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.

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.

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.

Melatonin stimulates the release of gonadotropin-inhibitory hormone by the avian hypothalamus.

Gonadotropin-inhibitory hormone (GnIH), a neuropeptide that inhibits gonadotropin synthesis and release, was first identified in quail hypothalamus. GnIH acts on the pituitary and GnRH neurons in the hypothalamus via GnIH receptor to inhibit gonadal development and maintenance. In addition, GnIH neurons express melatonin receptor and melatonin induces GnIH expression in the quail brain. Thus, it seems that melatonin is a key factor controlling GnIH neural function. In the present study, we investigated the role of melatonin in the regulation of GnIH release and the correlation of GnIH release with LH release in quail. Melatonin administration dose-dependently increased GnIH release from hypothalamic explants in vitro. GnIH release was photoperiodically controlled. A clear diurnal change in GnIH release was observed in quail, and this change was negatively correlated with changes in plasma LH concentrations. GnIH release during the dark period was greater than that during the light period in explants from quail exposed to long-day photoperiods. Conversely, plasma LH concentrations decreased during the dark period. In contrast to LD, GnIH release increased under short-day photoperiods, when the duration of nocturnal secretion of melatonin increases. These results indicate that melatonin may play a role in stimulating not only GnIH expression but also GnIH release, thus inhibiting plasma LH concentrations in quail. This is the first report describing the effect of melatonin on neuropeptide release.

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.

[Effects of hypothalamic mediator systems on the hormonal changes in rabbit blood during prolonged electric stimulation of emotiogenic zones of the hypothalamus]. / O vliianii mediatornykh sistem gipotalamusa na gormonal'nye izmeneniia v krovi krolikov pri dlitel'noi élektrostimuliatsii émotsiogennykh zon gipotalamusa.

Changes in the blood hormonal levels were studied in 36 rabbits with electrodes implanted to the area of the dorsomedial nuclei of the hypothalamus in the course of a 5-cycle electrostimulation experiment. After each period blood hormonal levels were correlated to the activities of the hypothalamic catecholamine-, GABA-, and serotoninergic systems. The first two cycles of the experiment were associated with a high activity of the hypothalamic mediator systems and with increased levels of all hormones in the blood. The functional activity of the hypothalamus was reduced due to the predominance of stress-limiting systems. The initial reduction of GABA, and then of serotonin in the hypothalamus caused be the end of experiment a reduction of the blood levels of the tested hormones, except the Ca-regulating ones and active renin. Disturbances in the regulatory mechanisms of hypothalamic mediator systems leads to an increase in its excitability and to transformation of the adaptive pattern of hormonal changes into pathological mechanisms of prolonged emotional stress.

[Methods of hypothalamo-hypophyseal portal blood collection]. / Méthodes de collection du sang porte hypothalamo-hypophysaire.

It is possible to assay hypothalamic factors in hypophysial portal blood from several species. However, hypophysial portal blood collection must be performed after anesthesia and surgical stress which can both modify the regulation of hypothalamo-pituitary secretion. However, this method has allowed some progress in our knowledge of the hypothalamic control of pituitary secretion. The methodology, advantages and limits of hypophysial portal blood collection are briefly described in this review.