Role of the hypothalamic–pituitary–thyroid axis in metabolic regulation by JNK1

The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic–pituitary–thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic–pituitary–thyroid axis represents an important target of metabolic signaling by JNK1.     

The cerebello-hypothalamic–pituitary–adrenal axis dysregulation hypothesis in depressive disorder

Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic–pituitary–adrenal (HPA) axis is an important node in the brain’s stress circuit and suggested to play a role in several subtypes of depression. While the hippocampus, amygdala and prefrontal cortex are considered important regions implicated in stress regulation and depressive disorder, the existence of reciprocal monosynaptic cerebello-hypothalamic connections and the presence of dense glucocorticoid binding sites point towards the view that the cerebellum plays a functional role in the regulation of HPA-axis as well. The present hypothesis may further contribute to contemporary neurobiological views on stress regulation and depressive disorder, and may offer a potential biological basis for developing novel neurosomatic treatment protocols.     

The cerebello-hypothalamic–pituitary–adrenal axis dysregulation hypothesis in depressive disorder

Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic–pituitary–adrenal (HPA) axis is an important node in the brain’s stress circuit and suggested to play a role in several subtypes of depression. While the hippocampus, amygdala and prefrontal cortex are considered important regions implicated in stress regulation and depressive disorder, the existence of reciprocal monosynaptic cerebello-hypothalamic connections and the presence of dense glucocorticoid binding sites point towards the view that the cerebellum plays a functional role in the regulation of HPA-axis as well. The present hypothesis may further contribute to contemporary neurobiological views on stress regulation and depressive disorder, and may offer a potential biological basis for developing novel neurosomatic treatment protocols.     

Folliculo-stellate cells – Potential mediators of the inflammaging-induced hyperactivity of the hypothalamic–pituitary–adrenal axis in healthy elderly individuals

Some evidence has suggested that, with age, the hypothalamic–pituitary–adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood–brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they secrete paracrine agents that act locally to modulate pituitary responses to hypothalamic and peripheral signals. There is evidence of cytokines characteristically involved in inflammaging. For example, IL-1 and TNF-α are thought to stimulate folliculo-stellate cells to release various paracrine agents, including IL-6, IL-11, leukemia inhibitory factor, and macrophage migration inhibitory factor. Through different mechanisms, these agents induce ACTH release by corticotropes. Therefore, it can be concluded that folliculo-stellate cells may act as potent mediators of the age-related HPA axis hyperactivity induced by cytokines characteristic of the inflammaging phenomenon in healthy elderly individuals.     

Effects of central FGF21 infusion on the hypothalamus–pituitary–thyroid axis and energy metabolism in rats

The aim of this study was to evaluate the impact of intracerebroventricular chronic fibroblast growth factor 21 (FGF21) infusion on hypothalamic–pituitary–thyroid (HPT) axis, energy metabolism, food intake and body weight. Thirty male Wistar albino rats were used and divided into three groups including control, sham (vehicle) and FGF21 infused groups (n = 10). Intracerebroventricularly, FGF21 and vehicle groups were infused for 7 days with FGF21 (0.72 µg/day) and artificial cerebrospinal fluid, respectively. During the experimental period, changes in food intake and body weight were recorded daily. Serum thyroid stimulating hormone (TSH), Triiodothyronine (T3) and thyroxine (T4) levels were measured using ELISA. TRH and uncoupling protein 1 (UCP1) gene expressions were analyzed by using RT-PCR in hypothalamus and adipose tissues, respectively. Chronic infusion of FGF21 significantly increased serum TSH (p < 0.05), T3 (p < 0.05) and T4 (p < 0.001) levels. Additionally, hypothalamic TRH (p < 0.05) and UCP1 gene expressions (p < 0.05) in white adipose tissue were found to be higher than in the vehicle and control groups. While FGF21 infusion did not cause a significant change in food consumption, it caused a reduction in the body weight of rats (p < 0.05). Our findings indicate that FGF21 may have an effect on energy metabolism via the HPT axis.     

The biological impact of living with chronic breathlessness – A role for the hypothalamic–pituitary–adrenal axis?

