Low-Dose Coconut Oil Supplementation Induces Hypothalamic Inflammation, Behavioral Dysfunction, and Metabolic Damage in Healthy Mice.

SCOPE: Coconut oil (CO) diets remain controversial due to the possible association with metabolic disorder and obesity. This study investigates the metabolic effects of a low amount of CO supplementation. METHODS AND RESULTS: Swiss male mice are assigned to be supplemented orally during 8 weeks with 300 µL of water for the control group (CV), 100 or 300 µL of CO (CO100 and CO300) and 100 or 300 µL of soybean oil (SO; SO100 and SO300). CO led to anxious behavior, increase in body weight gain, and adiposity. In the hypothalamus, CO and SO increase cytokines expression and pJNK, pNFKB, and TLR4 levels. Nevertheless, the adipose tissue presented increases macrophage infiltration, TNF-α and IL-6 after CO and SO consumption. IL-1B and CCL2 expression, pJNK and pNFKB levels increase only in CO300. In the hepatic tissue, CO increases TNF-α and chemokines expression. Neuronal cell line (mHypoA-2/29) exposed to serum from CO and SO mice shows increased NFKB migration to the nucleus, TNF-α, and NFKBia expression, but are prevented by inhibitor of TLR4 (TAK-242). CONCLUSIONS: These results show that a low-dose CO changes the behavioral pattern, induces inflammatory pathway activation, TLR4 expression in healthy mice, and stimulates the pro-inflammatory response through a TLR4-mediated mechanism.

The chronic syndromes after previous treatment of pituitary tumours.

Ultimately, almost all patients who are appropriately treated for pituitary tumours enter a chronic phase with control or cure of hormonal excess, adequate treatment of pituitary insufficiency and relief of mass effects. This phase is associated with improvement of initial signs and symptoms, but also with the persistent consequences of the initial disease and associated treatments. Pituitary insufficiency is a common denominator in many of these patients, and is associated with a reduction in quality of life, despite adequate endocrine substitution. Hypothalamic dysfunction can be present in patients previously treated for visual impairments caused by large suprasellar adenomas, or craniopharyngiomas. In addition to hypopituitarism, these patients can have multisystem morbidities caused by altered hypothalamic function, including weight gain and disturbed regulation of sleep-wake cycles. Mortality can also be affected. Patients cured of Cushing disease or acromegaly have chronic multisystem morbidities (in the case of Cushing disease, also affecting mortality) caused by irreversible effects of the previous excesses of cortisol in Cushing disease and growth hormone and insulin-like growth factor 1 in acromegaly. In addition to early diagnosis and treatment of pituitary tumours, research should focus on the amenability of these chronic post-treatment syndromes to therapeutic intervention, to improve quality of life and clinical outcomes.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children.

BACKGROUND AND OBJECTIVE: Hypothalamic-pituitary-adrenal axis suppression (HPAS) when treating children with corticosteroids is thought to be rare. Our objective was to determine the prevalence of and predictive factors for various degrees of HPAS. METHODS: Clinical features of HPAS, doses, adherence, asthma score, and lung functions were recorded in 143 asthmatic children. The overnight metyrapone test was performed if morning cortisol was >83 nmol/L. Spearman correlations coefficients (r) were calculated between 3 postmetyrapone outcomes and each continuous variable. A multiple linear regression model of √postmetyrapone adrenocorticotropic hormone (ACTH) and a logistic regression model for HPAS were developed. RESULTS: Hypocortisolemia was seen in 6.1% (1.8-10.5), hypothalamic-pituitary suppression (HPS) in 22.2% (14.5-29.9), adrenal suppression in 32.3% (23.7-40.9), HPAS in 16.3% (9.3-23.3), and any hypothalamic-pituitary-adrenal axis dysfunction in 65.1% (56.5-72.9). Log daily nasal steroid (NS) dose/m(2) was associated with HPAS in the logistic regression model (odds ratio = 3.7 [95% confidence interval: 1.1-13.6]). Daily inhaled corticosteroids (ICSs) + NS dose/m(2) predicted HPAS in the univariate logistic regression model (P = .038). Forced expiratory volume in 1 second/forced vital capacity <80% was associated with HPAS (odds ratio = 4.1 [95% confidence interval: 1.0-14.8]). Daily ICS + NS/m(2) dose was correlated with the postmetyrapone ACTH (r = -0.29, P < .001). BMI (P = .048) and percent adherence to ICS (P < .001) and NS (P = .002) were predictive of √postmetyrapone ACTH (R(2) = .176). CONCLUSIONS: Two-thirds of children on corticosteroids may have hypothalamic-pituitary-adrenal axis dysfunction. In one-third, central function had recovered but adrenal suppression persisted. Predictive factors for HPAS are NS use, BMI, and adherence to ICS and NS.

