The role of obesity in the immune response during sepsis.

BACKGROUND/OBJECTIVES: Sepsis is one of the most important causes of mortality in the developed world, where almost two-thirds of the population suffer from obesity. Therefore, the coexistence of both conditions has become frequent in clinical practice and a growing number of clinical studies attempts to examine the potential effect of obesity on sepsis with controversial results up to now. The present study investigates how obesity influences the immune response of septic patients, by assessing the number and activation state of adipose tissue macrophages, serum and adipose tissue tumor necrosis factor-alpha (TNFα) levels and plasma oxidative stress markers. SUBJECTS/METHODS: The study included 106 patients, divided into four groups (control n=26, obesity n=27, sepsis n=27 and sepsis and obesity n=26). The number of macrophages in subcutaneous and visceral adipose tissue (SAT and VAT) and their subtypes (M1 and M2) were defined with immunohistochemical staining techniques under light microscopy. TNFα mRNA levels were determined in SAT and VAT using real-time reverse transcription-PCR. Serum levels of TNFα were determined with sandwich enzyme-linked immunosorbent assay. Plasma oxidative stress was evaluated using selective biomarkers (thiobarbituric acid-reactive substances (TBARS), protein carbonyls and total antioxidant capacity (TAC)). RESULTS: Sepsis increased the total number of macrophages and their M2 subtype in (VAT), whereas obesity did not seem to affect the concentration of macrophages in fat. Obesity increased TNFα mRNA levels (P<0.05) in VAT as well as the plasma TBARS (P<0.001) and protein carbonyls (P<0.001) in septic patients. The plasma TAC levels were decreased and the serum TNFα levels were increased in sepsis although they were not influenced by obesity. CONCLUSIONS: Obesity is associated with elevated TNFα adipose tissue production and increased oxidative stress biomarkers, promoting the proinflammatory response in septic patients.

Activated hypothalamic pituitary adrenal axis in patients with metabolic syndrome.

Metabolic syndrome (MetS) is correlated with the activity of hypothalamic-pituitary-adrenal axis (HPA), but the underlying mechanism still remains elusive. The aim of this study was to investigate the HPA axis function in patients with MetS. This case-control study included 159 people. They were divided into 2 groups. The first group included 73 healthy volunteers (control group: 19 males, 54 females, mean±SD: 49.9±7.5 years old, with BMI: 27.9±4.42 kg/m2) and the second group included 86 patients with MetS (case group: 48 males, 38 females, mean±SD: 52.2±7.6 years old, with BMI: 30.5±5.35 kg/m2). An oral glucose tolerance test (OGTT) was performed for all subjects after a 12-h overnight fast, and blood samples were obtained for determination of ACTH, cortisol, insulin, C-peptide, and glucose levels. Serum cortisol after an overnight dexamethasone suppression test was determined in both groups. Patients with MetS had serum cortisol levels after an overnight dexamethasone suppression test significantly higher than controls. During OGTT plasma ACTH levels were higher at all time points in patients with MetS compared to controls, whereas serum cortisol levels were comparable between the 2 groups. Plasma ACTH during OGTT was also correlated with most of the components of MetS. The HPA axis in patients with MetS seems to be more active as evidenced by the higher cortisol levels after the overnight dexamethasone suppression test and by the higher ACTH levels during OGTT. This functional hypercortisolism might be involved in the pathogenesis of the metabolic syndrome.

Ghrelin response to oral glucose load in hyperthyroidism, before and after treatment with antithyroid drugs.

Hyperthyroidism is characterized by hyperphagia and increased basal metabolic rate. Ghrelin peptide is implicated in food intake through activation of the orexigenic neuropeptide Y/agouti related protein in the arcuate nucleus of hypothalamus. Also different studies suggested that ghrelin might play a role in states of energy insufficiency, controlling body weight. We therefore evaluate ghrelin levels in severe hyperthyroidism before and after medical treatment when euthyroidism was achieved, in order to evaluate its possible role in the increase of appetite and in the metabolic changes observed in hyperthyroidism. Serum ghrelin and insulin levels were measured after an oral glucose tolerance test (OGTT), in 7 severe hyperthyroid female patients, before and after medical treatment when euthyroidism was achieved. Body mass index (BMI), percentage of body fat and lean mass was also estimated in hyperthyroidism as well as in euthyroidism. Basal insulin levels were statistically higher in hyperthyroid patients with respect to euthyroid state after treatment (p=0.02, t=3.379), while homeostasis model assessment (HOMA) index for insulin sensitivity was statistically higher in hyperthyroidism (group 1) compared to euthyroidism (group 2) (1.64+/-0.69 vs 0.78+/-0.44, p=0.019, t=3.389). Fasting ghrelin concentrations were significantly reduced in group 1 compared to group 2 (938+/-578 pg/ml vs 1402+/-566 pg/ml, p<0.05, t=-2.489). Oral glucose loading induced suppression of ghrelin level in both groups, but the area under the curve for ghrelin during the OGTT in euthyroidism was greater compared to hyperthyroidism (p=0.05, t=-2.485). After medical treatment, a statistically significant increase in BMI (23.1+/-4.3 vs 25.9+/-5.1) (p=0.007, t=-4.399) was also observed. In hyperthyroidism, basal ghrelin levels showed a negative correlation with BMI (p=0.042, r=-0.829), insulin (p<0.001, r=-1.000), and HOMA index (p=0.019, r=-0.886). No correlation was found between ghrelin levels and thyroid hormone values. Ghrelin levels are decreased in hyperthyroidism and increase when euthyroidism is achieved. BMI and insulin are the main factors that influence ghrelin concentration in hyperthyroidism. T3 and T4 levels do not influence ghrelin levels. There is no evidence that ghrelin is responsible for the increase appetite seen in hyperthyroidism.