Breathlessness is a common and distressing symptom in advanced cardiorespiratory disease, with recognised psychological, functional and social consequences. The biological impact of living with chronic breathlessness has not been explored. As breathlessness is often perceived as a threat to survival, we propose that episodic breathlessness engages the stress-response, as regulated by the hypothalamic–pituitary–adrenal (HPA) axis. Furthermore, we hypothesise that chronic breathlessness causes excessive stimulation of the HPA axis, resulting in dysfunctional regulation of the HPA axis and associated neuropsychological, metabolic and immunological sequelae. A number of observations provide indirect support for this hypothesis. Firstly, breathlessness and the HPA axis are both associated with anxiety. Secondly, similar cortico-limbic system structures govern both breathlessness perception and HPA axis regulation. Thirdly, breathlessness and HPA axis dysfunction are both independent predictors of survival. There is a need for direct observational evidence as well as experimental data to investigate this hypothesis which, if plausible, could lead to the identification of a new biomarker pathway to support breathlessness research.     

Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic–pituitary–adrenal axis via estrogen receptor alpha within the hypothalamus

Numerous studies have established a link between individuals with affective disorders and a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, most notably characterized by a reduced sensitivity to glucocorticoid negative (−) feedback. Furthermore there is a sex difference in the etiology of mood disorders with incidence in females being two to three times that of males, an association that may be a result of the influence of estradiol (E2) on HPA axis function. In these studies, we have examined the effect of E2 on glucocorticoid-mediated HPA axis (−) feedback during both the diurnal peak and the stress-induced rise in corticosterone (CORT). Young adult female Sprague–Dawley (SD) rats were ovariectomized (OVX) and 1 week later treated subcutaneous (s.c.) with oil or estradiol benzoate (EB) for 4 days. On the 4th day of treatment, animals were injected with a single dose of dexamethasone (DEX), or vehicle. EB treatment significantly increased the evening elevation in CORT and the stress-induced rise in CORT. In contrast, DEX treatment reduced the diurnal and stress induced rise in CORT and adrenocorticotropic hormone (ACTH), and this reduction was not apparent following co-treatment with EB. To determine a potential site of E2's action, female SD rats were OVX and 1 week later, wax pellets containing E2, the estrogen receptor beta (ERβ) agonist diarylpropionitrile (DPN), or the estrogen receptor alpha (ERα) agonist propylpyrazoletriol (PPT), was implanted bilaterally and dorsal to the paraventricular nucleus of the hypothalamus (PVN). Seven days later, animals were injected s.c. with a single dose of DEX, or vehicle to test for glucocorticoid-dependent (−) feedback. Results show that E2 and PPT increased, while DPN decreased the diurnal peak and stress-induced CORT and ACTH levels as compared to controls. Furthermore, E2 and PPT impaired the ability of DEX to inhibit both the diurnal and the stress-induced rise in CORT and ACTH, whereas DPN had no effect. Neuronal activation was measured by c-fos mRNA expression within the PVN following restraint. E2 and PPT increased c-fos mRNA, and impaired the normal DEX suppression of neuronal activation in the PVN. Taken together, these data indicate that estradiol causes a dysregulation of HPA axis (−) feedback as evidenced by the inability of DEX to suppress diurnal and stress-induced CORT and ACTH secretion. Additionally, the ability of E2 to inhibit glucocorticoid (–) feedback occurs specifically via ERα acting at the level of the PVN.     

Gestational hypoxia alone or combined with restraint sensitizes the hypothalamic–pituitary–adrenal axis and induces anxiety-like behavior in adult male rat offspring