Low-Intensity swimming training after weaning improves glucose and lipid homeostasis in MSG hypothalamic obese mice.

Low-intensity swimming training, started at an early age, was undertaken to observe glycemic control in hypothalamic obese mice produced by neonatal monosodium l-glutamate (MSG) treatment. Although swimming exercises by weaning pups inhibited hypothalamic obesity onset and recovered sympathoadrenal axis activity, this event was not observed when exercise training is applied to young adult mice. However, the mechanisms producing this improved metabolism are still not fully understood. Current work verifies whether, besides reducing fat tissue accumulation, low-intensity swimming in MSG-weaned mice also improves glycemic control. Although MSG and control mice swam for 15 min/day, 3 days a week, from the weaning stage up to 90 days old, sedentary MSG and normal mice did not exercise at all. After 14 h of fasting, animals were killed at 90 days of age. Retroperitonial fat accumulation was measured to estimate obesity. Fasting blood glucose and insulin concentrations were also measured. Mice were also submitted to ipGTT. MSG obese mice showed fasting hyperglycemia, hyperinsulinemia, and glucose intolerance and insulin resistance. However, the exercise was able to block MSG treatment effects. Higher total cholesterol and triglycerides observed in MSG mice were normalized by exercise after weaning. Exercised MSG animals had higher HDLc than the sedentary group. Data suggest that early exercise training maintains normoglycemia, insulin tissue sensitivity, and normal lipid profile in mice programmed to develop metabolic syndrome.

Inflammation of the hypothalamus leads to defective pancreatic islet function.

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic ß-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic ß-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

[Neurohormonal effects following treatment with dopamine. More advantages or disadvantages?]. / Neurohormonalne nastepstwa leczenia dopamina. Wiecej korzysci czy dzialarí ubocznych?

Due to a big amount of dopaminergic receptors set in the vertebrate central nervous system (CNS), endogenously freed dopamine determines motor and cognitive activities of an organism. It influences neurohormonal regulation of the body, among all, other catecholamines' production; it also regulates kidney's functioning, the cardiovascular system and alimentary canal. Dopamine (a natural catecholamine) containing specimens are often used for the sake of intensive medical care. A particular effect, which is natriuretic, inotropic and vasopressive, is expected under inpatient treatment conditions depending on a selected dose. In practice, however, a potential influence of such treatment on neurohormonal processes, among all, an impact on hypothalamo-hypophyseal-adrenal axis is rarely taken into account. Considering numerous adverse events, a risk of renal failure development and blood redistribution disorders in the mucous membrane of the gastrointestinal tract, a negative impact on the respiratory system, as well as in the event of insufficient evidence for dopamine's effectiveness in both prevention and acute renal failure) treatment, dopamine's implementation in so called diuretic doses is controversial. Its implementation as a drug with the vasopressor effect must be reconsidered and individualised.

The recreational drug ecstasy disrupts the hypothalamic-pituitary-gonadal reproductive axis in adult male rats.

