The Long-Term Impact of High Levels of Alpha-Melanocyte-Stimulating Hormone in Energy Balance Among Obese Adolescents.

BACKGROUND: Deregulation of orexigenic and anorexigenic pathways occurs among adolescents with obesity. Alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis and an important anorexigenic neuropeptide in the control of energy balance and thermogenesis. However, it was not well explored if α-MSH can modulate long-term weight loss therapy responses in a dependent manner according to its concentration. Our hypothesis is that a high α-MSH concentration at baseline promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents. METHODS: One hundred ten post-pubertal obese adolescents (body mass index >95th percentile) were submitted to 1 year of interdisciplinary therapy (clinical, nutritional, psychological, physical exercise, and physiotherapy support). Body composition and plasma levels of α-MSH, neuropeptide Y (NPY), melanin-concentrating hormone, and agouti-related peptide (AgRP) were measured before and after therapy. The volunteers were grouped on the basis of Tertiles of α-MSH concentration: Low (<0.75 ng/mL), Medium (≤0.76 to ≥1.57 ng/mL), and High (>1.57 ng/mL). Significance was set as p < 0.05. RESULTS: The treatment promoted a significant improvement in body adiposity and fat free mass for all groups. It is important to note that only in the high α-MSH group, a significant increase of the α-MSH/NPY ratio and decrease NPY/AgRP ratio post treatment were observed. CONCLUSION: The high α-MSH concentration promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents following long-term weight loss therapy and this is important in clinical practice.

Insulin-Sensitizer Effects of Fenugreek Seeds in Parallel with Changes in Plasma MCH Levels in Healthy Volunteers.

In developed, developing and low-income countries alike, type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases, the severity of which is substantially a consequence of multiple organ complications that occur due to long-term progression of the disease before diagnosis and treatment. Despite enormous investment into the characterization of the disease, its long-term management remains problematic, with those afflicted enduring significant degradation in quality-of-life. Current research efforts into the etiology and pathogenesis of T2DM, are focused on defining aberrations in cellular physiology that result in development of insulin resistance and strategies for increasing insulin sensitivity, along with downstream effects on T2DM pathogenesis. Ongoing use of plant-derived naturally occurring materials to delay the onset of the disease or alleviate symptoms is viewed by clinicians as particularly desirable due to well-established efficacy and minimal toxicity of such preparations, along with generally lower per-patient costs, in comparison to many modern pharmaceuticals. A particularly attractive candidate in this respect, is fenugreek, a plant that has been used as a flavouring in human diet through recorded history. The present study assessed the insulin-sensitizing effect of fenugreek seeds in a cohort of human volunteers, and tested a hypothesis that melanin-concentrating hormone (MCH) acts as a critical determinant of this effect. A test of the hypothesis was undertaken using a hyperinsulinemic euglycemic glucose clamp approach to assess insulin sensitivity in response to oral administration of a fenugreek seed preparation to healthy subjects. Outcomes of these evaluations demonstrated significant improvement in glucose tolerance, especially in patients with impaired glucose responses. Outcome data further suggested that fenugreek seed intake-mediated improvement in insulin sensitivity correlated with reduction in MCH levels.

The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa.

Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa.

Melanin-concentrating hormone in peripheral circulation in the human.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a well-characterised role in energy homeostasis and emergent roles in diverse physiologic functions such as arousal, mood and reproduction. Work to date has predominantly focused on its hypothalamic functions using animal models; however, little attention has been paid to its role in circulation in humans. The aims of this study were to (a) develop a radioimmunoassay for the detection of MCH in human plasma; (b) establish reference ranges for circulating MCH and (c) characterise the pattern of expression of circulating MCH in humans. A sensitive and specific RIA was developed and cross-validated by RP-HPLC and MS. The effective range was 19.5-1248 pg MCH/mL. Blood samples from 231 subjects were taken to establish a reference range of 19.5-55.4 pg/mL for fasting MCH concentrations. There were no significant differences between male and female fasting MCH concentrations; however, there were correlations between MCH concentrations and BMI in males and females with excess fat (P < 0.001 and P = 0.020) and between MCH concentrations and fat mass in females with excess fat (P = 0.038). Plasma MCH concentrations rose significantly after feeding in a group of older individuals (n = 50, males P = 0.006, females P = 0.023). There were no robust significant correlations between fasting or post-prandial MCH and resting metabolic rate, plasma glucose, insulin or leptin concentrations although there were correlations between circulating MCH and leptin concentrations in older individuals (P = 0.029). These results indicate that the role of circulating MCH may not be reflective of its regulatory hypothalamic role.