Hormonal responses to marathon running in non-elite athletes.

BACKGROUND: Exercise is known to be a powerful stimulus for the endocrine system. The hormonal response to exercise is dependent on several factors including the intensity, duration, mode of exercise (endurance versus resistance), and training status of the subject. The aim of the present study was to determine the steroid hormonal response (immediately after a race and 1 week later) to endurance exercise under the real conditions of the classic Athens marathon in a group of well-trained, middle-aged, non-elite athletes. METHODS: Blood samples were drawn 1 week before the race, directly after completion of the race, and 1 week later. RESULTS: Serum cortisol and prolactin showed distinct rises 1 h after the race and returned to baseline 1 week later. Androstenedione and dehydroepiandrosterone sulphate did not show any changes. Total testosterone as well as free testosterone dropped significantly 1 h after the race but returned to baseline 1 week later. CONCLUSION: In this particular group of non-elite, middle-aged marathon runners, the race resulted in an acute increase in serum cortisol and prolactin levels and in a concomitant decline in testosterone level. The aforementioned changes returned to baseline 1 week later.

Type 2 diabetes mellitus and worm longevity: a transcriptional link to cure?

In Caenorhabditis elegans, an insulin-like signalling pathway culminates in a transcription factor (TF) that is homologous to a subfamily of TFs responsible for the regulation of a subset of insulin-responsive genes in humans. Under harsh conditions, C. elegans reduces signalling through this pathway and arrests developmentally in a manner that is similar to the metabolic syndrome of humans. We propose that an understanding of this pathway could lead to drugs with optimal potency and selectivity in the treatment of type 2 diabetes mellitus.

A novel multifunctional motif in the amino-terminal A/B domain of T3Ralpha modulates DNA binding and receptor dimerization.

We reported previously that deletion of the 50-amino acid NH2-terminal A/B domain of the chicken (c) or rat thyroid hormone (T3) receptor-alpha (T3Ralpha) decreased the T3-dependent stimulation of genes regulated by native thyroid hormone response elements (TREs). This requirement of the NH2-terminal A/B domain for transcriptional activation was mapped to amino acids 21-30 of cT3Ralpha. Expression of transcription factor IIB (TFIIB) in cells was shown to enhance T3-dependent transcriptional activation by cT3Ralpha, and this enhancement by TFIIB was dependent on the same 10-amino acid sequence. In vitro binding studies indicated that cT3Ralpha interacts efficiently with TFIIB, and this interaction requires amino acids 23KRKRK27 in the A/B domain. In this study we document the functional importance of these five basic residues in transcriptional activation by cT3Ralpha, further supporting the biological significance of these residues and their interaction with TFIIB. Interestingly, we also find that the same amino acids also affect DNA binding and dimerization of cT3Ralpha. Gel mobility shift assays reveal that a cT3Ralpha mutant that has all five basic amino acids changed from 23KRKRK27 to 23TITIT27 binds to a palindromic TRE predominantly as a homodimer, whereas cT3Ralpha with the wild-type 23KRKRK27 sequence binds predominantly as a monomer. This results from both a marked decrease in the ability of the cT3Ralpha mutant to bind as a monomer and from an enhanced ability to dimerize as reflected by an increase in DNA-bound T3R-retinoic X receptor heterodimers. These effects of 23KRKRK27 on DNA binding, dimerization, transcriptional activation, and the association of T3Ralpha with TFIIB support the notion that this basic amino acid motif may influence the overall structure and function of T3Ralpha and, thus, play a role in determining the distinct context-dependent transactivation potentials of the individual T3R isoforms.