scholarly journals Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin

2010 ◽  
Vol 108 (1) ◽  
pp. 355-360 ◽  
Author(s):  
Masoud Ghamari-Langroudi ◽  
Dollada Srisai ◽  
Roger D. Cone
Keyword(s):  
Paraventricular Nucleus ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Ventromedial Hypothalamus ◽  
Postsynaptic Membrane ◽  
Firing Frequency ◽  
Dependent Manner ◽  
Primary Control ◽  
Regulation Of Activity

Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from first-order neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.

scholarly journals Dynorphin Knockout Reduces Fat Mass and Increases Weight Loss during Fasting in Mice

2007 ◽  
Vol 21 (7) ◽  
pp. 1722-1735 ◽  
Author(s):  
Amanda Sainsbury ◽  
Shu Lin ◽  
Keely McNamara ◽  
Katy Slack ◽  
Ronaldo Enriquez ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Ventromedial Hypothalamus ◽  
Nutrient Absorption ◽  
Endogenous Opioids ◽  
Acid Oxidation ◽  
Hypothalamic Arcuate Nucleus ◽  
White Fat

Abstract Endogenous opioids, particularly dynorphins, have been implicated in regulation of energy balance, but it is not known how they mediate this in vivo. We investigated energy homeostasis in dynorphin knockout mice (Dyn−/− mice) and probed the interactions between dynorphins and the neuropeptide Y (NPY) system. Dyn−/− mice were no different from wild types with regards to body weight and basal and fasting-induced food intake, but fecal output was increased, suggesting decreased nutrient absorption, and they had significantly less white fat and lost more weight during a 24-h fast. The neuroendocrine and thermal responses to fasting were at least as pronounced in Dyn−/− as in wild types, and there was no stimulatory effect of dynorphin knockout on 24-h energy expenditure (kilocalories of heat produced) or physical activity. However, Dyn−/− mice showed increased circulating concentrations of 3,4-dihydroxyphenlacetic acid and 3,4-dihydroxyphenylglycol, suggesting increased activity of the sympathetic nervous system. The respiratory exchange ratio of male but not female Dyn−/− mice was reduced, demonstrating increased fat oxidation. Interestingly, expression of the orexigenic acting NPY in the hypothalamic arcuate nucleus was reduced in Dyn−/− mice. However, fasting-induced increases in pre-prodynorphin expression in the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus but not the lateral hypothalamus were abolished by deletion of Y1 but not Y2 receptors. Therefore, ablation of dynorphins results in increases in fatty acid oxidation in male mice, reductions in adiposity, and increased weight loss during fasting, possibly via increases in sympathetic activity, decreases in intestinal nutrient absorption, and interactions with the NPYergic system.

scholarly journals Galanin and Galanin-Like Peptide Differentially Modulate Neuronal Activities in Rat Arcuate Nucleus Neurons

2006 ◽  
Vol 95 (5) ◽  
pp. 3228-3234 ◽  
Author(s):  
Yan Dong ◽  
Joanna P. Tyszkiewicz ◽  
Tung M. Fong
Keyword(s):  
G Protein ◽  
Differential Effect ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Reproductive Function ◽  
Resting Membrane Potential ◽  
Protein Activity ◽  
Neurophysiological Mechanism ◽  
Spike Firing

Neuropeptides galanin and galanin-like peptide (GALP) share similar amino acid sequence and presumably interact with the same group of receptors, but they differentially regulate a variety of physiological and pathophysiological processes including metabolism and reproduction. Here we explored the neurophysiological basis of the in vivo differential effect between galanin and GALP by examining galanin and GALP modulation of neuronal activities of neurons in the arcuate nucleus (Arc), a brain region critically involved in energy homeostasis and reproductive function. We demonstrated that galanin and GALP inhibited excitatory and inhibitory postsynaptic currents in a similar way. In contrast, galanin and GALP differentially affected the intrinsic membrane property. In most recorded Arc neurons, galanin perfusion induced significant hyperpolarization of the resting membrane potential, which was not affected by GALP perfusion. In addition, galanin perfusion substantially suppressed the spontaneous spike firing in most Arc neurons, whereas in response to GALP perfusion, about half of the Arc neurons exhibited mild reduction in spontaneous spike firing and the other half showed enhancement. Furthermore, the Arc neurons that had been previously responsive to galanin perfusion no longer responded to galanin if co-applied with GALP, indicating that GALP can physiologically antagonize galanin effect. This differential effect appears to be mediated by G protein within the recorded cell, as the galanin effect on firing rate was abolished when the recorded cell was loaded with GDP-βS, an agent that blocks G protein activity. Taken together, these differential effects of galanin and GALP may provide a neurophysiological mechanism through which galanin and GALP differentially regulate energy balance, reproductive function, and other physiological processes.