We have reported that hypoxia affects the hypothalamic–pituitary–adrenal (HPA) axis and behavior by driving the expression of central corticotropin-releasing hormone (CRH) and its receptors in adult mammals, and this effect is modulated by other factors. Here, we address whether or not intermittent hypoxia (IH) or restraint (R) or a combination of both (IH+R) during gestation would result in differential alteration of the HPA axis and behavior of the adult male offspring. Gravid rats were exposed to IH in a hypobaric chamber (10.8% O₂, altitude of 5 km), R, or both, daily for 4 h for 21 days. Control parameters were set at sea level (20.9% O₂). All the stressors significantly and differentially increased CRH and corticotropin-releasing factor receptor type 1 (CRHR1) expression but decreased corticotropin-releasing factor receptor type 2 (CRHR2) in the paraventricular nucleus of the hypothalamus (PVN), enhanced CRHR1 mRNA and CRHR2 mRNA expression in the anterior pituitary, and increased plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels and adrenal weight in adult male offspring aged 120 days. Furthermore, norepinephrine (NE) and dopamine (DA) levels significantly increased in the locus coeruleus (LC), while the percentage of entries into the open arms of the elevated-plus maze test (EPM) markedly declined. In all the above effects, the combination-induced effect was stronger than each stressor alone. Confocal imaging showed a rich colocalization of CRHR1 with CRH or urocortin I (Ucn I), and CRHR2 with CRH or urocortin III (Ucn III) in the PVN, and CRHR1 with CRH in the LC in EPM-tested groups. In conclusion, IH or R alone or both in combination during gestation sensitize the HPA axis and induce anxiety-like behavior of the adult male offspring, and the combined effects are significantly great than IH or R alone. The CRH-NE neural circuit between the PVN and LC through CRH receptor driving might partly be involved in the effects. The differential colocalization of CRH with CRHR1 might be the neural basis of these effects.     

Histological and morphofunctional parameters of the hypothalamic–pituitary–adrenal system are sensitive to daidzein treatment in the adult rat

The isoflavone, daidzein is a biologically active, plant-derived compound that interacts with estrogen receptors. Data from previous studies have suggested that daidzein exerts beneficial effects in many diseases; however, as an endocrine disrupter, it may also alter the functioning of the endocrine system. Data regarding the effect of daidzein on the morphofunctional and histological parameters of the hypothalamic–pituitary–adrenal (HPA) system is still lacking. Therefore, using the newCAST stereological software, we investigated the effects of chronic (21 days) daidzein treatment on corticotropin-releasing hormone (CRH) neurons within the hypothalamus and corticotropes (ACTH cells) in the pituitary, while image analysis was employed to-examine the intensity of fluorescence of CRH in the median eminence (ME) and adrenocorticotropin hormone in the pituitary in adult orchidectomized (Ovx) rats. Circulating ACTH and corticosterone levels were also analyzed. This study showed that daidzein treatment decreased the volume density of CRH neurons within the paraventricular nucleus as well as CRH immunofluorescence in the ME. The total number of ACTH cells was decreased, while ACTH cell volume and the intensity of ACTH fluorescence were increased following daidzein treatment. Both ACTH and corticosterone blood levels were increased after daidzein administration. The results of performed experiments clearly demonstrate that volume density of CRH neurons; total number and volume of ACTH cells, as well as stress hormones levels are vulnerable to the effects of daidzein.     

Regulation and dysregulation of Epstein–Barr virus latency: Implications for the development of autoimmune diseases

Epstein–Barr virus (EBV) is a human herpesvirus hiding in a latent form in memory B cells in the majority of the world population. Although, primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis, the virus is associated with a wide variety of neoplasms developing in immunosuppressed or immunodeficient individuals, but also in patients with an apparently intact immune system. In memory B cells, tumor cells, and lymphoblastoid cell lines (LCLs, transformed by EBV in vitro) the expression of the viral genes is highly restricted. There is no virus production (lytic viral replication associated with the expression of all viral genes) in tight latency. The expression of latent viral oncogenes and RNAs is under a strict epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of latent promoters in tumor cells, germinal center B cells, and LCLs. Both the latent and lytic EBV proteins are potent immunogens and elicit vigorous B- and T-cell responses. In immunosuppressed and immunodeficient patients, or in individuals with a functional defect of EBV-specific T cells, lytic EBV replication is regularly activated and an increased viral load can be detected in the blood. Enhanced lytic replication results in new infection events and EBV-associated transformation events, and seems to be a risk factor both for malignant transformation and the development of autoimmune diseases. One may speculate that an increased load or altered presentation of a limited set of lytic or latent EBV proteins that cross-react with cellular antigens triggers and perpetuates the pathogenic processes that result in multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis. In addition, in SLE patients EBV may cause defects of B-cell tolerance checkpoints because latent membrane protein 1, an EBV-encoded viral oncoprotein can induce BAFF, a B-cell activating factor that rescues self-reactive B cells and induces a lupus-like autoimmune disease in transgenic mice.     

