Ivana Dostálová

Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity.

Objective  Fibroblast growth factor‐21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions.

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.

The endocrine profile of subcutaneous and visceral adipose tissue of obese patients

The aim of the present study was to evaluate the expression profile of genes potentially related to metabolic complications of obesity in the whole adipose tissue and isolated adipocytes from subcutaneous (SAT) and visceral adipose tissue (VAT) from 12 non-diabetic obese women and 12 lean women. Real-time polymerase chain reaction was used for expression analysis of 41 genes of interest and two housekeeping genes. We found increased expression of specific proinflammatory and adipogenic genes and reduced expression of specific lipogenic and insulin signaling pathway genes in obese relative to lean women with no preferable localization in SAT or VAT depot. The gene expression significantly differed between adipocytes and adipose tissue but both contributed to the proinflammatory profile in obesity. We conclude that both SAT and VAT exhibit alterations in the expression of specific genes possibly contributing to proinflammatory and insulin resistance state and consequently to metabolic complications of obesity.

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.

Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors alpha and beta were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-alpha, CD68, IL-6, IL-8, ER alpha, ER beta) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Leptin concentrations in the abdominal subcutaneous adipose tissue of patients with anorexia nervosa assessed by in vivo microdialysis

OBJECTIVE The adipocyte-derived hormone leptin is involved in energy metabolism and body weight regulation. Plasma leptin concentrations are significantly reduced in patients with anorexia nervosa (AN) and with severe malnutrition. Whether reduced plasma leptin is reflected by its decreased production by the adipose tissue is unknown. METHODS In the present study we measured leptin concentrations locally in the abdominal subcutaneous adipose tissue of 9 female AN patients and 11 healthy controls by in vivo microdialysis. RESULTS Adipose tissue free leptin levels were not different in patients with AN compared to controls (2.59+/-1.99 vs 2.36+/-0.25 ng/ml, P>0.05). Plasma leptin soluble receptor (sOb-R) levels were significantly higher in patients with AN than in healthy subjects (58.05+/-38.69 vs 12.79+/-5.08 U/ml, P<0.01). The area of adipocyte in AN was considerably smaller than in the controls (183+/-104.01 microm2 compared to 2145.8+/-1003.41). CONCLUSIONS We conclude that decreased plasma leptin levels in patients with AN are not directly related to dialysate leptin levels in the abdominal subcutaneous adipose tissue.

Basal and exercise-induced sympathetic nervous activity and lipolysis in adipose tissue of patients with anorexia nervosa

Background  The sympathetic nervous system plays an important role in the regulation of adipose tissue (AT) lipolysis, which is a key step in the metabolic processes leading to the decrease of fat mass. The present study was designed to determine in vivo basal and exercise‐stimulated lipolysis and concentrations of catecholamines, the major hormones controlling lipolysis, in subcutaneous abdominal AT in patients with anorexia nervosa (AN), characterized by self‐induced starvation and excessive exercises resulting in severe malnutrition and fat store loss. The results of local catecholamines and glycerol levels were compared with those in plasma in both experimental groups.

Application of in vivo microdialysis to measure leptin concentrations in adipose tissue

Microdialysis is a relatively new in vivo sampling technique, which allows repeated collecting of interstitial fluid and infusion of effector molecules into the tissue without influencing whole body function. The possibility of using microdialysis catheter with a large-pore size dialysis membrane (100 kDa) to measure concentrations of the adipocyte-derived peptide hormone leptin in interstitial fluid of adipose tissue was explored. Krebs-Henseleit buffer with 40 g/l dextran-70 was used to prevent perfusion fluid loss across the dialysis membrane. The relative recovery of leptin in vitro was determined using CMA/65 microdialysis catheter (100 kDa cut-off, membrane length 30 mm; CMA, Stockholm, Sweden) and four perfusion rates were tested (0.5, 1.0, 2.0, 5.0 microl/min). Furthermore, the microdialysis catheter CMA/65 was inserted into subcutaneous abdominal adipose tissue of 11 healthy human subjects and leptin concentrations in the interstitial fluid of adipose tissue in vivo were measured. The present findings are the first documentation on the use of microdialysis to study local leptin concentrations in the interstitial fluid of adipose tissue.