Reproductive function involves an interaction of three regulatory levels: hypothalamus, pituitary, and gonad. The primary drive upon this system comes from hypothalamic gonadotropin-releasing hormone (GnRH) neurosecretory cells, which receive afferent inputs from other neurotransmitter systems in the central nervous system to result in the proper coordination of reproduction and the environment. Here, we hypothesized that the recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy'), which acts through several of the neurotransmitter systems that affect GnRH neurons, suppresses the hypothalamic-pituitary-gonadal reproductive axis of male rats. Adult male Sprague-Dawley rats self-administered saline or MDMA either once (acute) or for 20 days (chronic) and were euthanized 7 days following the last administration. We quantified hypothalamic GnRH mRNA, serum luteinizing hormone concentrations, and serum testosterone levels as indices of hypothalamic, pituitary, and gonadal functions, respectively. The results indicate that the hypothalamic and gonadal levels of the hypothalamic-pituitary-gonadal axis are significantly altered by MDMA, with GnRH mRNA and serum testosterone levels suppressed in rats administered MDMA compared to saline. Furthermore, our finding that hypothalamic GnRH mRNA levels are suppressed in the context of low testosterone concentrations suggests that the central GnRH neurosecretory system may be a primary target of inhibitory regulation by MDMA usage.

Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome.

Prenatal exposure to alcohol has adverse effects on offspring neuroendocrine and behavioural functions. Alcohol readily crosses the placenta, thus directly affecting developing foetal endocrine organs. In addition, alcohol-induced changes in maternal endocrine function can disrupt the normal hormonal interactions between the pregnant female and foetal systems, altering the normal hormone balance and, indirectly, affecting the development of foetal metabolic, physiological and endocrine functions. The present review focuses on the adverse effects of prenatal alcohol exposure on offspring neuroendocrine function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis, a key player in the stress response. The HPA axis is highly susceptible to programming during foetal and neonatal development. Here, we review data demonstrating that alcohol exposure in utero programmes the foetal HPA axis such that HPA tone is increased throughout life. Importantly, we show that, although alterations in HPA responsiveness and regulation are robust phenomena, occurring in both male and female offspring, sexually dimorphic effects of alcohol are frequently observed. We present updated findings on possible mechanisms underlying differential effects of alcohol on male and female offspring, with special emphasis on effects at different levels of the HPA axis, and on modulatory influences of the hypothalamic-pituitary-gonadal hormones and serotonin. Finally, possible mechanisms underlying foetal programming of the HPA axis, and the long-term implications of increased exposure to endogenous glucocorticoids for offspring vulnerability to illnesses or disorders later in life are discussed.

KiSS-1 mRNA in adipose tissue is regulated by sex hormones and food intake.

Hypothalamic KiSS-1 gene expression is critical for the maintenance of reproductive function, and levels are attenuated by sex hormones and by food restriction, providing a link between fat mass and fertility. We hypothesized that adipose tissue (FAT) would express KiSS-1. KiSS-1 mRNA was quantified in FAT, hypothalamus (HYP) and pituitary gland (PIT) using realtime RT-PCR. FAT KiSS-1 expression was sensitive to sex steroids and to nutritional status. Gonadectomized rats given estradiol (E; females) or testosterone (T; males) revealed striking increases in KiSS-1 mRNA in FAT (E: 8-fold, p<0.01; T: 5-fold, p<0.01). In contrast, HYP KiSS-1 expression was reduced by E/T, whereas PIT expression was reduced by gonadectomy only in females, reversed by E. Food restriction (18 h) increased FAT KiSS-1 mRNA in both sexes (2.5-4.0-fold, p<0.01), but decreased levels in male PIT and female HYP. Conversely, FAT expression was reduced in rats fed a high fat diet (HFD), as well as in obese Zucker rats, whereas PIT expression was increased in Zucker rats (p<0.05) but not by HFD. In contrast HYP KiSS-1 mRNA was elevated by HFD. Experiments in which the arcuate nucleus was damaged by an excitotoxic lesion revealed that hypothalamic KiSS-1 mRNA was significantly reduced, whereas FAT levels were unaffected, suggesting that regulation of KiSS-1 in FAT is independent of the hypothalamus. In conclusion, KiSS-1 expression is differentially regulated by sex hormones, food intake and obesity in FAT, HYP and PIT. Kisspeptins of adipose tissue origin may act as adipokines or as local regulators of adipocyte function.

Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat.

Hypothalamic MSG-obese rats show hyperinsulinemia and tissue insulin resistance, and they display intense parasympathetic activity. Current analysis investigates whether early subdiaphragmatic vagotomy prevents tissue insulin sensitivity impairment in adult obese MSG-rats. Hypothalamic obesity was induced by MSG (4 mg/g BW), daily, from birth up to 5 days. Control animals receiving saline solution. On the 30th day rats underwent bilateral subdiaphragmatic vagotomy or sham surgery. An intravenous glucose tolerance test (i.v.GTT) was performed when rats turned 90 days old. Total white fat tissue (WAT) from rat carcass was extracted and isolated; the interscapular brown fat tissue (IBAT) was weighed. Rather than blocking obesity, vagotomy reduced WAT and IBAT in MSG-obese rats when the latter were compared to sham MSG-rats. High blood fasting insulin and normal glucose levels were also observed in MSG-obese rats. Although glucose intolerance, high insulin secretion, and significant insulin resistance were recorded, vagotomy improved fasting insulinemia, glucose tolerance and insulin tissue sensitivity in MSG-obese rats. Results suggest that increased fat accumulation is caused, at least in part, by high blood insulin concentration, and enhanced parasympathetic activity on MSG-obese rats.

Impact of transient correction of increased adrenocortical activity in hypothalamo-damaged, hyperadipose female rats.

OBJECTIVE: To explore the effects of transient correction of enhanced corticoadrenal activity in monosodium L-glutamate (MSG)-damaged female rats on peripheral insulin sensitivity and in vitro retroperitoneal (RP) adipocyte function. DESIGNS: A dose of 4 mg/g body weight (BW) of MSG or vehicle (CTR) was i.p. injected, once every 2 days, between days 2 and 10 of age, in female rats. Intact and 21 day-operated (sham or adrenal enucleation (AE)) rats from both (CTR and MSG) groups were used for experimentation on day 120 of age. Circulating levels of several hormones, in basal and after i.v. high-glucose load conditions, and RP adiposity morphology and function were then evaluated. RESULTS: MSG rats developed increased adrenocortical function, hyperadiposity, hyperleptinemia, hyperinsulinemia and decreased peripheral insulin sensitivity. These characteristics were fully reversed after transient correction of corticoadrenal hyperactivity induced by AE. In addition, in vitro experimentation with isolated RP adipocytes indicated that cells from intact MSG animals displayed decreased sensitivity to insulin and dexamethasone stimulation of leptin secretion. Interestingly, adipocyte dysfunction in MSG rats was fully abrogated after AE-induced transient correction of insulinemia, leptinemia and adrenocortical activity. Importantly, the reversion of these metabolic abnormalities, induced by AE for 21 days, in MSG animals did occur, despite no significant changes in BW values. CONCLUSION: Our results support that the changes in adipocyte characteristics and peripheral insulin resistance, developed in this pseudo-obese female rat model, are mainly due to increased glucocorticoid production. Importantly, appropriate correction of the enhanced adrenocortical activity fully reversed these abnormal functions.

Nature of changes in adrenocortical function in chronic hyperleptinemic female rats.

