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  1. Paes-Leme B, Monteiro LDRN, Gholami K, Hoe SZ, Ferguson AV, Murphy D, et al.
    J Neuroendocrinol, 2023 Nov;35(11):e13334.
    PMID: 37667574 DOI: 10.1111/jne.13334
    In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.
    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism
  2. Hassan Z, Sattar MZ, Suhaimi FW, Yusoff NH, Abdulla MH, Yusof AP, et al.
    Acta Neurol Belg, 2013 Sep;113(3):319-25.
    PMID: 23242937 DOI: 10.1007/s13760-012-0165-3
    The hypothalamic paraventricular nucleus (PVN) is involved in the regulation of sympathetic outflow and particularly affects the heart. This study sets out to determine the role of GABA of the paraventricular nucleus (PVN) in cardiovascular regulation in streptozotocin-induced diabetic rats. Pharmacological stimulation of glutamatergic receptors with DL-Homocysteic acid (200 mM in 100 nL) in the PVN region showed a significant depression in both mean arterial pressure (MAP) and heart rate (HR) of diabetic rats (Diabetic vs. non-diabetic: MAP 15.0 ± 1.5 vs. 35.8 ± 2.8 mmHg; HR 3.0 ± 2.0 vs. 30.0 ± 6.0 bpm, P < 0.05). Microinjection of bicuculline methiodide (1 mM in 100 nL), a GABAA receptor antagonist, produced an increase in baseline MAP and HR in both non-diabetic and diabetic rats. In the diabetic rats, bicuculline injection into the PVN reduced the pressor and HR responses (Diabetic vs. non-diabetic: MAP 6.2 ± 0.8 vs. 25.1 ± 2.2 mmHg; HR 1.8 ± 1.1 vs. 25.4 ± 6.2 bpm, P < 0.05). A microinjection of muscimol (2 mM in 100 nL), which is a GABAA receptor agonist, in the PVN elicited decreases in MAP and HR in both groups. The diabetic group showed a significantly blunted reduction in HR, but not MAP (Diabetic vs. non-diabetic: MAP -15.7 ± 4.0 vs. -25.0 ± 3.8 mmHg; HR -5.2 ± 2.1 vs. -39.1 ± 7.9 bpm). The blunted vasopressor and tachycardic responses to bicuculline microinjection in the diabetic rats are likely to result from decreased GABAergic inputs, attenuated release of endogenous GABA or alterations in GABAA receptors within the PVN.
    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism*
  3. Loewen SP, Paterson AR, Loh SY, Rogers MF, Hindmarch CCT, Murphy D, et al.
    Exp Physiol, 2017 11 01;102(11):1373-1379.
    PMID: 28762571 DOI: 10.1113/EP086436
    NEW FINDINGS: What is the topic of this review? We describe roles of crucial signalling molecules in the paraventricular nucleus of the hypothalamus and highlight recent data suggesting sex-specific changes in the expression of crucial signalling molecules and their receptors, which may underlie sex differences in both cardiovascular and metabolic function. What advances does it highlight? This review highlights the integrative capacity of the paraventricular nucleus in mediating cardiovascular and metabolic effects by integrating information from multiple signalling molecules. It also proposes that these signalling molecules have sex-specific differential gene expression, indicating the importance of considering these differences in our ongoing search to understand the female-male differences in the regulation of crucial autonomic systems. Many traditional cardiovascular hormones have been implicated in metabolic function. Conversely, many hormones traditionally involved in metabolic regulation have an effect on cardiovascular function. Many of these signalling molecules exert such effects through specific actions in the paraventricular nucleus, an integrative autonomic control centre located in the hypothalamus. Here, we focus on four cardiovascular/metabolic peptide hormones that signal within the paraventricular nucleus, namely angiotensin II, orexin, adiponectin and nesfatin-1. Each of these hormones has specific electrophysiological effects on paraventricular nucleus neurons that can be related to its physiological actions. In addition, we introduce preliminary transcriptomic data indicating that the genes for some of these hormones and their receptors have sex-specific differential expression.
    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism*
  4. Greenwood M, Greenwood MP, Mecawi AS, Loh SY, Rodrigues JA, Paton JF, et al.
    Mol Brain, 2015 Oct 26;8(1):68.
    PMID: 26503226 DOI: 10.1186/s13041-015-0159-1
    BACKGROUND: Arginine vasopressin (AVP), a neuropeptide hormone that functions in the regulation of water homeostasis by controlling water re-absorption at kidneys, is synthesised in supraoptic nucleus and paraventricular nucleus of the hypothalamus. An increase in plasma osmolality stimulates secretion of AVP to blood circulation and induces AVP synthesis in these nuclei. Although studies on mechanism of AVP transcriptional regulation in hypothalamus proposed that cAMP and glucocorticoids positively and negatively regulate Avp expression, respectively, the molecular mechanisms have remained elusive. Recently, we identified CREB3L1 (cAMP-responsive element binding protein 3 like 1) as a putative transcription factor of Avp transcription in the rat hypothalamus. However the mechanism of how CREB3L1 is regulated in response of hyperosmotic stress in the neurons of hypothalamus has never been reported. This study aims to investigate effect of previously reported regulators (cAMP and glucocorticoid) of Avp transcription on transcription factor CREB3L1 in order to establish a molecular explanation for cAMP and glucocorticoids effect on AVP expression.

