Leptin-reactive antibodies are distinctly correlated with body composition parameters and metabolic risk indexes in children and adolescents

Studies have demonstrated the presence of low-affinity immunoglobulins (Igs) directed to leptin, a key hormone of the neuroendocrine axis that regulates appetite and metabolism, in adult healthy subjects, patients with obesity and type 2 diabetes mellitus. In the present exploratory study, IgG leptin-reactive antibodies were analyzed for the first time in children and adolescents according to body mass index (BMI) and were correlated with biochemical profile (lipid profile, insulin, glucose and leptin) and metabolic risk indexes (HOMA-IR, HOMA-β, AIP). One hundred and thirty-six participants were included (children n=63, adolescents n=73). An in-house ELISA test was performed to measure IgG anti-leptin antibodies (free, total and immune complexes). In adolescents, free and total IgG anti-leptin antibodies levels were higher in groups with overweight or obesity than in normal-weight group (p<0.01), while in children, the total fractions were lower in groups with overweight and obesity than in normal-weight (p<0.02). Immune complexes percentage showed opposite correlations with BMI in children (r=0.4004, p=0.0473) and adolescents (r=-0.3983, p=0.0133). IgG anti-leptin antibodies were also correlated with HOMA-IR in children (r=-0.4569, p=0.0217) and adolescents (r=-0.3589, p=0.0316), and with AIP (r=-0.3608, p=0.0261) in adolescents. Our data suggest that the production and affinity of IgG anti-leptin antibodies can be affected by age, body composition and metabolic conditions; additionally, in normal conditions, IgG anti-leptin antibodies may have a protective role in insulin resistance and cardiovascular events.

Brain adiponectin signaling controls peripheral insulin response in Drosophila

The brain plays a key role in energy homeostasis, detecting nutrients, metabolites and circulating hormones from peripheral organs and integrating this information to control food intake and energy expenditure. Here, we show that a group of neurons in the Drosophila larval brain expresses the adiponectin receptor (AdipoR) and controls systemic growth and metabolism through insulin signaling. We identify glucose-regulated protein 78 (Grp78) as a circulating antagonist of AdipoR function produced by fat cells in response to dietary sugar. We further show that central AdipoR signaling inhibits peripheral Juvenile Hormone (JH) response, promoting insulin signaling. In conclusion, we identify a neuroendocrine axis whereby AdipoR-positive neurons control systemic insulin response.

Multifactorial control of gonadotropin release for induction of oocyte maturation: Influence of gonadotropin-releasing hormone, gonadotropin release-inhibiting factor and dopamine receptors in the catfish, Heteropneustes fossilis

Several external and internal factors contribute to the reproductive success of teleosts, which makes the reproductive process complex and unique. In the Indian freshwater catfish, Heteropneustes fossilis, monsoon plays a crucial role as it fine tunes the neuroendocrine axis, culminating in oocyte maturation. Therefore, induction of oocyte maturation requires the coordinated interaction among hypothalamic, hypophyseal, and peripheral hormones. In the present investigation, dual neuroendocrine control of oocyte maturation has been demonstrated in the catfish, H. fossilis. The maturational response in gravid catfish is inhibited in the presence of dopamine but GnRH evokes the oocyte maturation and ovulation. GnRH upregulates the expression of lhb gene as well as increases plasma levels of LH significantly within 30 minutes of its administration. Destruction of the preoptic region in gravid catfish by electrolytic or chemical lesions also causes oocyte maturation and ovulation. But this response is inhibited if dopamine is injected into the nucleus preopticus periventricularis-lesioned fishes. These observations support the role of dopamine as an inhibitory factor, therefore specific receptors of dopamine have been characterized in catfish and their expression in the brain has been quantified. Dopamine receptors are upregulated in dopamine-treated fishes and downregulated if a dopamine antagonist (pimozide) is injected. The present study suggests the presence of inhibitory mechanism for LH secretion in gravid catfish. Abolition of this inhibition is necessary to release LH surge, which in turn stimulates resumption of meiosis and ovulation. Thus peptidergic as well as aminergic systems regulate oocyte maturation in H. fossilis. Neuroendocrine regulation of oocyte maturation and ovulation has major implications for inducing spawning in aquaculture.