Neonatal treatment of rats with monosodium L-glutamate, which destroys hypothalamic arcuate nucleus neuronal bodies, induces several metabolic abnormalities; as a result, rats develop a phenotype of pseudoobesity. This study was designed to explore, in the monosodium L-glutamate-treated female rat, the influence of chronic hyperleptinemia on adrenal cortex functionality. For this purpose, we evaluated in control and hypothalamic-damaged rats: (a) in vivo and in vitro adrenocortical function, (b) adrenal leptin receptor immunodistribution and mRNA expression, and (c) whether the inhibitory effect of leptin on adrenal function remains. Our results indicate that, compared to normal counterparts, pseudoobese animals displayed (1) hyperadiposity, despite being hypophagic and of lower body weight, (2) in vivo and in vitro enhanced adrenocortical response to ACTH stimulation, (3) an in vitro adrenal fasciculata-reticularis cell hyper-sensitivity to ACTH stimulus, (4) hyperplasia of their adrenal zona fasciculata cells, and (5) adrenal fasciculata-reticularis cell refractoriness to the inhibitory effect of leptin on ACTH-stimulated glucocorticoid production due, at least in part, to decreased adrenal leptin receptor expression. These data further support that increased hypothalamo-pituitary-adrenal axis function, in the adult neurotoxin-lesioned female rat, is mainly dependent on the development of both hyperplasia of adrenal zona fasciculata and adrenal gland refractoriness to leptin inhibitory effect. Our study supports that adrenal leptin resistance could be responsible, at least in part, for enhanced glucocorticoid circulating levels in this phenotype of obesity.

Adrenal medullary function and expression of catecholamine-synthesizing enzymes in mice with hypothalamic obesity.

The mechanisms underlying the onset of obesity are complex and not completely understood. An imbalance of autonomic nervous system has been proposed to be a major cause of great fat deposits accumulation in hypothalamic obesity models. In this work we therefore investigated the adrenal chromaffin cells in monosodium glutamate (MSG)-treated obese female mice. Newborn mice were injected daily with MSG (4 mg/g body weight) or saline (controls) during the first five days of life and studied at 90 days of age. The adrenal catecholamine content was 56.0% lower in the obese group when compared to lean controls (P < 0.0001). Using isolated adrenal medulla we observed no difference in basal catecholamine secretion percentile between obese and lean animals. However, the percentile of catecholamine secretion stimulated by high K+ concentration was lower in the obese group. There was a decrease in the tyrosine hydroxylase enzyme expression (57.3%, P < 0.004) in adrenal glands of obese mice. Interestingly, the expression of dopamine beta-hydroxylase was also reduced (47.0%, P < 0.005). Phenylethanolamine N-methyltransferase expression was not affected. Our results show that in the MSG model, obesity status is associated with a defective adrenal chromaffin cell function. We conclude that in MSG obesity the low total catecholamine content is directly related to a decrease of key catecholamine-synthesizing enzymes, which by its turn may lead to a defective catecholamine secretion.

Androgenic anabolic steroid use and severe hypothalamic-pituitary dysfunction: a case study.

The data of the present case demonstrate that the abuse of androgenic anabolic steroids (AAS) may lead to serious health effects. Although most clinical attention is usually directed towards peripheral side effects, the most serious central side effect, hypothalamic-pituitary-dysfunction, is often overlooked in severe cases. Although this latter central side-effect usually recovers spontaneously when AAS intake is discontinued, the present case shows that spontaneous recovery does not always take place. We suggest that hypothalamic-pituitary dysfunction should always be considered in the differential diagnosis in athletes seen with typical presentation of anabolic steroid use. In order to regain normal hypothalamic-pituitary function, supraphysiological doses of 200 microg LH-RH should be considered when the physiological challenge test with LH-RH (50 microg) fails to show an acceptable response.

Rats with hypothalamic obesity are insensitive to central leptin injections.