    RESULTS: The effect of cAMP and glucocorticoid treatment on Creb3l1 was investigated in both AtT20 cells and hypothalamic organotypic cultures. The expression of Creb3l1 was increased in both mRNA and protein level by treatment with forskolin, which raises intracellular cAMP levels. Activation of cAMP by forskolin also increased Avp promoter activity in AtT20 cells and this effect was blunted by shRNA mediated silencing of Creb3l1. The forskolin induced increase in Creb3l1 expression was diminished by combined treatment with dexamethasone, and, in vivo, intraperitoneal dexamethasone injection blunted the increase in Creb3l1 and Avp expression induced by hyperosmotic stress.

    CONCLUSION: Here we shows that cAMP and glucocorticoid positively and negatively regulate Creb3l1 expression in the rat hypothalamus, respectively, and regulation of cAMP on AVP expression is mediated through CREB3L1. This data provides the connection between CREB3L1, a newly identified transcription factor of AVP expression, with the previously proposed mechanism of Avp transcription which extends our understanding in transcription regulation of Avp in the hypothalamus.

    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism
  5. Greenwood MP, Greenwood M, Mecawi AS, Antunes-Rodrigues J, Paton JF, Murphy D
    Mol Brain, 2016 Jan 07;9:1.
    PMID: 26739966 DOI: 10.1186/s13041-015-0182-2
    BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain.

    RESULTS: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress.

    CONCLUSIONS: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain.

    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism
  6. Vilhena-Franco T, Mecawi AS, Elias LL, Antunes-Rodrigues J
    J Endocrinol, 2016 Nov;231(2):167-180.
    PMID: 27613338
    Water deprivation (WD) induces changes in plasma volume and osmolality, which in turn activate several responses, including thirst, the activation of the renin-angiotensin system (RAS) and vasopressin (AVP) and oxytocin (OT) secretion. These systems seem to be influenced by oestradiol, as evidenced by the expression of its receptor in brain areas that control fluid balance. Thus, we investigated the effects of oestradiol treatment on behavioural and neuroendocrine changes of ovariectomized rats in response to WD. We observed that in response to WD, oestradiol treatment attenuated water intake, plasma osmolality and haematocrit but did not change urinary volume or osmolality. Moreover, oestradiol potentiated WD-induced AVP secretion, but did not alter the plasma OT or angiotensin II (Ang II) concentrations. Immunohistochemical data showed that oestradiol potentiated vasopressinergic neuronal activation in the lateral magnocellular PVN (PaLM) and supraoptic (SON) nuclei but did not induce further changes in Fos expression in the median preoptic nucleus (MnPO) or subfornical organ (SFO) or in oxytocinergic neuronal activation in the SON and PVN of WD rats. Regarding mRNA expression, oestradiol increased OT mRNA expression in the SON and PVN under basal conditions and after WD, but did not induce additional changes in the mRNA expression for AVP in the SON or PVN. It also did not affect the mRNA expression of RAS components in the PVN. In conclusion, our results show that oestradiol acts mainly on the vasopressinergic system in response to WD, potentiating vasopressinergic neuronal activation and AVP secretion without altering AVP mRNA expression.
    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism
  7. Brunton PJ, Donadio MV, Yao ST, Greenwood M, Seckl JR, Murphy D, et al.
    J Neurosci, 2015 Jan 14;35(2):666-77.
    PMID: 25589761 DOI: 10.1523/JNEUROSCI.5104-13.2015
    Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β; IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3β-androstanediol (3β-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.
    Matched MeSH terms: Paraventricular Hypothalamic Nucleus/metabolism
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