Effects of repeated freeze-thaw cycles on endocrine parameters in plasma and serum.

Background Repeated freezing and thawing of plasma (or serum) may influence the stability of plasma (or serum) constituents. Despite the alarming warnings from commercial manuals that freeze-thaw cycles affect the stability of hormones in plasma (or serum), surprisingly little, consistent information about this concept is available in literature. Methods We studied the stability of 15 endocrine parameters (adrenocorticotropic hormone, osteocalcin, plasma renin activity, α-subunits, cortisol binding globulin, glucagon, inhibin B, fT4, TT4, TT3, rT3, TBG, TSH, chromogranin A and thyroglobulin upon repeated freeze-thaw cycles in plasma (or serum) samples from 10 volunteers. Blood was collected by venipuncture and after centrifugation and aliquoting, all samples were frozen at -20℃. Aliquots were thawed up to four times and changes in concentrations of endocrine parameters were compared to baseline condition. Results Repeated freeze-thaw cycling resulted in significant and relevant increases of plasma renin activity and a small decrease of adrenocorticotropic hormone. Conclusions For most of the analysed endocrine parameters, we found no effects of multiple freeze-thaw cycles despite alarming notifications in assay manuals. Plasma renin activity was the only endocrine parameter that showed significant and relevant changes following repeated freeze-thaw cycling.

Normal Morning Melanin-Concentrating Hormone Levels and No Association with Rapid Eye Movement or Non-Rapid Eye Movement Sleep Parameters in Narcolepsy Type 1 and Type 2.

STUDY OBJECTIVES: Other than hypocretin-1 (HCRT-1) deficiency in narcolepsy type 1 (NT1), the neurochemical imbalance of NT1 and narcolepsy type 2 (NT2) with normal HCRT-1 levels is largely unknown. The neuropeptide melanin-concentrating hormone (MCH) is mainly secreted during sleep and is involved in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep regulation. Hypocretin neurons reciprocally interact with MCH neurons. We hypothesized that altered MCH secretion contributes to the symptoms and sleep abnormalities of narcolepsy and that this is reflected in morning cerebrospinal fluid (CSF) MCH levels, in contrast to previously reported normal evening/afternoon levels. METHODS: Lumbar CSF and plasma were collected from 07:00 to 10:00 from 57 patients with narcolepsy (subtypes: 47 NT1; 10 NT2) diagnosed according to International Classification of Sleep Disorders, Third Edition (ICSD-3) and 20 healthy controls. HCRT-1 and MCH levels were quantified by radioimmunoassay and correlated with clinical symptoms, polysomnography (PSG), and Multiple Sleep Latency Test (MSLT) parameters. RESULTS: CSF and plasma MCH levels were not significantly different between narcolepsy patients regardless of ICSD-3 subtype, HCRT-1 levels, or compared to controls. CSF MCH and HCRT-1 levels were not significantly correlated. Multivariate regression models of CSF MCH levels, age, sex, and body mass index predicting clinical, PSG, and MSLT parameters did not reveal any significant associations to CSF MCH levels. CONCLUSIONS: Our study shows that MCH levels in CSF collected in the morning are normal in narcolepsy and not associated with the clinical symptoms, REM sleep abnormalities, nor number of muscle movements during REM or NREM sleep of the patients. We conclude that morning lumbar CSF MCH measurement is not an informative diagnostic marker for narcolepsy.

Phoenixin is negatively associated with anxiety in obese men.