Endocrine Manifestations of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems. It affects primarily female patients in the reproductive age. The disease has a variable course from very mild to severe and may be fatal. It is characterized by exacerbations of disease activity called flares. Estrogens seem to be involved in SLE pathogenesis as they have multiple immunomodulating properties. In SLE the autoimmune process affects the neuroendocrine axis. Stress modulates disease expression in lupus patients. The disease affects the endocrine system. Hypothyroidism occurs in SLE patients in a higher rate than that of the general population. Hyperthyroidism is also observed in SLE, however, in the rate expected for the general population. Hashimoto’s thyroiditis is observed in SLE in a higher rate than that of the general population. Hyperparathyroidism is also observed in SLE, primary and secondary in the context of renal insufficiency due to lupus nephritis. Addison’s disease is rare in SLE. Cushing’s disease due to an adrenal adenoma has been observed, but it is rare. Ovarian function may be compromised in SLE, due to autoimmune oophoritis or drug toxicity. The recognition of endocrine disease in SLE is important as it may guide proper management and symptom amelioration.

Distribution of Myeloid and Plasmacytoid Dendritic Cell Subpopulations in Peripheral Blood of Hyperprolactinemic Women

Dendritic cells (DCs) play key roles in regulating the immune response using the specialized function of processing and presenting antigens. Prolactin (PRL), a hormone produced by the pituitary gland, participates in DC maturation and function. The present study was aimed to determine the frequencies of peripheral blood DC subpopulations of myeloid DC (MDC) and plasmacytoid DC (PDC) in hyperprolactinemic (HPRL) women compared to normal healthy volunteers. This study was conducted on 70 women, including 35 HPRL patients and 35 matched healthy controls, whose PRL serum levels were in the normal range (lower than 25 ng/mL). Serum thyroid-stimulating hormone (TSH) levels were measured in both groups as an indicator of normal thyroid function. The electrochemiluminescence immunoassay method was applied to measure the serum levels of TSH and PRL. The frequencies of MDC and PDC in the peripheral blood samples of both groups were determined by flow cytometry. The mean serum PRL levels in the HPRL patients and healthy individuals were 46.41±21.96 and 13.75±11.19, respectively (p<0.0001); however TSH levels in both groups were similar and within the normal range (0.4–4.5 mIU/mL) (p=0.2). The frequencies of both MDC and PDC subpopulations in the peripheral blood of HPRL patients were significantly lower than they were in the healthy controls. However, the ratio of MDCs/PDCs in HPRL patients was not significantly different between the two groups (p=0.8). Our study revealed that an increased level of serum PRL may lead to a reduction in the number of MDC and PDC subpopulations. These results could help clarify the complex relationship between the immune system and the neuroendocrine axis and may be of potential use in understanding the pathogenesis of endocrine and immune disorders.

Lithium Enhances the GABAergic Synaptic Activities on the Hypothalamic Preoptic Area (hPOA) Neurons

Lithium (Li+) salt is widely used as a therapeutic agent for treating neurological and psychiatric disorders. Despite its therapeutic effects on neurological and psychiatric disorders, it can also disturb the neuroendocrine axis in patients under lithium therapy. The hypothalamic area contains GABAergic and glutamatergic neurons and their receptors, which regulate various hypothalamic functions such as the release of neurohormones, control circadian activities. At the neuronal level, several neurotransmitter systems are modulated by lithium exposure. However, the effect of Li+ on hypothalamic neuron excitability and the precise action mechanism involved in such an effect have not been fully understood yet. Therefore, Li+ action on hypothalamic neurons was investigated using a whole-cell patch-clamp technique. In hypothalamic neurons, Li+ increased the GABAergic synaptic activities via action potential independent presynaptic mechanisms. Next, concentration-dependent replacement of Na+ by Li+ in artificial cerebrospinal fluid increased frequencies of GABAergic miniature inhibitory postsynaptic currents without altering their amplitudes. Li+ perfusion induced inward currents in the majority of hypothalamic neurons independent of amino-acids receptor activation. These results suggests that Li+ treatment can directly affect the hypothalamic region of the brain and regulate the release of various neurohormones involved in synchronizing the neuroendocrine axis.