Association of macrophage inhibitory cytokine-1 with nutritional status, body composition and bone mineral density in patients with anorexia nervosa: the influence of partial realimentation.

BackgroundMacrophage inhibitory cytokine-1 (MIC-1) is a key inducer of cancer-related anorexia and weight loss. However, its possible role in the etiopathogenesis of nutritional disorders of other etiology such as anorexia nervosa (AN) is currently unknown.MethodsWe measured fasting serum concentrations of MIC-1 in patients with AN before and after 2-month nutritional treatment and explored its relationship with nutritional status, metabolic and biochemical parameters. Sixteen previously untreated women with AN and twenty-five normal-weight age-matched control women participated in the study. We measured serum concentrations of MIC-1 and leptin by ELISA, free fatty acids by enzymatic colorimetric assay, and biochemical parameters by standard laboratory methods; determined resting energy expenditure by indirect calorimetry; and assessed bone mineral density and body fat content by dual-energy X-ray absorptiometry. ANOVA, unpaired t-test or Mann-Whitney test were used for groups comparison as appropriate. The comparisons of serum MIC-1 levels and other studied parameters in patients with AN before and after partial realimentation were assessed by paired t-test or Wilcoxon Signed Rank Test as appropriate.ResultsAt baseline, fasting serum MIC-1 concentrations were significantly higher in patients with AN relative to controls. Partial realimentation significantly reduced serum MIC-1 concentrations in patients with AN but it still remained significantly higher compared to control group. In AN group, serum MIC-1 was inversely related to Buzby nutritional risk index, serum insulin-like growth factor-1, serum glucose, serum total protein, serum albumin, and lumbar bone mineral density and it significantly positively correlated with the duration of AN and age.ConclusionsMIC-1 concentrations in AN patients are significantly higher relative to healthy women. Partial realimentation significantly decreased MIC-1 concentration in AN group. Clinical significance of these findings needs to be further clarified.

Changes of Noradrenergic Activity and Lipolysis in the Subcutaneous Abdominal Adipose Tissue of Hypo‐ and Hyperthyroid Patients: An In Vivo Microdialysis Study

Abstract: Thyroid function plays an important role in the regulation of overall metabolic rate and lipid metabolism. However, it is uncertain whether thyroid hormones directly affect lipolysis in adipose tissue and to what extent those changes contribute to overall metabolic phenotype. Our study was designed, using the microdialysis technique, to determine basal and isoprenaline‐stimulated local lipolysis and to determine local concentrations of lipolysis‐regulating catecholamines in abdominal subcutaneous adipose tissue in 12 patients with hypothyroidism, 6 patients with hyperthyroidism, and 12 healthy control subjects. Plasma norepinephrine (NE) concentrations in hypothyroid subjects were significantly higher than in the control and hyperthyroid groups. In contrast, systemic, adipose NE levels in hypothyroid patients were decreased relative to controls. Hyperthyroidism, on the other hand, resulted in four‐fold higher adipose NE levels. Basal lipolysis measured by glycerol concentrations in adipose tissue was significantly attenuated in hypothyroid patients and markedly increased in hyperthyroid patients in comparison with the control group. In addition to differences in basal lipolysis, hypothyroidism resulted in attenuated, and hyperthyroidism in enhanced, lipolytic response to local stimulation with β1,2‐adrenergic agonist isoprenaline. These results demonstrate that lipolysis in abdominal subcutaneous adipose tissue is strongly modulated by thyroid function. We suggest that thyroid hormones regulate lipolysis primarily by affecting local NE concentration and/or adrenergic postreceptor signaling.