Phoenixin was recently identified in the rat hypothalamus and initially implicated in reproductive functions. A subsequent study described an anxiolytic effect of the peptide. The aim of the study was to investigate a possible association of circulating phoenixin with anxiety in humans. We therefore enrolled 68 inpatients with a broad spectrum of psychometrically measured anxiety (GAD-7). We investigated men since a menstrual cycle dependency of phoenixin has been assumed. Obese subjects were enrolled since they often report psychological comorbidities. In addition, we also assessed depressiveness (PHQ-9) and perceived stress (PSQ-20). Plasma phoenixin levels were measured using a commercial ELISA. First, we validated the ELISA kit performing a spike-and-recovery experiment showing a variance of 6.7±8.8% compared to the expected concentrations over the whole range of concentrations assessed, while a lower variation of 1.6±0.8% was observed in the linear range of the assay (0.07-2.1ng/ml). We detected phoenixin in the circulation of obese men at levels of 0.68±0.50ng/ml. These levels showed a negative association with anxiety scores (r=-0.259, p=0.043), while no additional associations with other psychometric parameters were observed. In summary, phoenixin is present in the human circulation and negatively associated with anxiety in obese men, a population often to report comorbid anxiety.

Surgical castration but not immuncastration is associated with reduced hypothalamic GnIH and GHRH/GH/IGF-I axis function in male rats.

Gonadotropin-inhibitory hormone (GnIH) is a potent positive regulator of the growth axis. The present study was aimed to comparatively investigate the effects of surgical and immunologic castration on hypothalamic GnIH expression and endocrine function of the growth axis. Thirty-six prepubertal male rats were randomly allocated into three groups (n = 12): control, surgically castrated or immunized against 100-µg D-Lys6-GnRH-tandem peptide conjugated to ovalbumin in Specol adjuvant at 6 weeks of age (with a booster 8 weeks later). Blood samples were collected (for hormone and urea nitrogen concentrations) at 2-week intervals, and growth performance was evaluated. Compared to intact controls, surgical castration reduced (P < 0.05) messenger RNA (mRNA) expressions of hypothalamic GnIH and growth hormone-releasing hormone (GHRH), pituitary growth hormone (GH), and liver insulin-like growth factor-1 (IGF-1), reduced (P < 0.05) serum concentrations of GH and IGF-1 and increased (P < 0.05) serum concentrations of urea nitrogen. In contrast, immunocastration did not alter messenger RNA expressions of hypothalamic GnIH, GHRH and pituitary GH, and the serum concentrations of GH (P > 0.05). Moreover, serum concentrations of IGF-1 and urea nitrogen in immunocastrates were substantially higher and lower than those in surgical castrates, respectively (P < 0.05). Compared to surgical castrates, immuncastrates had superior feed conversion efficiency and faster daily weight gain (P < 0.05). We concluded that surgical castration but not immunocastration is associated with reduced hypothalamic GnIH and GHRH/GH/IGF-I axis function in male rats.

Manganese protects against the effects of alcohol on hypothalamic puberty-related hormones.

AIMS: Since manganese (Mn) is capable of stimulating the hypothalamic-pituitary unit and advancing female puberty, we assessed the possibility that this element might overcome some of the detrimental effects of prepubertal alcohol (ALC) exposure on the hypothalamic control of pituitary function. MAIN METHODS: Rats received either saline or Mn (10mg/kg) daily by gastric gavage from day 12 to day 31. After weaning, all rats were provided Lab Chow diet ad libitum until day 27 when they began receiving either the Bio Serv control or ALC diet regime. On day 31, the medial basal hypothalamus (MBH) was collected to assess luteinizing hormone-releasing hormone (LHRH) and cyclooxygenase 2 (COX2) protein levels. Release of prostaglandin-E2 (PGE2), LHRH and serum luteinizing hormone (LH) were also assessed. Other animals were not terminated on day 31, but remained in study to assess timing of puberty. KEY FINDINGS: Short-term ALC exposure caused elevated hypothalamic LHRH content, suggesting an inhibition in peptide release, resulting in a decrease in LH. Both actions of ALC were reversed by Mn supplementation. COX2 synthesis, as well as PGE2 and LHRH release were suppressed by ALC exposure, but Mn supplementation caused an increase in COX2 synthesis and subsequent PGE2 and LHRH release in the presence of ALC. Mn supplementation also ameliorated the action of ALC to delay puberty. SIGNIFICANCE: These results suggest that low level Mn supplementation acts to protect the hypothalamus from some of the detrimental effects of ALC on puberty-related hormones.