Dynamic hormone control of stress and fertility

ABSTRACTNeuroendocrine axes display a remarkable diversity of dynamic signalling processes relaying information between the brain, endocrine glands, and peripheral target tissues. These dynamic processes include oscillations, elastic responses to perturbations, and plastic long term changes observed from the cellular to the systems level. While small transient dynamic changes can be considered physiological, larger and longer disruptions are common in pathological scenarios involving more than one neuroendocrine axes, suggesting that a robust control of hormone dynamics would require the coordination of multiple neuroendocrine clocks. The idea of apparently different axes being in fact exquisitely intertwined through neuroendocrine signals can be investigated in the regulation of stress and fertility. The stress response and the reproductive cycle are controlled by the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Hypothalamic-Pituitary-Gonadal (HPG) axis, respectively. Despite the evidence surrounding the effects of stress on fertility, as well as of the reproductive cycle on stress hormone dynamics, there is a limited understanding on how perturbations in one neuroendocrine axis propagate to the other. We hypothesize that the links between stress and fertility can be better understood by considering the HPA and HPG axes as coupled systems. In this manuscript, we investigate neuroendocrine rhythms associated to the stress response and reproduction by mathematically modelling the HPA and HPG axes as a network of interlocked oscillators. We postulate a network architecture based on physiological data and use the model to predict responses to stress perturbations under different hormonal contexts: normal physiological, gonadectomy, hormone replacement with estradiol or corticosterone (CORT), and high excess CORT (hiCORT) similar to hypercortisolism in humans. We validate our model predictions against experiments in rodents, and show how the dynamic responses of these endocrine axes are consistent with our postulated network architecture. Importantly, our model also predicts the conditions that ensure robustness of fertility to stress perturbations, and how chronodisruptions in glucocorticoid hormones can affect the reproductive axis’ ability to withstand stress. This insight is key to understand how chronodisruption leads to disease, and to design interventions to restore normal rhythmicity and health.

The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity

Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.

Regulation of the neuroendocrine axis in male rats by soy-based diets is independent of age and due specifically to isoflavone action†

Soy-based foods are consumed for their health beneficial effects, implying that the population is exposed to soy isoflavones in the diet. Herein, male rats at 21, 35, and 75 days of age were maintained either on a casein control diet, soybean meal (SBM), or control diet supplemented with daidzin and genistin (G + D) for 14 days. Feeding of SBM and G + D diets decreased testicular testosterone (T) secretion regardless of age. Altered androgen secretion was due to decreased (P &lt; 0.05) Star and Hsd17β protein in the testes and was associated with increased (P &lt; 0.05) Lhβ and Fshβ subunit protein expression in pituitary glands. Second, male rats were fed either a casein control diet, control diet + daidzin, control diet + genistin, or control diet + genistin + daidzin (G + D). Compared to control, feeding of all isoflavone-containing diets decreased (P &lt; 0.05) testicular T concentrations, and more so in the G + D diet group. Interestingly, Esr1 and androgen receptor protein and pituitary Fshβ with Lhβ subunit protein were increased (P &lt; 0.05) by feeding of genistin and G + D diets, but not the daidzin diet. However, daidzein and genistein both caused a concentration dependent inhibition (P &lt; 0.05) of T secretion by Leydig cells in vitro with IC50 of 184 ηM and 36 ηM, respectively. Results demonstrated that altered testicular steroidogenic capacity and pituitary FSHβ and LHβ subunit expression due to soy-based diets result from specific actions by genistein and daidzein. Experiments to assess effects of isoflavone regulation of intratesticular androgen concentrations on male fertility are warranted.