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.

SOCS2 modulates adipose tissue inflammation and expansion in mice.

INTRODUCTION: Obesity is usually triggered by a nutrient overload that favors adipocyte hypertrophy and increases the number of pro-inflammatory cells and mediators into adipose tissue. These mediators may be regulated by suppressors of cytokine signaling (SOCS), such as SOCS2, which is involved in the regulation of the inflammatory response of many diseases, but its role in obesity is not yet known. We aimed to investigate the role of SOCS2 in metabolic and inflammatory dysfunction induced by a high-refined carbohydrate-containing diet (HC). MATERIAL AND METHODS: Male C57BL/6 wild type (WT) and SOCS2 deficient (SOCS2-/-) mice were fed chow or an HC diet for 8 weeks. RESULTS: In general, SOCS2 deficient mice, independent of the diet, showed higher adipose tissue mass compared with their WT counterparts that were associated with decreased lipogenesis rate in adipose tissue, lipolysis in adipocyte culture and energy expenditure. An anti-inflammatory profile was observed in adipose tissue of SOCS2-/- by reduced secretion of cytokines, such as TNF and IL-6, and increased M2-like macrophages and regulatory T cells compared with WT mice. Also, SOCS2 deficiency reduced the differentiation/expansion of pro-inflammatory cells in the spleen but increased Th2 and Treg cells compared with their WT counterparts. CONCLUSION: The SOCS2 protein is an important modulator of obesity that regulates the metabolic pathways related to adipocyte size. Additionally, SOCS2 is an inflammatory regulator that appears to be essential for controlling the release of cytokines and the differentiation/recruitment of cells into adipose tissue during the development of obesity.

Adipokines, inflammatory mediators, and insulin-resistance parameters may not be good markers of metabolic syndrome after liver transplant.

OBJECTIVE: The role of adipokines in liver transplantation (LTx) recipients who have metabolic syndrome (MetS) has seldom been assessed. The aim of this study was to investigate the concentrations of adipokines, inflammatory mediators, and insulin-resistance markers in liver recipients with MetS and its components. METHODS: Serum samples from 34 patients (55.9% male; 54.9 ± 13.9 y; 7.7 ± 2.9 y after LTx; 50% presented with MetS) were assessed for adiponectin, resistin, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, C-reactive protein (CRP), homeostatic model assessment-insulin resistance (HOMA-IR) and free fatty acid (FFA) levels. The dosages were uni- and multivariate analyzed to cover MetS (using the Harmonizing MetS criteria), its components, and dietary intake. RESULTS: A higher concentration of adiponectin (P < 0.05) was observed among patients with MetS (5.2 ± 3.2 µg/mL) compared with those without MetS (3.2 ± 1.2 µg/mL), as well as those with MetS components versus those without them: abdominal obesity (4.6 ± 2.6 µg/mL versus 2.6 ± 0.6 µg/mL), high triacylglycerols (TGs; 5.6 ± 3.1 µg/mL versus 3 ± 0.9 µg/mL) and low high-density lipoprotein (HDL; 6.1 ± 2.7 µg/mL versus 3.3 ± 1.9 µg/mL). Increased TNF-α and HOMA-IR values were seen in patients with abdominal obesity. Patients with high TGs also had greater FFA values. Independent predictors for adiponectin were waist-to-hip ratio, low HDL and high TGs. High TGs and fasting blood glucose were independent predictors for HOMA-IR. Independent predictors could not be identified for CRP, TNF-α, MCP-1, IL-6, or FFA. CONCLUSIONS: MetS and its components are related to an increased HOMA-IR concentration and FFA. Adiponectin, resistin, and inflammatory markers, such as TNF-α, IL-6, MCP-1, and CRP, were not associated with MetS in this sample of post-LTx patients.

Immunologic and metabolic effects of high-refined carbohydrate-containing diet in food allergic mice.