Genetically determined obesities, involving leptin- and melanocortin-signaling pathways, have focused attention on the four medial hypothalamic nuclei as primary sources of feeding- and metabolically-based obesity. All four medial cell groups contain leptin receptors. To determine which of these cell groups normally mediates the effects of leptin on food intake and body weight gain, we injected colchicine bilaterally into each nucleus and determined the pathophysiological effects of disruption and responsivity to leptin injected intracerebroventricularly. Intracerebroventricular injections of leptin in sham-lesioned rats decreased food intake during the dark period, but not during the light period. Lesions of the arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) nuclei all resulted in leptin insensitivity; by contrast, lesions of the dorsomedial nuclei (DMN) augmented sensitivity to leptin on feeding and body weight gain. Although rats with ARC and PVN lesions were obese, they were still capable of reducing caloric efficiency over the 5 days of study and increasing uncoupling protein content in interscapular brown adipose tissue. Caloric efficiency and uncoupling protein content were unchanged in rats with VMN and DMN lesions. Finally, the slope of the relationship between leptin and mesenteric white adipose tissue was increased in rats with VMN lesions and abolished in rats with ARC lesions. Thus, lesions of the ARC, PVN, and VMN produced obesity via separate pathways. We conclude that the medial hypothalamic cell groups, each with a different role in energy balance, are all necessary for normal leptin responsiveness.

Hypothalamic obesity: multiple routes mediated by loss of function in medial cell groups.

Cell groups of the medial hypothalamus are key to the regulation of energy balance. Functional disruption by colchicine injected in the hypothalamic arcuate (ARC), paraventricular (PVN), and ventromedial (VMN) cell groups produced increased food intake and obesity; disruption of the dorsomedial nuclei (DMN) produced decreased food intake. Colchicine in ARC or PVN increased food intake during both light and dark periods and increased cumulative food intake. By contrast, colchicine in VMN increased food intake only during the light, and cumulative food intake was not increased. Both leptin and insulin were elevated in the obese rats. Compared with sham, the slope of regression of leptin on insulin was increased by disruption of PVN and DMN but was not altered by disruption of VMN. ARC disruption abolished the relationship between leptin and insulin. Colchicine injected in the DMN did not cause obesity but altered feeding and the normal relationship between leptin, fat, and insulin, suggesting that blockade of signals, for example, from the lateral hypothalamus to DMN may disinhibit the normal medial hypothalamic drive to decrease energy stores. Changes in caloric efficiency with time after colchicine injections suggest that rats with both ARC and PVN disruption respond to signals of obesity, whereas rats with VMN disruption do not. These studies distinguish among functions in the four medial hypothalamic nuclei and suggest that interactions among them normally serve to regulate energy balance through alterations in food acquisition and storage.

[Effect of regulation of kidney-yin and kidney-yang on hypothalamus-pituitary-adrenal-thymus axis in monosodium L-glutamate rats].

OBJECTIVE: To study the interrelationship between hypothalamus-pituitary-adrenal-thymus (HPAT) axis and Kidney-Yang and Kidney-Yin in arcuate nucleus destroyed rats. METHODS: Monosodium glutamate (MSG) 4 mg/g body weight was given subcutaneously to neonatal rats at 2, 4, 6, 8 and 10th day after born to destroy the ARC, and Zuogui pill or Yougui pill (5 g/kg daily) was given respectively by gastrogavage when the model rats entered adulthood. RESULTS: Immunohistochemical staining showed that in the model group the number of corticotropin-releasing hormone (CRH) positive neurons in hypothalamic paraventricular nucleus and anterior pituitary adrenotrophin (ACTH) positive secretory cells, which stained deeply, were more than those in the control group, the adrenal fasciculate zone disturbed with increased cells and obviously dilated sinusoid. The thymus atrophied with lymphocyte proliferation apparently lower, blood corticosterone, ACTH content and hypothalamic CRF level higher in the model than those in the control. Zuogui pill could improve above-mentioned pathophysiologic changes effectively but Yougui pill could not. CONCLUSION: Process of pathophysiology of HPA axis hyperfunction accompanied cell-mediated immunodeficiency may belong to the category of Kidney-Yin Deficiency Syndrome.