Hypothalamic-Pituitary Function in Brain Death: A Review.

The Uniform Determination of Death Act (UDDA) states that an individual is dead when "all functions of the entire brain" have ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some modest generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these findings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggesting that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord.

Food restriction negatively affects multiple levels of the reproductive axis in male house finches, Haemorhous mexicanus.

Nutrition influences reproductive functions across vertebrates, but the effects of food availability on the functioning of the hypothalamic-pituitary-gonadal (HPG) axis in wild birds and the mechanisms mediating these effects remain unclear. We investigated the influence of chronic food restriction on the HPG axis of photostimulated house finches, Haemorhous mexicanus. Food-restricted birds had underdeveloped testes with smaller seminiferous tubules than ad libitum-fed birds. Baseline plasma testosterone increased in response to photostimulation in ad libitum-fed but not in food-restricted birds. Food availability did not, however, affect the plasma testosterone increase resulting from a gonadotropin-releasing hormone-I (GnRH) or a luteinizing hormone (LH) challenge. The number of hypothalamic GnRH immunoreactive (ir) but not proGnRH-ir perikarya was higher in food-restricted than in ad libitum-fed finches, suggesting inhibited secretion of GnRH. Hypothalamic gonadotropin-inhibitory hormone (GnIH)-ir and neuropeptide Y (NPY)-ir were not affected by food availability. Plasma corticosterone (CORT) was also not affected by food availability, indicating that the observed HPG axis inhibition did not result from increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. This study is among the first to examine multilevel functional changes in the HPG axis in response to food restriction in a wild bird. The results indicate that food availability affects both hypothalamic and gonadal function, but further investigations are needed to clarify the mechanisms by which nutritional signals mediate these effects.

Dynamics of melanin-concentrating hormone (MCH) serum levels in major depressive disorder during antidepressant treatment.

BACKGROUND: In preclinical studies, the hypothalamic polypeptide melanin-concentrating hormone (MCH) has been shown to be involved in depression-like behavior and modulations of MCH and MCH-receptors were proposed as potential new antidepressant drug targets. METHODS: For the first time, MCH serum levels were explored in 30 patients with major depressive disorder (MDD) prior to (T1) and after 2 (T2) and 4 weeks (T3) of antidepressant treatment and in 30 age- and sex-matched healthy controls by applying a fluorescence immunoassay. RESULTS: Levels of MCH did not differ significantly between un-medicated patients (444.11±174.63pg/mL SD) and controls (450.68±210.03pg/mL SD). In MDD patients, MCH levels significantly decreased from T1 to T3 (F=4.663; p=0.013). Post-hoc analyses showed that these changes were limited to patients treated with mirtazapine but not escitalopram and female but not male patients. MCH-levels showed high correlations from T1 to T3 (r≥0.964, p<0.001) and were found to correlate significantly with parameters of sleep within the controls. LIMITATIONS: Small sample size. No follow-up measures were performed within the control group. CONCLUSIONS: Our findings suggest peripheral MCH-levels not to be altered in depression but possibly reflecting depression-related state properties that can be modulated by sleep, medication and sex.

Increased hypothalamic-pituitary-adrenal drive is associated with decreased appetite and hypoactivation of food-motivation neurocircuitry in anorexia nervosa.

