Diet-induced Obese Control Research Articles

Exercise Improves Innate and Adaptive Immune Responses in Obese Mice

Obesity increases the risk of several solid tumors. Obesity-induced impairments in immunity may contribute to this relationship. We have previously shown that numerous innate and adaptive immune responses, including NK cell cytotoxicity, antigen-specific CD4+ T cell proliferation, and CD8+ T cell cytotoxicity, are impaired in diet-induced obese (DIO) mice. PURPOSE: The current study was designed to determine if the obesity-induced decrements in immunity were reversible with weight loss achieved via the most common obesity interventions used in humans: exercise (EX), energy restriction (ER), or a combination of EX+ER. METHODS: Female C57BL/6 mice consumed a 60 kcal% fat diet, with 20 kcal% protein & carbohydrate, ad libitum for 15 weeks to induce obesity. After achieving a mean (± SD) body weight of 48.3 ± 1.9 grams, DIO mice were randomized to one of the following intervention groups (n=7-9/group): 1) DIO controls, which continued on 60 kcal% fat diet ad libitum; 2) DIO mice with access to running wheels (DIO+EX); 3) DIO mice placed on an energy-restricted diet consisting of a 30% reduction in kcal from fat (DIO+ER); or 4) DIO mice placed on an ER diet with access to running wheels (DIO+ER+EX). Mice were on one of the four interventions for 8 weeks prior to receiving a primary vaccination followed by 2 booster vaccinations 2 weeks apart. Animals were sacrificed 3 weeks following the last boost, and spleens were collected for assessment of immune function. RESULTS: Only mice on the ER diets (DIO+ER and DIO+ER+EX mice) weighed significantly less than the DIO control mice (P<0.05). Despite the lack of significant change in body weight with the exercise intervention alone, EX (either alone or in combination with ER) significantly (P <0.05) enhanced NK cell cytotoxicity, antigen-specific CD4+ T cell proliferation, and CD8+ T cell cytotoxicity in DIO mice, whereas ER alone did not. These findings demonstrate that obesity-induced immune impairments in NK cell and T cell function can be reversed by EX or a combination of ER plus EX, but not ER alone. CONCLUSION: These results suggest that in obese mice exercise enhances immune function independently of changes in body weight, and that in humans exercise may be an important intervention to couple with energy restriction to reduce body weight and enhance immune responsiveness in obese patients.

Abstract B144: Obesity-induced impairments in innate and adaptive immune responses are differentially altered by exercise and dietary restriction.

Abstract B144 Obesity increases the risk of several solid tumors, including breast, prostate, pancreatic, and colon. One of several mechanisms that may contribute to the relationship between obesity and tumor risk is an obesity-induced impairment in immunity. We have previously shown that numerous innate and adaptive immune responses, including NK cell cytotoxicity, antigen-specific CD4+ T cell proliferation, and CD8+ T cell cytotoxicity, are impaired in diet-induced obese (DIO) mice. The current study was designed to determine if the obesity-induced decrements in immunity were reversible with weight loss achieved via the most common obesity interventions used in humans: exercise (EX), energy restriction (ER), or a combination of EX+ER. Female C57BL/6 mice consumed a 60 kcal % fat diet, with 20 kcal % protein and carbohydrate, ad libitum for 15 weeks to induce obesity. After achieving a mean (± SD) body weight of 48.3 ± 1.9 grams, DIO mice were randomized to one of the following intervention groups (n=7-9/group): 1) DIO controls, which continued on 60 kcal % fat diet ad libitum; 2) DIO mice with access to running wheels (DIO+EX); 3) DIO mice placed on an energy-restricted diet consisting of a 30% reduction in kcal from fat (42 kcal % fat diet, with 29 kcal% protein &amp; carbohydrate) (DIO+ER); or 4) DIO mice placed on an ER diet with access to running wheels (DIO+ER+EX). Mice on the aforementioned interventions consumed 20.9 ± 0.6 kcal/d, 20.6 ± 0.3 kcal/d, 15.6 ± 0.4 kcal/d, and 15.4 ±0.3 kcal/d, respectively. Mice were on one of the four interventions for 8 weeks prior to receiving a primary vaccination with a subcutaneous pox virus-based vaccine, followed by 2 booster vaccinations 2 and 4 weeks following the prime. Animals were sacrificed 3 weeks following the last boost, and spleens were collected for assessment of immune function. Following 15 weeks on the interventions, DIO, DIO+EX, DIO+ER, and DIO+ER+EX mice weighed 55.3 ± 1.3 g, 50.2 ± 1.3 g, 39.3 ± 1.7 g, 28.5 ± 0.8 g, respectively. Only mice on the ER diets (DIO+ER and DIO+ER+EX mice) weighed significantly less than the DIO control mice (P&amp;lt;0.05). Despite the lack of significant change in body weight with the exercise intervention alone, EX (either alone or in combination with ER) significantly (P &amp;lt;0.05) enhanced NK cell cytotoxicity, antigen-specific CD4+ T cell proliferation, and CD8+ T cell cytotoxicity in DIO mice, whereas ER alone did not. These findings demonstrate that obesity-induced immune impairments in NK cell and T cell function can be reversed by EX or a combination of ER plus EX, but not ER alone. These results suggest that in obese mice exercise enhances immune function independently of changes in body weight, and that in humans exercise may be an important intervention to couple with energy restriction to reduce body weight and enhance immune responsiveness in obese patients. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B144.

Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression.

The effects of the chronic activation of the central melanocortin (MC) system by melanotan II (MTII) were assessed in chow-fed (CH) and high-fat (HF) diet-induced obese (DIO) Sprague-Dawley rats. Six-day central infusion of MTII (1 nmol/day) reduced body weight and visceral adiposity compared with ad libitum-fed control and pair-fed groups and markedly suppressed caloric intake in both CH and DIO rats. The anorexic response to MTII was similar in DIO relative to CH rats. MTII induced a sustained increase in oxygen consumption in DIO but a delayed response in CH rats. In both diet groups, MTII reduced serum insulin and cholesterol levels compared with controls. HF feeding increased brown adipose tissue (BAT) uncoupling protein 1 (UCP1) by over twofold, and UCP1 levels were further elevated in MTII-treated CH and DIO rats. MTII lowered acetyl-CoA carboxylase expression and prevented the reduction in muscle-type carnitine palmitoyltransferase I mRNA by pair-feeding in the muscle of DIO rats. Compared with CH controls, hypothalamic MC3 and MC4 receptor expression levels were reduced in DIO controls. This study has demonstrated that, despite reduced hypothalamic MC3/MC4 receptor expression, anorexic and thermogenic responses to MTII are unabated with an initial augmentation of energy expenditure in DIO versus CH rats. The HF-induced up-regulation of UCP1 in BAT may contribute to the immediate increase in MTII-stimulated thermogenesis in DIO rats. MTII also increased fat catabolism in the muscle of DIO rats and improved glucose and cholesterol metabolism in both groups.

Treatment with CL 316,243, a β3-adrenoceptor agonist, reduces serum leptin in rats with diet- or aging-associated obesity, but not in Zucker rats with genetic (fa/fa) obesity

To assess the effect of chronic treatment with a beta 3-adrenoceptor agonist, CL 316,243 (CL) on serum leptin concentration in rats with diet-induced obesity (DIO) or with genetic obesity (fa/fa Zucker). Leptin concentration was measured in serum of young control rats, young rats with DIO and old control or genetically obese fa/fa Zucker rats, that were treated chronically with CL for 2-4 weeks in our previous studies. Treatment with CL reduced elevated leptin concentrations in young rats with DIO and in old mildly obese control rats to the low concentration of young lean rats. It did not alter the grossly elevated concentration in fa/fa rats. This effect of CL correlated well with its effect to reduce white adipocyte size, except in fa/fa rats. In CL-treated fa/fa rats, despite reductions in body fat mass and in white adipocyte size, and despite normalization of both hyperglycemia and hyperinsulinemia, the leptin concentration did not change. The reason for lack of change in leptin concentrations in fa/fa rats, despite shrinking of white adipocytes and partial reversal of the obesity, may be due to another defect. The large increase in white adipocyte number in these animals was not reversed by the treatment and might have contributed to elevated leptin production. In addition, all forms of leptin receptor are known to be defective in fa/fa rats. Since leptin is rapidly excreted in urine and leptin receptors (including a form known to be involved in leptin transport) are expressed in the kidney, we suggest that leptin excretion is impaired in the fa/fa rat. This impairment contributes to maintenance of an elevated concentration of leptin in its blood and prevents treatment with a beta 3-adrenoceptor agonist from reducing this elevated concentration despite reversal of both obesity and diabetes. In addition, we suggest that CL-induced suppression of hyperphagia in fa/fa rats is leptin-independent and due to the large increase in thermogenesis.