OBJECTIVE: Allergic mice show a reduction in body weight and adiposity with a higher inflammatory response in the adipose tissue similar to obese fat tissue. This study aimed to evaluate whether the low-grade inflammatory milieu of mice with diet-induced mild obesity interferes with the allergic response induced by ovalbumin (OVA). METHODS: BALB/c mice were divided into four groups: 1) non-allergic (OVA-) mice fed chow diet, 2) allergic (OVA+) mice fed chow diet, 3) OVA- mice fed high-refined carbohydrate-containing (HC) diet, and 4) OVA+ mice fed HC diet. After 5 wk, allergic groups were sensitized with OVA and received a booster 14 d later. All groups received an oral OVA challenge 7 d after the booster. RESULTS: Allergic groups showed increased serum levels of total IgE, anti-OVA IgE, and IgG1; a high disease activity index score; aversion to OVA; and increased intestinal eosinophil infiltration. Non-allergic mild-obese mice also showed aversion to OVA and an increased number of eosinophils in the proximal jejunum. After the allergic challenge, OVA+ mice fed chow diet showed weight loss and lower adiposity in several adipose tissue depots. OVA+ mice fed HC diet showed a loss of fat mass only in the mesenteric adipose tissue. Furthermore, increased levels of TNF, IL-6, and IL-10 were observed in this tissue. CONCLUSIONS: Our data show that mild-obese allergic mice do not present severe pathologic features of food allergy similar to those exhibited by lean allergic mice. Mild obesity promoted by HC diet ingestion causes important intestinal disorders that appear to modulate the inflammatory response during the antigen challenge.

Osteopetrosis in obese female rats is site-specifically inhibited by physical training.

NEW FINDINGS: What is the central question of this study? Clinical studies suggest that obesity 'protects' against osteoporosis. However, these studies used only bone densitometry and assessed only one bone site, which is insufficient to enable conclusions to be drawn about the response of the whole skeleton. Furthermore, the effects of exercise on bone responses in obesity have not been explored previously. What is the main finding and what is its importance? We show that obesity causes osteopetrosis. Therefore, the classical perspective of 'protective effects of obesity' needs to be reviewed, and exercise is an important tool to avoid these alterations and to maintain the homeostasis of bone. A sedentary lifestyle and obesity induce systemic inflammatory responses. Although the effects of physical inactivity on osseous tissue have been well established, the effects of obesity on bone tissue remain controversial. Furthermore, the effects of physical training on bone tissue responses in the presence of diet-induced obesity are unknown. Our aim was to investigate the effects of obesity and physical training at multiple bone sites in rats. Female Wistar rats were divided into the following four groups: (i) control diet, non-trained (C-NT); (ii) high-refined carbohydrate-containing diet, non-trained (HC-NT); (iii) control diet, trained (C-T); and (iv) high-refined carbohydrate-containing diet, trained (HC-T). At 5 months of age, the rats were submitted to daily exercise for 30 min day(-1). After 13 weeks, blood samples, adipose and skeletal tissues were harvested. Two-way ANOVA was applied to detect differences (significance accepted when P ≤ 0.05). The HC-NT group exhibited increased body mass, adiposity, serum leptin, serum insulin, insulin resistance index and concentrations of tumour necrosis factor-α and interleukin-6. Obese rats (HC-NT) exhibited thickening of nasal bones, trabecular bones in the lumbar vertebrae and long bones in a site-dependent manner. The HC-T group exhibited similar adiposity and inflammatory results. Morphological analysis of the lumbar vertebrae in rats fed the HC diet revealed characteristics of osteopetrosis that were inhibited by exercise. In conclusion, the HC diet induced obesity and inflammatory/hormonal alterations and increased the trabecular bone in a site-dependent manner. However, obesity caused osteopetrosis in the lumbar vertebrae, which could be inhibited by physical training. Although exercise inhibited the development of bone alterations, physical training did not inhibit the HC diet-induced obesity responses.