OBJECTIVE: Corticotrophin-releasing hormone (CRH)-mediated hypercortisolemia has been demonstrated in anorexia nervosa (AN), a psychiatric disorder characterized by food restriction despite low body weight. While CRH is anorexigenic, downstream cortisol stimulates hunger. Using a food-related functional magnetic resonance imaging (fMRI) paradigm, we have demonstrated hypoactivation of brain regions involved in food motivation in women with AN, even after weight recovery. The relationship between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and appetite and the association with food-motivation neurocircuitry hypoactivation are unknown in AN. We investigated the relationship between HPA activity, appetite, and food-motivation neurocircuitry hypoactivation in AN. DESIGN: Cross-sectional study of 36 women (13 AN, ten weight-recovered AN (ANWR), and 13 healthy controls (HC)). METHODS: Peripheral cortisol and ACTH levels were measured in a fasting state and 30, 60, and 120 min after a standardized mixed meal. The visual analog scale was used to assess homeostatic and hedonic appetite. fMRI was performed during visual processing of food and non-food stimuli to measure the brain activation pre- and post-meal. RESULTS: In each group, serum cortisol levels decreased following the meal. Mean fasting, 120 min post-meal, and nadir cortisol levels were high in AN vs HC. Mean postprandial ACTH levels were high in ANWR compared with HC and AN subjects. Cortisol levels were associated with lower fasting homeostatic and hedonic appetite, independent of BMI and depressive symptoms. Cortisol levels were also associated with between-group variance in activation in the food-motivation brain regions (e.g. hypothalamus, amygdala, hippocampus, orbitofrontal cortex, and insula). CONCLUSIONS: HPA activation may contribute to the maintenance of AN by the suppression of appetitive drive.

Aerobic training (AT) is more effective than aerobic plus resistance training (AT+RT) to improve anorexigenic/orexigenic factors in obese adolescents.

BACKGROUND: The regulation of energy balance is influenced by physical exercise. Although some studies show a stimulation of hormones related to food intake, others show that exercise provides satiety. AIM: The aim of this study was to compare the effects of aerobic training (AT) and aerobic plus resistance training (AT+RT) on anorexigenic and orexigenic factors in obese adolescents undergoing interdisciplinary weight loss therapy. METHODS: A total of 26 obese adolescents, aged 15-19 years with BMI≥P95 were submitted to 12 months of interdisciplinary intervention (clinical support, nutrition, psychology and physical exercise) and divided into two groups, aerobic training (AT) (n=13) or aerobic plus resistance training (AT+RT) (n=13), which were matched according to gender and body mass. Blood samples were collected to analyze orexigenic factors (AgRP, NPY, MCH) and the anorexigenic factor alpha-MSH. RESULTS: The AT and AT+RT groups significantly reduced body mass, body mass index and body fat mass (kg) during the therapy. The AT group showed no significant changes in body lean mass (kg), whereas the AT+RT group showed an increase in body lean mass (kg) during the interdisciplinary intervention. There was an increase in AgRP levels (ng/ml) only in the AT+RT group after 6 months of interdisciplinary intervention compared with baseline condition. Conversely, α-MSH levels (ng/ml) increased only in the AT group after 12 months of interdisciplinary intervention compared with baseline condition. CONCLUSION: Aerobic training (AT) as part of an interdisciplinary therapy is more effective than aerobic plus resistance training (AT+RT) to improve secretion of anorexigenic/orexigenic factors in obese adolescents.

The associations of anxiety and depression symptoms with weight change and incident obesity: The HUNT Study.

OBJECTIVE: To investigate the associations of anxiety and depression symptoms with weight change and incident obesity in men and women. DESIGN: We conducted a prospective cohort study using the Norwegian Nord-Trøndelag Health Study (HUNT). SUBJECTS: The study cohort included 25 180 men and women, 19-55 years of age from the second survey of the HUNT (1995-1997). MEASUREMENTS: Anxiety and depression symptoms were measured using the Hospital Anxiety and Depression Scale. Weight change was determined for the study period of an average 11 years. Incident obesity was new-onset obesity classified as having a body mass index of 30.0 kg m(2) at follow-up. The associations of anxiety or depression with weight change in kilograms (kg) was estimated using linear regression models. Risk ratios (RRs) for incident obesity associated with anxiety or depression were estimated using log-binomial regression. RESULTS: In men, any anxiety or depression was associated with an average 0.81 kg (95% confidence interval (CI) 0.27-1.34) larger weight change after 11 years compared with those without such symptoms (mean weight change: 5.04 versus 4.24 kg). Women with any anxiety or depression had an average 0.98 kg (95% confidence interval (CI) 0.49-1.47) larger weight change compared with those without such symptoms (mean weight change: 5.02 versus 4.04 kg). Participants with any anxiety or depression had a significantly elevated cumulative incidence of obesity (men: RR 1.37, 95% CI 1.13-1.65; women: RR 1.18, 95% CI 1.00-1.40). CONCLUSION: We found that symptoms of anxiety and depression were associated with larger weight change and an increased cumulative incidence of obesity in both men and women.

