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.

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.

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.

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 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.

Characterization of xenobiotic-induced hepatocellular enzyme induction in rats: anticipated thyroid effects and unique pituitary gland findings.

During routine safety evaluation of RO2910, a non-nucleoside reverse transcriptase inhibitor for HIV infection, histopathology findings concurrent with robust hepatocellular induction occurred in multiple organs, including a unique, albeit related, finding in the pituitary gland. For fourteen days, male and female rats were administered, by oral gavage vehicle, 100, 300, or 1000 mg/kg/day of RO2910. Treated groups had elevated serum thyroid-stimulating hormone and decreased total thyroxine, and hypertrophy in the liver, thyroid gland, and pituitary pars distalis. These were considered consequences of hepatocellular induction and often were dose dependent and more pronounced in males than in females. Hepatocellular centrilobular hypertrophy corresponded with increased expression of cytochrome P450s 2B1/2, 3A1, and 3A2 and UGT 2B1. Bilateral thyroid follicular cell hypertrophy occurred concurrent to increased mitotic activity and sometimes colloid depletion, which were attributed to changes in thyroid hormone levels. Males had hypertrophy of thyroid-stimulating hormone-producing cells (thyrotrophs) in the pituitary pars distalis. All findings were consistent with the well-established adaptive physiologic response of rodents to xenobiotic-induced hepatocellular microsomal enzyme induction. Although the effects on the pituitary gland following hepatic enzyme induction-mediated hypothyroidism have not been reported previously, other models of stress and thyroid depletion leading to pituitary stimulation support such a shared pathogenesis.

Potential roles for GNIH and GNRH-II in reproductive axis regulation of an opportunistically breeding songbird.

The ability to breed at any time of year enables opportunistically breeding species to respond to good conditions whenever they occur. We investigate the neuroendocrine basis for this relatively unusual reproductive pattern in the avian world. One proposed mechanism for year-round breeding ability is tonic activation of gonadotropin-releasing hormone-I (GnRH-I) production that is flexibly modified by gonadotropin-inhibitory hormone (GnIH) production during unfavorable conditions. GnIH could inhibit GnRH secretion from the hypothalamus and/or inhibit GnRH action on the anterior pituitary gland. We studied neuroendocrine patterns in wild Australian zebra finches (Taeniopygia guttata) sampled during a breeding period in Southern Australia, a non-breeding period in central Australia, and in juvenile males in the latter location. We asked whether patterns in immunoreactivity of three neuropeptides important for reproductive axis regulation, GnRH-I, GnRH-II and GnIH, during periods of breeding and non-breeding reflect this flexibility. We found that the numbers and sizes of immunoreactive (-ir) GnRH-I cells did not vary between breeding stages and ages. Contrary to our predictions, irGnIH cell number and size, as well as the synthesis of GnIH mRNA were similar in breeding and non-breeding conditions. However, breeding males had more and larger irGnRH-II cells in the midbrain compared to non-breeding males. Hence, while changes in irGnIH cells are not associated with fluctuations in gonadotropin secretion or gonad volume, the regulation of irGnRH-II cells might represent a previously-unidentified mechanism by which reproductive flexibility can be achieved; namely via behavioral neurotransmitter actions of GnRH-II rather than through the typical sensory-CNS integration-GnRH-I route.

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.

[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.

Incomplete deficiency of hypothalamic hormones in hypothalamic hypopituitarism associated with an old traumatic brain injury.

