Role of IL-18 in adipose tissue remodeling and metabolic dysfunction.

BACKGROUND/OBJECTIVES: Proinflammatory cytokines are increased in obese adipose tissue, including inflammasome key masters. Conversely, IL-18 protects against obesity and metabolic dysfunction. We focused on the IL-18 effect in controlling adipose tissue remodeling and metabolism. MATERIALS/SUBJECTS AND METHODS: We used C57BL/6 wild-type (WT) and interleukine-18 deficient (IL-18-/-) male mice fed a chow diet and samples from bariatric surgery patients. RESULTS: IL-18-/- mice showed increased adiposity and proinflammatory cytokine levels in adipose tissue, leading to glucose intolerance. IL-18 was widely secreted by stromal vascular fraction but not adipocytes from mice's fatty tissue. Chimeric model experiments indicated that IL-18 controls adipose tissue expansion through its presence in tissues other than bone marrow. However, IL-18 maintains glucose homeostasis when present in bone marrow cells. In humans with obesity, IL-18 expression in omental tissue was not correlated with BMI or body fat mass but negatively correlated with IRS1, GLUT-4, adiponectin, and PPARy expression. Also, the IL-18RAP receptor was negatively correlated with IL-18 expression. CONCLUSIONS: IL-18 signaling may control adipose tissue expansion and glucose metabolism, as its absence leads to spontaneous obesity and glucose intolerance in mice. We suggest that resistance to IL-18 signaling may be linked with worse glucose metabolism in humans with obesity.

Acute exercise modulates the inflammatory response in adipose tissue in both lean and obese mice.

OBJECTIVES: Acute physical exercise acts as a metabolic stressor, promoting activation of the immune system, and this response could be relevant in the adipose tissue remodeling process. In addition, some cytokines have important functions in lipolysis. Because chronic exercise improves obesity-related metabolic and inflammatory dysfunction, herein we investigated the effect of acute exercise on the inflammatory responses in the adipose tissues of lean and obese mice. METHODS: Lean mice were fed a standard chow diet, whereas obese mice were fed a high-refined carbohydrate diet for 8 wk. Both groups were subjected to 60 min of moderate-intensity exercise. RESULTS: In the epididymal adipose tissue of lean mice, exercise enhanced interleukin (IL)-6 and tumor necrosis factor-α levels, which correlated positively with increased serum free fatty acid concentrations. In vivo confocal imaging of epididymal adipose tissue vessels revealed higher recruitment of neutrophils after exercise. Also, the number of leukocytes expressing CD11b+F480- was elevated 6 h after exercise. Similarly, the chemokine (C-X-C motif) ligand 1 level increased at 6 h and remained high until 24 h after exercise. Myeloperoxidase activity was increased at 6, 12, and 24 h after exercise. Surprisingly, however, no changes were observed in epididymal adipose tissue from obese mice, considering proinflammatory cytokines (IL-6 and tumor necrosis factor-α). On the other hand, IL-13, IL-4, and IL-10 levels were higher in obese mice after exercise. CONCLUSIONS: These data suggest that acute exercise promotes an inflammatory response in the adipose tissue of lean mice that is observed as part of its role in adipose tissue remodeling. In contrast, acute exercise promotes an antiinflammatory response in adipose tissue from obese mice, likely as an important tool for restoring homeostasis.

Effect of high-refined carbohydrate diet on intestinal integrity.

OBJECTIVES: One of the leading causes of obesity is the consumption of excess nutrients. Obesity is characterized by adipose tissue expansion, chronic low-grade inflammation, and metabolic alterations. Although consumption of a high-fat diet has been demonstrated to be a diet-induced obesity model associated with gut disorders, the same effect is not well explored in a mild-obesity model induced by high-refined carbohydrate (HC) diet intake. The intestinal tract barrier comprises mucus, epithelial cells, tight junctions, immune cells, and gut microbiota. This system is susceptible to dysfunction by excess dietary components that could increase intestinal permeability and bacterial translocation. The aim of this study was to evaluate whether an HC diet and the alterations resulting from its intake are linked to small intestine changes. METHODS: Male BALB/c mice were fed a chow or an HC diet for 8 wk. RESULTS: Although differences in body weight gain were not observed between the groups, mice fed the HC diet showed increased adiposity associated with metabolic alterations. The interferon-γ expression and myeloperoxidase levels were increased in the small intestine in mice fed an HC diet. However, the intestinal villi length, the expression of tight junctions (zonula occludens-1 and claudin-4) and tumor necrosis factor-α cytokine, and the percentage of intraepithelial lymphocytes did not differ in the jejunum or ileum between the groups. We did not observe differences in intestinal permeability and bacterial translocation. CONCLUSION: Metabolic alterations caused by consumption of an HC diet lead to a mild obesity state that does not necessarily involve significant changes in intestinal integrity.