Microbes,metabolites, and the gut–lung axis

The microbiota plays an essential role in the education, development, and function of the immune system, both locally and systemically. Emerging experimental and epidemiological evidence highlights a crucial cross-talk between the intestinal microbiota and the lungs, termed the ‘gut–lung axis’. Changes in the constituents of the gut microbiome, through either diet, disease or medical interventions (such as antibiotics) is linked with altered immune responses and homeostasis in the airways. The importance of the gut–lung axis has become more evident following the identification of several gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), as key mediators for setting the tone of the immune system. Recent studies have supported a role for SCFAs in influencing hematopoietic precursors in the bone marrow—a major site of innate and adaptive immune cell development. Here, we review the current understanding of host–microbe cross-talk along the gut–lung axis. We highlight the importance of SCFAs in shaping and promoting bone marrow hematopoiesis to resolve airway inflammation and to support a healthy homeostasis.     

GABAergic regulation of the perifornical–lateral hypothalamic neurons during non-rapid eye movement sleep in rats

The perifornical–lateral hypothalamic area (PF–LHA) has been implicated in the regulation of behavioral arousal. The PF–LHA predominantly contains neurons that are active during behavioral and cortical activation and quiescent during non-rapid eye movement (nonREM) sleep, that is, are nonREM-off neurons. Some in vitro and in vivo studies indicate that PF–LHA neurons, including hypocretin-expressing neurons, are under GABAergic control. However, a role of GABA in suppressing the discharge of PF–LHA neurons during spontaneous nonREM sleep has not been confirmed. We recorded the sleep–wake discharge profiles of PF–LHA neurons and simultaneously assessed the contributions of local GABA_A receptor activation and blockade on their wake- and nonREM sleep-related discharge activities by delivering GABA_A receptor agonist, muscimol (500 nm, 5 μM, and 10 μM) and its antagonist, bicuculline (5 μM, 10 μM, and 20 μM), adjacent to the recorded neurons via reverse microdialysis. Muscimol dose-dependently decreased the discharge of PF–LHA neurons including nonREM-off neurons. Muscimol-induced suppression of discharge during nonREM sleep was significantly weaker than the suppression produced during waking. In the presence of bicuculline, PF–LHA neurons, including nonREM-off neurons, exhibited elevated discharge, which was dose-dependent and was significantly higher during nonREM sleep, compared to waking. These results suggest that GABA_A receptor mediated increased GABAergic tone contributes to the suppression of PF–LHA neurons, including nonREM-off neurons, during spontaneous nonREM sleep.     

A role for the heat shock protein–CD91 axis in the initiation of immune responses to tumors

For over 100 years, it has been established that tumor-specific immune responses can frequently be detected in the tumor-bearing host. Whether or not these immune responses are capable of controlling the growth of the tumor is influenced by many factors. However, the mechanism by which the immune responses are initiated in the first place has remained a dilemma. In this chapter, we present evidence that heat shock protein-peptide complexes released by tumor cells are the entity responsible for initiating the immune responses. Interaction of the extracellular HSP with its receptor CD91 is necessary for priming the immune response. We propose that the disruption of the HSP-CD91 interaction may be an active mechanism by which tumors prevent the generation of immune responses against it.     

Fine-needle aspiration cytology of Hürthle cell carcinoma of the thyroid

Specific criteria for the diagnosis of fine-needle aspiration (FNA) of Hürthle Cell Carcinoma (HCC) have rarely been discussed in the literature. A retrospective review of 35 FNA cases with the diagnosis of Hürthle cell lesion or Hürthle cell neoplasm was performed. In each case, there was a subsequent surgical excision. The FNA specimens were divided according to histologic diagnoses as HCC (12 cases), Hürthle cell adenoma (HCA) (14 cases), and benign nonneoplastic Hürthle cell lesions (BNHCL) (9 cases). Each case was examined using a semiquantitative scoring system for the following 11 features: presence or absence of colloid, lymphocytes, and transgressed blood vessels (each scored 0 or 1); the percentage of nuclear enlargement, small cell dysplasia, large cell dysplasia, nuclear crowding, and cellular dyshesion (each scored 0-3); and age, gender, and size of lesion. When diagnosed by FNA as either Hürthle cell neoplasm or Hürthle cell lesion, males were much more likely to have malignant tumors than females. Statistically significant cytologic features that favored malignant (HCC) over benign lesions (HCA and BNHCL) included small cell dysplasia, large cell dysplasia, nuclear crowding, and cellular dyshesion. The presence of colloid and lymphocytes favored a benign lesion. Nuclear enlargement and large tumor size are significantly more common in neoplasms than BNHCL.     