Long-term effects of aerobic plus resistance training on the adipokines and neuropeptides in nonalcoholic fatty liver disease obese adolescents.

OBJECTIVE: To compare the effects of aerobic training (AT) with aerobic plus resistance training (AT+RT) in nonalcoholic fatty liver disease (NAFLD) obese adolescents. DESIGN: Long-term interdisciplinary weight-loss therapy (1 year of clinical, nutritional, psychological, and exercise-related intervention). PARTICIPANTS: Fifty-eight postpubertal obese adolescents were randomized to AT or AT+RT according to NAFLD diagnosis. Adipokine and neuropeptide concentrations were measured by enzyme-linked immunosorbent assay, visceral fat by ultrasound, and body composition by plethysmography. RESULTS: The NAFLD group that followed the AT+RT protocol presented lower insulin, homeostasis model assessment-insulin resistance (HOMA-IR), and alanine transaminase (ALT) values after intervention compared with AT. It was verified that there was a higher magnitude of change in the subcutaneous fat, glycemia, total cholesterol (TC), low-density lipoprotein-cholesterol, ALT, and adiponectin in response to AT+RT than in the control group (AT). All patients who underwent the AT+RT exhibited significantly higher adiponectin, leptin, and Δadiponectin and lower melanin-concentrating hormone (MCH) concentrations after therapy compared with the AT group. In the simple linear regression analysis, changes in glycemia, insulin, and HOMA-IR were independent predictors of significant improvement in adiponectin concentration. Indeed, ΔAST (aspartate transaminase) and ΔGGT (γ-glutamyl transpeptidase) were independent predictors of ΔALT, while Δfat mass and ΔAgRP (agouti-related protein) were independent predictors of ΔMCH. Although the number of patients was limited, we showed for the first time the positive effects of AT+RT protocol in a long-term interdisciplinary therapy to improve inflammatory biomarkers and to reduce orexigenic neuropeptide concentrations in NAFLD obese adolescents. CONCLUSION: The long-term interdisciplinary therapy with AT+RT protocol was more effective in significantly improving noninvasive biomarkers of NAFLD that are associated with the highest risk of disease progression in the pediatric population.

The phosphodiesterases type 5 inhibitor tadalafil reduces the activation of the hypothalamus-pituitary-adrenal axis in men during cycle ergometric exercise.

Phosphodiesterase type 5 inhibitors may influence human physiology, health, and performance by also modulating endocrine pathways. We evaluated the effects of a 2-day tadalafil administration on adenohypophyseal and adrenal hormone adaptation to exercise in humans. Fourteen healthy males were included in a double-blind crossover trial. Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day with a 36-h interval) before a maximal exercise was performed. After a 2-wk washout, the volunteers were crossed over. Blood samples were collected at -30 and -15 min and immediately before exercise, immediately after, and during recovery (+15, +30, +60, and +90 min) for adrenocorticotropin (ACTH), ß-endorphin, growth hormone (GH), prolactin, cortisol (C), corticosterone, dehydroepiandrosterone-sulfate (DHEAS), and cortisol binding globulin (CBG) assays. C-to-CBG (free cortisol index, FCI) and DHEAS-to-C ratios were calculated. Exercise intensity, perceived exertion rate, O2 consumption, and CO2 and blood lactate concentration were evaluated. ACTH, GH, C, corticosterone, and CBG absolute concentrations and/or areas under the curve (AUC) increased after exercise after both placebo and tadalafil. Exercise increased DHEAS only after placebo. Compared with placebo, tadalafil administration reduced the ACTH, C, corticosterone, and FCI responses to exercise and was associated with higher ß-endorphin AUC and DHEAS-to-C ratio during recovery, without influencing cardiorespiratory and performance parameters. Tadalafil reduced the activation of the hypothalamus-pituitary-adrenal axis during exercise by probably influencing the brain's nitric oxide- and cGMP-mediated pathways. Further studies are necessary to confirm our results and to identify the involved mechanisms, possible health risks, and potential clinical uses.