scholarly journals Carnitine Palmitoyltransferase-1 (CPT-1) Activity Stimulation by Cerulenin via Sympathetic Nervous System Activation Overrides Cerulenin’s Peripheral Effect

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3197-3204 ◽  
Author(s):  
Yong-Jun Jin ◽  
Song-Zhe Li ◽  
Zheng-Shan Zhao ◽  
Juan Ji An ◽  
Ryang Yeo Kim ◽  
...  
Keyword(s):  
Nervous System ◽  
Sympathetic Nervous System ◽  
Core Temperature ◽  
Arcuate Nucleus ◽  
Late Phase ◽  
Ventromedial Hypothalamus ◽  
Sympathetic Nervous ◽  
Carnitine Palmitoyltransferase 1

Abstract To clarify the paradoxic effects of cerulenin, namely its in vitro inhibitory effects on fat catabolism and its in vivo reduction of fat mass, we studied the in vivo and in vitro effects of cerulenin on carnitine palmitoyltransferase-1 (CPT-1) activity, the rate-limiting enzyme of fatty acid oxidation. A single ip injection of cerulenin significantly reduced body weight and increased core temperature without significantly reducing food intake. In situ hybridization study revealed that a single injection of cerulenin did not affect the expression of orexigenic neuropeptide mRNA. Cerulenin’s effect on CPT-1 activity was biphasic in the liver and muscle: early suppression during the first 1 h and late stimulation in the 3–5 h after ip treatment. In vitro cerulenin treatment reduced CPT-1 activity, which was overcome by cotreating with catecholamine. Intracerebroventricular injection of cerulenin increased CPT-1 activity significantly in soleus muscle, and this effect was sustained for up to 3 h. Pretreatment with α-methyl-p-tyrosine inhibited the cerulenin-induced increase in core temperature and the late-phase stimulating effect of cerulenin on CPT-1 activity. In adrenalectomized mice, cerulenin also increased the activity. In vivo cerulenin treatment enhanced muscle CPT-1 activity in monosodium glutamate-treated arcuate nucleus lesioned mice but not in gold thioglucose-treated ventromedial hypothalamus lesioned mice. These findings suggest that cerulenin-induced late-phase stimulating effects on CPT-1 activity and energy expenditure is mediated by the activation of innervated sympathetic nervous system neurons through the firing of undefined neurons of the ventromedial hypothalamus, rather than the arcuate nucleus.

scholarly journals In Vivo Discharge Properties of Hypothalamic Paraventricular Nucleus Neurons With Axonal Projections to the Rostral Ventrolateral Medulla

2010 ◽  
Vol 103 (1) ◽  
pp. 4-15 ◽  
Author(s):  
Qing-Hui Chen ◽  
Glenn M. Toney
Keyword(s):  
Paraventricular Nucleus ◽  
Extracellular Recording ◽  
Firing Frequency ◽  
Rostral Ventrolateral Medulla ◽  
Hypothalamic Paraventricular Nucleus ◽  
Ventrolateral Medulla ◽  
Spontaneous Discharge ◽  
Axonal Projections ◽  
Arterial Blood

The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) are key components of a neural network that generates and regulates sympathetic nerve activity (SNA). Although each region has been extensively studied, little is presently known about the in vivo discharge properties of individual PVN neurons that directly innervate the RVLM. Here extracellular recording was performed in anesthetized rats, and antidromic stimulation was used to identify single PVN neurons with axonal projections to the RVLM ( n = 94). Neurons were divided into two groups that had either unbranched axons terminating in the RVLM (i.e., PVN-RVLM neurons, n = 65) or collateralized axons targeting both the RVLM and spinal cord [i.e., PVN-RVLM/intermediolateral cell column (IML) neurons, n = 29]. Many PVN-RVLM (32/65, 49%) and PVN-RVLM/IML (17/29, 59%) neurons were spontaneously active. The average firing frequency was not different across groups. Spike-triggered averaging revealed that spontaneous discharge of most neurons was temporally correlated with renal SNA (PVN-RVLM: 12/21, 57%; PVN-RVLM/IML: 6/9, 67%). Time histograms triggered by the electrocardiogram (ECG) R-wave indicated that discharge of most cells was also cardiac rhythmic (PVN-RVLM: 25/32, 78%; PVN-RVLM/IML: 10/17, 59%). Raising and lowering arterial blood pressure to increase and decrease arterial baroreceptor input caused a corresponding decrease and increase in firing frequency among cells of both groups (PVN-RVLM: 9/13, 69%; PVN-RVLM/IML: 4/4, 100%). These results indicate that PVN-RVLM and PVN-RVLM/IML neurons are both capable of contributing to basal sympathetic activity and its baroreflex modulation.