Role of adipose tissue inflammation in fat pad loss induced by fasting in lean and mildly obese mice.

Inflammation induced by obesity contributes to insulin resistance and atherosclerosis. Indeed, high levels of proinflammatory cytokines trigger chronic low-grade inflammation and promote detrimental metabolic effects in the adipose tissue. On the other hand, inflammation seems to control fat pad expansion and to have important functions on lipolysis and glucose metabolism. Thus, it is possible that inflammation may also drive fat pad loss, as seen during long-fast periods. Herein, we have used fasting as a strategy to induce weight loss and evaluate the possible role of inflammation on adipose tissue remodeling. Male BALB-c mice were fed with chow diet (lean mice) or with high-carbohydrate refined diet (mildly obese mice) for 8 weeks. After that, animals were subjected to 24 h of fasting. There was a 63% reduction of adiposity in lean mice following fasting. Furthermore, the adipose tissue was enriched of immune cells and had a higher content of IL-6, TNF-alpha, IL-10, TGF-ß and CXCL-1. Interestingly, mildly obese mice, subjected to the same 24-h fasting period, lost only 33% of their adiposity. Following fasting, these mice did not show any increment in leukocyte recruitment and cytokine levels, as did lean mice. Our findings indicate that inflammation participates in fat mass loss induced by fasting. Although the chronic low-grade inflammation seen in obesity is associated with metabolic diseases, a lower inflammatory response triggered by fasting in mildly obese mice impairs fat pad mobilization.

L-arginine supplementation prevents increases in intestinal permeability and bacterial translocation in male Swiss mice subjected to physical exercise under environmental heat stress.

Dietary supplementation with l-arginine has been shown to improve the intestinal barrier in many experimental models. This study investigated the effects of arginine supplementation on the intestinal permeability and bacterial translocation (BT) induced by prolonged physical exercise under heat stress. Under anesthesia, male Swiss mice (5-wk-old) were implanted with an abdominal sensor to record their core body temperature (T(core)). After recovering from surgery, the mice were divided into 3 groups: a non-supplemented group that was fed the standard diet formulated by the American Institute of Nutrition (AIN-93G; control), a non-supplemented group that was fed the AIN-93G diet and subjected to exertional hyperthermia (H-NS), and a group supplemented with l-arginine at 2% and subjected to exertional hyperthermia (H-Arg). After 7 d of treatment, the H-NS and H-Arg mice were forced to run on a treadmill (60 min, 8 m/min) in a warm environment (34°C). The control mice remained at 24°C. Thirty min before the exercise or control trials, the mice received a diethylenetriamine pentaacetic acid (DTPA) solution labeled with technetium-99m ((99m)Tc-DTPA) or (99m)Tc-Escherichia coli by gavage to assess intestinal permeability and BT, respectively. The H-NS mice terminated the exercise with T(core) values of ∼40°C, and, 4 h later, presented a 12-fold increase in the blood uptake of (99m)Tc-DTPA and higher bacterial contents in the blood and liver than the control mice. Although supplementation with arginine did not change the exercise-induced increase in T(core), it prevented the increases in intestinal permeability and BT caused by exertional hyperthermia. Our results indicate that dietary l-arginine supplementation preserves the integrity of the intestinal epithelium during exercise under heat stress, acting through mechanisms that are independent of T(core) regulation.

Physical exercise-induced changes in the core body temperature of mice depend more on ambient temperature than on exercise protocol or intensity.

The mechanisms underlying physical exercise-induced hyperthermia may be species specific. Therefore, the present study aimed to investigate the effects of exercise intensity and ambient temperature on the core body temperature (T core) of running mice, which provide an important experimental model for advancing the understanding of thermal physiology. We evaluated the influence of different protocols (constant- or incremental-speed exercises), treadmill speeds and ambient temperatures (T a) on the magnitude of exercise-induced hyperthermia. To measure T core, a telemetric sensor was implanted in the abdominal cavity of male adult Swiss mice under anesthesia. After recovering from the surgery, the animals were familiarized to running on a treadmill and then subjected to the different running protocols and speeds at two T a: 24 °C or 34 °C. All of the experimental trials resulted in marked increases in T core. As expected, the higher-temperature environment increased the magnitude of running-induced hyperthermia. For example, during incremental exercise at 34 °C, the maximal T core achieved was increased by 1.2 °C relative to the value reached at 24 °C. However, at the same T a, neither treadmill speed nor exercise protocol altered the magnitude of exercise-induced hyperthermia. We conclude that T core of running mice is influenced greatly by T a, but not by the exercise protocols or intensities examined in the present report. These findings suggest that the magnitude of hyperthermia in running mice may be regulated centrally, independently of exercise intensity.