A 62 year-old man was admitted to determine the pathogenesis of his hypoglycemia. He was unconscious and his plasma glucose level was 26 mg/dL. When he was 31 years old, he had a traffic accident and was unconscious for several days. Physical findings on admittance showed that the patient's BMI was 17.8 and blood pressure, 114/70 mmHg. He was alert. He had a hypogonadal face with a lack of beard, and he had an atrophic testis with a volume of 1 to 2 ml. Laboratory findings showed that his fasting plasma glucose was 73 mg/dL; serum sodium, 133 mmol/l; potassium, 4.1 mmol/l; serum insulin, less than 1.0 muU/ml.; plasma ACTH, 45.8 pg/ml; serum cortisol, 5.2 microg/dL; and free cortisol urinary excretion, less than 4.5 microg/day; serum LH, 0.8 mIU/ml; serum testosterone, less than 0.05 ng/ml; serum TSH, 2.0 uIU/ml; free T(4), 0.7 ng/dL; free T(3), 1.5 pg/ml; and serum prolactin, 29.0 ng/ml. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no increased secretion of adrenocorticotropic hormone (ACTH) in response to hypoglycemia (induced by the administration of insulin) and there was no increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to the administration of clomiphene. Magnetic resonance imaging revealed an atrophied pituitary gland with an empty sella, but there were no abnormal findings of the hypothalamus. Hydrocortisone replacement at a dosage of 20 mg/day increased the patient's plasma glucose from 73 to 100 mg/dL and his serum sodium from 133 to 138 mmol/l. These findings therefore indicate a partial impairment in hypothalamic hormone release, resulting from a traumatic brain injury that the patient had received 31 years ago.

The young female athlete.

Participation of adolescents and young women in strenuous sports activity may lead to various metabolic and psychological derangements of clinical relevance to the endocrinologist. The most common manifestations encountered in practice are primary and secondary amenorrhea, reduced bone mineral density and eating disorders. The occurrence of all three together has been named "the athletic triad". The underlying hormonal drivers that lead to some of these manifestations are the reduced leptin level as well as the persistent low grade stress response commonly observed in such females. "Exercise-related female reproductive dysfunction" (ERFRD), can possibly include short-term (infertility) and long-term (osteoporosis) consequences. Functional hypothalamic amenorrhea, a manifestation of ERFRD in adolescence, is an integrated response to the combination of excessive physical and emotional stress, exercise, and/or reduced food intake characterized by decreased endogenous GNRH secretion. The primary aim of treating these athletes should be the prevention of the development of any component of the triad as well as the whole complex by educating athletes, trainers, parents and health care professionals about proper nutrition and safe training. The long term prognosis is good. However, significant long term morbidity may affect these young women later in life.

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.

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.

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.

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.

Circulating hormones and hypothalamic energy balance: regulatory gene expression in the Lou/C and Wistar rats.

To ascertain the mechanisms underlying low caloric intake and low body weight in the Lou/C rat, the circulating hormone levels and gene expression of hypothalamic peptides and receptors important in energy balance and the induction of suppressor of cytokine signalling 3 (SOCS3) gene expression in response to leptin challenge were compared with Wistar rats. Plasma leptin levels were lower in the Lou/C rat, as were levels of rat corticosterone, TSH and T4 but not T3. Ghrelin levels were higher in the Lou/C rat. Total leptin receptor (Ob-R) and the long form of the leptin receptor (Ob-Rb) gene expression were lower in the arcuate (ARC) and ventromedial nuclei (VMN) in Lou/C rat. Ghrelin receptor expression in the ARC and VMN was lower in Lou/C than in Wistar rats. However, agouti gene-related peptide (AgRP) and neuropeptide Y (NPY) gene expression were higher in the Lou/C rat. There was no difference in the level of cocaine- and amphetamine-regulated transcript gene expression in the ARC, but both were higher in the paraventricular nuclei of the Lou/C breed. There was no difference in Ob-R gene expression in, or [(125)I]leptin binding to, the choroid plexus. SOCS3 mRNA induction in response to leptin was lower in the Lou/C rat. This study reveals that the comparatively low plasma leptin, TSH and T4 levels, and high ghrelin levels together with high levels of AgRP and NPY gene expression seen in the Lou/C rat are indicative of a strong drive to eat and decreased energy expenditure, which are in direct opposition to the comparatively low body weight and adiposity of this rat strain.

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.