Metabolomic profiling of urinary changes in mice with monosodium glutamate-induced obesity.

Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor-gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months.

The influence of deep hypothermia on inflammatory status, tissue hypoxia and endocrine function of adipose tissue during cardiac surgery.

Changes in endocrine function of adipose tissue during surgery, such as excessive production of proinflammatory cytokines, can significantly alter metabolic response to surgery and worsen its outcomes and prognosis of patients. Therapeutic hypothermia has been used to prevent damage connected with perioperative ischemia and hypoperfusion. The aim of our study was to explore the influence of deep hypothermia on systemic and local inflammation, adipose tissue hypoxia and adipocytokine production. We compared serum concentrations of proinflammatory markers (CRP, IL-6, IL-8, sIL-2R, sTNFRI, PCT) and mRNA expression of selected genes involved in inflammatory reactions (IL-6, TNF-α, MCP-1, MIF) and adaptation to hypoxia and oxidative stress (HIF1-α, MT3, GLUT1, IRS1, GPX1, BCL-2) in subcutaneous and visceral adipose tissue and in isolated adipocytes of patients undergoing cardiosurgical operation with hypothermic period. Deep hypothermia significantly delayed the onset of surgery-related systemic inflammatory response. The relative gene expression of the studied genes was not altered during the hypothermic period, but was significantly changed in six out of ten studied genes (IL-6, MCP-1, TNF-α, HIF1-α, GLUT1, GPX1) at the end of surgery. Our results show that deep hypothermia suppresses the development of systemic inflammatory response, delays the onset of local adipose tissue inflammation and thus may protect against excessive expression of proinflammatory and hypoxia-related factors in patients undergoing elective cardiac surgery procedure.

Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet.

OBJECTIVE: Macrophage inhibitory cytokine-1 (MIC-1) is a novel regulator of energy homeostasis. We explored whether alterations in MIC-1 levels contribute to metabolic disturbances in patients with obesity and/or obesity and type 2 diabetes mellitus (T2DM). DESIGN: We measured serum MIC-1 levels and its mRNA expression in subcutaneous and visceral adipose tissue of 17 obese nondiabetic women, 14 obese women with T2DM and 23 healthy lean women. We also explored the relationship of MIC-1 with anthropometric and biochemical parameters and studied the influence of 2-week very low calorie diet (VLCD) on serum MIC-1 levels. METHODS: Serum MIC-1 levels were measured by ELISA and its mRNA expression was determined by RT-PCR. RESULTS: Both obese and T2DM group had significantly elevated serum MIC-1 levels relative to controls. T2DM group had significantly higher serum MIC-1 levels relative to obese group. Serum MIC-1 positively correlated with body weight, body fat, and serum levels of triglycerides, glucose, HbAlc, and C-reactive protein and it was inversely related to serum high-density lipoprotein cholesterol. Fat mRNA MIC-1 expression did not significantly differ between lean and obese women but it was significantly higher in subcutaneous than in visceral fat in both groups. VLCD significantly increased serum MIC-1 levels in obese but not T2DM group. CONCLUSION: Elevated MIC-1 levels in patients with obesity are further increased by the presence of T2DM. We suggest that in contrast to patients with cancer cachexia, increased MIC-1 levels in obese patients and diabetic patients do not induce weight loss.

Increased production of proinflammatory cytokines in adipose tissue of patients with end-stage renal disease.

OBJECTIVE: The number of patients with end-stage renal disease (ESRD) is rising and these patients are at higher risk of cardiovascular disease. We studied the role of hormonal production of adipose tissue in the development of chronic inflammation in patients with ESRD before kidney transplantation. METHODS: Fifteen women with ESRD and 17 healthy women (control) underwent single blood drawing and visceral and subcutaneous adipose tissue sampling during surgery (kidney transplantation in the ESRD group or cholecystectomy in the control group). Serum concentrations of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, leptin, adiponectin, resistin, monocyte chemoattractant protein-1 were measured. Messenger RNA expression of the same hormones, adiponectin receptors 1 and 2 and immunocompetent cell marker CD68 in subcutaneous and visceral samples were measured using real-time polymerase chain reaction. Adipose tissue was examined immunohistochemically for CD68-positive cells. RESULTS: Serum concentrations of C-reactive protein, adiponectin, resistin, interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 were significantly higher in the ESRD versus control group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-alpha and CD68 were significantly increased in the ESRD versus control group. Adiponectin receptor-1 and monocyte chemoattractant protein-1 mRNA expressions were significantly higher in visceral but not in subcutaneous adipose tissue of the ESRD group. Messenger RNA expressions of resistin, leptin, adiponectin, interleukin-6, and adiponectin receptor-2 in both fat depots did not significantly differ between groups. Increased infiltration of subcutaneous and visceral adipose tissue with CD68-positive immunocompetent cells was found in the ESRD group by histologic examination. CONCLUSION: Subcutaneous and visceral adipose tissues in ESRD express higher amounts of proinflammatory cytokines and may play a role in the development of systemic inflammation.

Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa.

CONTEXT: Fibroblast growth factor 19 (FGF19) and FGF21 are novel metabolic regulators that improve insulin sensitivity and decrease adiposity in mice. However, little is known about the nutritional regulation of these factors in humans. OBJECTIVE: The objective of this study was to measure plasma FGF19 and FGF21 levels in patients with anorexia nervosa (AN) and to explore its relationship with anthropometric and endocrine parameters. DESIGN: This was a single-center cross-sectional study. SETTING: The study was performed in a university hospital. PATIENTS: Seventeen untreated women with a restrictive type of AN and 17 healthy women (control group) were included. MAIN OUTCOME MEASURES: Fasting plasma FGF19 and FGF21, serum insulin, leptin, soluble leptin receptor, adiponectin, resistin, and C-reactive protein were the main outcome measures. RESULTS: Plasma FGF19 levels did not significantly differ between the groups studied, whereas plasma FGF21 levels were significantly reduced in AN relative to the control group. Plasma FGF21 positively correlated with body mass index and serum leptin and insulin and was inversely related to serum adiponectin in both groups. In contrast, plasma FGF19 was not related to any of parameters studied. Partial realimentation significantly reduced plasma FGF21 levels in AN. CONCLUSION: Circulating levels of FGF21 but not FGF19 are strongly related to body weight and serum levels of leptin, adiponectin, and insulin in both anorectic and normal-weight women. We suggest that reduced plasma FGF21 levels could be involved in the pathophysiology of AN or in a complex adaptive response to this disease.

Gene polymorphisms of superoxide dismutases and catalase in diabetes mellitus.

BACKGROUND: Reactive oxygen species generated by hyperglycaemia modify structure and function of lipids, proteins and other molecules taking part in chronic vascular changes in diabetes mellitus (DM). Low activity of scavenger enzymes has been observed in patients with DM. Protective role of scavenger enzymes may be deteriorated by oxidative stress. This study was undertaken to investigate the association between gene polymorphisms of selected antioxidant enzymes and vascular complications of DM. RESULTS: Significant differences in allele and genotype distribution among T1DM, T2DM and control persons were found in SOD1 and SOD2 genes but not in CAT gene (p < 0,01). Serum SOD activity was significantly decreased in T1DM and T2DM subjects compared to the control subjects (p < 0,05). SOD1 and SOD2 polymorphisms may affect SOD activity. Serum SOD activity was higher in CC than in TT genotype of SOD2 gene (p < 0,05) and higher in AA than in CC genotype of SOD1 gene (p < 0,05). Better diabetes control was found in patients with CC than with TT genotype of SOD2 gene. Significantly different allele and genotype frequencies of SOD2 gene polymorphism were found among diabetic patients with macroangiopathy and those without it. No difference was associated with microangiopathy in all studied genes. CONCLUSION: The results of our study demonstrate that oxidative stress in DM can be accelerated not only due to increased production of ROS caused by hyperglycaemia but also by reduced ability of antioxidant defense system caused at least partly by SNPs of some scavenger enzymes.

Changes of endocrine function of adipose tissue in anorexia nervosa: comparison of circulating levels versus subcutaneous mRNA expression.

OBJECTIVE: To study the influence of chronic malnutrition in patients with anorexia nervosa on endocrine function of adipose tissue on both circulating and subcutaneous fat mRNA expression level. PATIENTS AND DESIGN: A total of 12 patients with anorexia nervosa and 18 normal weight age-matched women underwent anthropometric examination, single blood drawing and subcutaneous adipose tissue biopsy. MEASUREMENTS: Serum concentrations of high-sensitive CRP (hsCRP), leptin, soluble leptin receptor, adiponectin, resistin, interleukin-6 and insulin were measured by Luminex, enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) kits. Subcutaneous adipose tissue mRNA expression of the same adipokines, adiponectin receptors 1 and 2 and immunocompetent cells marker CD68 was measured by real-time polymerase chain reaction (PCR). RESULTS: Decreased body fat content of patients with anorexia nervosa was accompanied by reduced hsCRP, leptin and increased adiponectin and soluble leptin receptor. Resistin, interleukin-6 and insulin levels did not differ from those of the control group. Fat mRNA adiponectin, leptin, interleukin-6 and CD68 expression was reduced, resistin mRNA expression was increased and adiponectin receptor 1 and 2 expression were unchanged as compared to the control group. CONCLUSIONS: Local perturbations in resistin, adiponectin and interleukin-6 mRNA expression in subcutaneous adipose tissue are not reflected by its circulating levels. These changes could be involved in some local metabolic disturbances in subcutaneous adipose tissue of anorexia nervosa patients.

Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance.

CONTEXT: Hyperglycemia and insulin resistance frequently occur in critically ill patients even without a history of diabetes. OBJECTIVE: Our objective was to study the role of adipose tissue hormonal production in the development of insulin resistance in cardiac surgery patients. PARTICIPANTS, INTERVENTIONS, AND SETTINGS: Fifteen patients with elective cardiac surgery underwent blood sampling before, at the end, and 6, 12, 24, 48, and 120 h after the end of their operation. Epicardial and sc adipose tissue sampling was done at the beginning and at the end of surgery in the Department of Cardiac Surgery. MAIN OUTCOME MEASURES: We measured serum concentrations and sc and epicardial adipose tissue mRNA expression of IL-6, monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, leptin, resistin, and adiponectin and sc and epicardial adipose tissue mRNA expression of CD14, CD45, and CD68. RESULTS: The rate of insulin infusion required to maintain euglycemia increased up to 7-fold 12 h after the operation, suggesting the development of insulin resistance. Serum IL-6 levels increased 43-fold 12 h after surgery. MCP-1 peaked 6-fold at the end of surgery. Smaller peaks of TNF-alpha and leptin appeared 6 and 12 h after surgery, respectively. Resistin levels peaked 4-fold 24 h after surgery, but adiponectin levels were not significantly affected. TNF-alpha and CD45 mRNA expression increased markedly during the operation in sc adipose tissue. IL-6, resistin, and MCP-1 mRNA expression increased in both sc and epicardial adipose tissue. Leptin, adiponectin, CD14, and CD68 mRNA expression did not change significantly. CONCLUSIONS: Both sc and epicardial adipose tissue is a source of proinflammatory cytokines in cardiac surgery patients and may contribute to the development of postoperative insulin resistance.

The effects of GH replacement in adult GH-deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance.

BACKGROUND: Growth hormone deficiency (GHD) in adult life has been associated with increased central adiposity, decreased insulin sensitivity, dyslipidaemia and increased risk of cardiovascular disease. The effects of GH replacement on adiponectin and resistin, adipokines which have a role in modulating insulin sensitivity have not been previously reported. AIM: To examine the effects of GH replacement on adipokine levels and insulin resistance in GHD patients. DESIGN: Seventeen adult GHD patients were examined at baseline and after 1 year of treatment with recombinant human GH (mean dose 0.31 mg/day, range 0.13-0.67 mg/day). RESULTS: GH replacement significantly increased IGF-I levels. The mean IGF-I SD score increased from -1.98 at baseline to 0.76 at study end. GH replacement was associated with a significant reduction in percentage body fat (34.11 +/- 1.33 vs. 30.65 +/- 1.27%, P < 0.0005) and a significant increase in lean body mass (63.57 +/- 1.24 vs. 66.96 +/- 1.18%, P < 0.0004), before and after treatment, respectively. Surprisingly, there was no effect of GH replacement on the plasma levels of leptin, resistin or adiponectin or on plasma lipid profile. Insulin sensitivity did not deteriorate during GH replacement despite the known 'anti-insulin' effect of GH. Fasting glucose, insulin and insulin resistance as calculated using the homeostasis model assessment insulin resistance index (HOMA-R) were unchanged by GH treatment. CONCLUSION: These data demonstrate GH replacement in adult subjects with GHD is effective in changing body composition and restoring IGF-I levels over a 12-month period; however, in our study, these changes were not accompanied by changes in adipokine levels or beneficial effects on plasma lipids or insulin resistance.

Plasma ghrelin levels in patients with short bowel syndrome.

Ghrelin is a novel peptide hormone which was identified as an endogenous growth hormone secretagogue. It is mainly secreted in the stomach, but important sites of its secretion are other parts of the gastrointestinal tract. Ghrelin is thought to be involved not only in regulation of growth hormone secretion but also in regulation of food intake and nutritional status. This study was aimed to investigate the changes in plasma ghrelin levels in patients with short bowel syndrome. Twenty-four patients with malnutrition due to short bowel syndrome and eleven healthy controls were included in the study. They underwent clinical examination and assessment of plasma or serum levels of ghrelin leptin, soluble leptin receptor, IGF-I, IGFBP-1 and IGFBP-3. Plasma ghrelin levels were decreased in patients with short bowel syndrome (p<0.01). Furthermore, decreased serum levels of IGF-I (p<0.01) and IGFBP-3 (p<0.001) were found in patients with short bowel syndrome. Other laboratory differences between both groups were not significant. No relationship between ghrelin and other determined variables was found. We conclude that plasma ghrelin levels are decreased in the group of patients with short bowel syndrome. It is probably because of a decrease in the tissue mass that is able to secrete ghrelin.