[High fat diet induces obesity and alters the expression of MCHR1 and OB-Rb in the adipose tissue].

OBJECTIVE: To investigate the effect of high-fat (HF) diet on the body weight and the mRNA expression of melanin concentrating hormone receptor 1 (MCHR1) and leptin receptor (OB-Rb) in the adipose tissue in rats, the two important and opposite factors in regulating the body weight. METHODS: Post-weaning rats were divided into 3 groups: the NC group were fed a normal-chow diet (NC) (13% calories from fat), the HF group with a HF-diet (47% calories from fat) and the PHF group pair-fed a HF-diet (47% calories from fat). At the end of 8th week, the gained bodyweight, the plasma melanin concentrating hormone (MCH) and leptin, and the expression levels of MCHR1 and OB-Rb in the adipose tissue were measured. RESULTS: Both the HF-diet and pair-fed HF-diet enhanced the body weight (P<0.01), plasma MCH (P<0.01) and leptin concentrations (P<0.05). In the adipose tissue, HF-diet resulted in significant increase in MCHR1 (PHF group,P<0.05) and decrease in OB-Rb mRNA levels (HF group,P<0.01; PHF group,P<0.05). No statistical difference was found between the HF group and the PHF group in terms of the aforementioned data (P>0.05). CONCLUSION: Chronic intake of iso-caloric HF-diet and ad libitum HF-diet obviously results in increase in the body weight, serum leptin, and MCH concentration. Diet-induced obesity and related metabolic disorders are possibly correlated with up-regulated expression of MCHR1 and down-regulated expression of OB-Rb in the adipose tissue.

Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress.

Detailed dynamics of the hypothalamic-pituitary-adrenal (HPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.

Alterations in downstream mediators involved in central control of eating behavior in obese adolescents submitted to a multidisciplinary therapy.

OBJECTIVE: The aim of this study was to verify the effects of a multidisciplinary therapy (24 weeks) on neurohormonal control of food intake, specifically in orexigenic (total ghrelin, agouti-related protein [AgRP], neuropeptide Y [NPY], and melanin-concentrating hormone) and anorexigenic factors (leptin, insulin, and alpha-melanocyte stimulating hormone [α-MSH]), in obese adolescents. METHODS: A total of 88 adolescents (38 boys and 50 girls), including 62 obese and 26 normal-weight, aged 15-19 years were recruited. Obese adolescents were submitted to a 24-week multidisciplinary therapy. AgRP, NPY, melanin-concentrating hormone, leptin, insulin, glucose, α-MSH, total ghrelin, and food intake were measured at three stages (at baseline, after 12 weeks, and after 24 weeks). RESULTS: At baseline, obese adolescents showed hyperleptinemia (circulating leptin levels, which were, in boys and girls, 40 and 35 times higher than in normal-weight subjects, respectively). After 24 weeks, these values decreased in all obese patients. Our results showed no differences in ghrelin levels between obese and normal-weight adolescents, in both genders. However, obese boys reduced their plasma ghrelin concentration after 24 weeks of therapy (p < .05). The multidisciplinary therapy decreased NPY and AgRP values and increased α-MSH; simultaneously with these changes there was a decrease in total food intake after 24 weeks of therapy. CONCLUSIONS: We can conclude that the multidisciplinary therapy was efficient to modulate neurohormonal control of food intake in obese adolescents.