-31 diet reduced in amount by 10, 25, and 40%. RESULTS: At 110 weeks of age, the incidence of cardiomyopathy was 95, 75, 45, and 15% for AL and 10, 25, and 40% DR rats, respectively; the incidence of nephropathy was 55, 20, 15, and 0% for AL and 10, 25, and 40% DR rats, respectively. The severity of chronic heart and kidney diseases was significantly reduced in all DR rat groups, with significant DR-dependent linear trends for these diseases. Moreover, DR prevented the progression of skin irritation to foot ulcers, and reduced the age-related degeneration in the adrenal, lacrimal, and thymus glands, and the liver. CONCLUSIONS: These results clearly indicate that even low DR levels were effective in preventing or slowing the progression of these non-neoplastic diseases.

Effect of the AIN-93M purified diet and dietary restriction on survival in Sprague-Dawley rats: implications for chronic studies.

Survival, growth and dietary intake (DI) variables were monitored in a chronic 114-wk study in which male Sprague-Dawley rats [n = 120; National Center for Toxicological Research (NCTR) colony] consumed the AIN-93M purified diet ad libitum (AL), or an amount reduced by 31% of total AL intake inclusive of all macro- and micronutrients. The main objectives were to ascertain the survival characteristics of rats fed the AIN-93M diet and to determine whether dietary restriction (DR) increases longevity of rats fed this casein-based diet compared with the use of mixed-protein sources of the NIH-31 cereal-based diet in an earlier study. Body, liver, brain, the brain/body ratio, spleen, thymus and kidney weights, body length and body density were decreased (P < 0.05) by DR, whereas testis weight and skull length were not altered by DR. Significant age effects at 58 and 114 wk were found for body, brain, the brain/body ratio, liver and testis weights, and body density. Survival rates for the AL and 31% DR groups were 43.3 and 57.5%, respectively. Survival curves were not significantly different. The survival rate for AL rats fed the AIN-93M diet was not different from that of AL rats fed the NIH-31 diet (43.3 and 51.7%, respectively). However, the survival rate for 31% DR rats fed the AIN-93M diet was significantly lower than 25% DR rats fed the NIH-31 diet (57.5 and 87.5%, respectively) although both groups had similar body weights and energy intake at various ages. Nutritional components in the NIH-31 diet that are missing and/or reduced in the AIN-93M diet may interact with DR to increase 114-wk survival. Although the survivability, growth and anatomical results of this study suggest that the AIN-93M diet is suitable for chronic rodent studies, additional studies such as comprehensive histopathologic and physiologic investigations must be undertaken to complete the evaluation process.