Obsessive–compulsive disorder and gut microbiota dysregulation

Obsessive–compulsive disorder (OCD) is a debilitating disorder for which the cause is not known and treatment options are modestly beneficial. A hypothesis is presented wherein the root cause of OCD is proposed to be a dysfunction of the gut microbiome constituency resulting in a susceptibility to obsessional thinking. Both stress and antibiotics are proposed as mechanisms by which gut microbiota are altered preceding the onset of OCD symptomology. In this light, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) leading to episodic OCD is explained not by group A beta-hemolytic streptococcal infections, but rather by prophylactic antibiotics that are administered as treatment. Further, stressful life events known to trigger OCD, such as pregnancy, are recast to show the possibility of altering gut microbiota prior to onset of OCD symptoms. Suggested treatment for OCD would be the directed, specie-specific (re)introduction of beneficial bacteria modifying the gut microbiome, thereby ameliorating OCD symptoms. Special considerations should be contemplated when considering efficacy of treatment, particularly the unhealthy coping strategies often observed in patients with chronic OCD that may need addressing in conjunction with microbiome remediation.     

Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing,less aggressive thyroid neoplasms?

Despite the large amount of information accumulated on the role played by ret activation in the oncogenesis of papillary thyroid carcinoma (PTC), the biological and clinical significance of such activation ‘in vivo’ remains controversial. The aim of this study was to address some of the existing controversies by comparing two groups of unselected PTCs, one with and the other without ret rearrangement, with regard to several clinicopathological and biological features. Thirty-three PTCs were selected at random. ret rearrangement was found in eight cases (24·2 per cent) using Southern blot analysis. The mean age of the patients with tumours displaying ret rearrangement (28±3·1 years) was significantly lower than that of the patients harbouring cases that did not present rearrangement (45±2·9 years). The large majority of the tumours with ret rearrangement displayed a papillary or mixed follicular–papillary pattern and very low proliferative activity. ret rearrangement correlated significantly with decreased cytoplasmic expression of E-cadherin. No significant differences were found regarding the gender of the patients, tumour size, multicentricity, extrathyroidal growth, vascular invasion, lymphocytic infiltration, lymph node involvement or the expression of E-cadherin (membrane), c-erb-B2, c-met, Bcl-2, and vimentin. It is proposed that sporadic PTCs harbouring a ret rearrangement occur frequently as slow growing, papillary, or predominantly papillary tumours that do not usually progress towards less differentiated neoplasms representing what might be described as a Bonsai phenotype. © 1998 John Wiley & Sons, Ltd.     

Is adolescence the missing developmental link in Microbiome–Gut–Brain axis communication?

Gut microbial research has recently opened new frontiers in neuroscience and potentiated novel therapies for mental health problems (Mayer, et al., 2014). Much of our understanding of the gut microbiome's role in brain function and behavior, however, has been largely derived from research on nonhuman animals. Even less is known about how the development of the gut microbiome influences critical periods of neural and behavioral development, particularly adolescence. In this review, we first discuss why the gut microbiome has become increasingly relevant to developmental cognitive neuroscience and provide a synopsis of the known connections of the gut microbiome with social–affective brain function and behavior, specifically highlighting human developmental work when possible. We then focus on adolescence, a key period of neurobiological and social–affective development. Specifically, we review the links between the gut microbiome and six overarching domains of change during adolescence: (a) social processes, (b) motivation and behavior, (c) neural development, (d) cognition, (e) neuroendocrine function, and (f) physical health and wellness. Using a developmental science perspective, we summarize key changes across these six domains to underscore the promise for the gut microbiome to bidirectionally influence and transform adolescent development.     

Does the BAFF dysregulation play a major role in the pathogenesis of systemic lupus erythematosus?

Given the prominent role currently assigned to B lymphocytes in systemic lupus erythematosus, it is not surprising that the B cell activity factor belonging to the tumor necrosis factor family (BAFF) is involved in its pathogenesis. This cytokine is produced in excess, and inserted into its receptors on the surface of circulating B cells. Up-regulation of BAFF is most likely to lead to breach of tolerance by aberrant survival of B cells directed to the self. Trials aimed at blocking BAFF have thus been set out. Yet the results are awaited.