scholarly journals DNA Binding-Independent Induction of IκBα Gene Transcription by PPARα

2002 ◽  
Vol 16 (5) ◽  
pp. 1029-1039 ◽  
Author(s):  
Philippe Delerive ◽  
Karolien De Bosscher ◽  
Wim Vanden Berghe ◽  
Jean-Charles Fruchart ◽  
Guy Haegeman ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Transcriptional Repression ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Dominant Negative ◽  
Site Directed Mutagenesis ◽  
Dependent Manner ◽  
Response Element

Abstract PPARs are ligand-activated transcription factors that regulate energy homeostasis. In addition, PPARs furthermore control the inflammatory response by antagonizing the nuclear factor-κB (NF-κB) signaling pathway. We recently demonstrated that PPARα activators increase IκBα mRNA and protein levels in human aortic smooth muscle cells. Here, we studied the molecular mechanisms by which PPARα controls IκBα expression. Using transient transfection assays, it is demonstrated that PPARα potentiates p65-stimulated IκBα transcription in a ligand-dependent manner. Site-directed mutagenesis experiments revealed that PPARα activation of IκBα transcription requires the NF-κB and Sp1 sites within IκBα promoter. Chromatin immunoprecipitation assays demonstrate that PPARα activation enhances the occupancy of the NF-κB response element in IκBα promoter in vivo. Overexpression of the oncoprotein E1A failed to inhibit PPARα-mediated IκBα promoter induction, suggesting that cAMP response element binding protein-binding protein/p300 is not involved in this mechanism. By contrast, a dominant-negative form of VDR-interacting protein 205 (DRIP205) comprising its two LXXLL motifs completely abolished PPARα ligand-mediated activation. Furthermore, cotransfection of increasing amounts of DRIP205 relieved this inhibition, suggesting that PPARα requires DRIP205 to regulate IκBα promoter activity. By contrast, DRIP205 is not involved in PPARα-mediated NF-κB transcriptional repression. Taken together, these data provide a molecular basis for PPARα-mediated induction of IκBα and demonstrate, for the first time, that PPARα may positively regulate gene transcription in the absence of functional PPAR response elements.

scholarly journals Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis

2020 ◽  
Author(s):  
Juliana Bezerra Medeiros de Lima ◽  
Lucas Kniess Debarba ◽  
Manal Khan ◽  
Chidera Ubah ◽  
Olesya Didyuk ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Brain Regions ◽  
Designer Drugs ◽  
Whole Body ◽  
Mouse Line ◽  
Hypothalamic Arcuate Nucleus

AbstractGrowth hormone (GH) receptor (GHR), expressed in different brain regions, is known to participate in the regulation of whole-body energy homeostasis and glucose metabolism. However, GH activation of these GHR-expressing neurons is less studied. We have generated a novel GHR-driven Cre recombinase transgenic mouse line (GHRcre) in combination with the floxed tdTomato reporter mouse line we tracked and activated GHR-expressing neurons in different regions of the brain. We focused on neurons of the hypothalamic arcuate nucleus (ARC) where GHR was shown to elicit a negative feedback loop that regulates GH production. We found that ARCGHR+ neurons are co-localized with AgRP, GHRH, and somatostatin neurons, which were activated by GH stimulation. Using designer receptors exclusively activated by designer drugs (DREADDs) to control GHRARC neuronal activity, we revealed that activation of GHRARC neurons was sufficient in regulating distinct aspects of energy balance and glucose metabolism. Overall, our study provides a novel mouse model to study in vivo regulation and physiological function of GHR-expressing neurons in various brain regions. Furthermore, we identified for the first time specific neuronal population that responds to GH and directly linked it to metabolic responses in vivo.

scholarly journals Photobiomodulation Therapy Ameliorates Glutamatergic Dysfunction in Mice with Chronic Unpredictable Mild Stress-Induced Depression

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Di Zhang ◽  
Qi Shen ◽  
Xiaolei Wu ◽  
Da Xing
Keyword(s):  
Ampa Receptors ◽  
Glutamate Transporter ◽  
Postsynaptic Membrane ◽  
Photobiomodulation Therapy ◽  
Mild Stress ◽  
Dependent Manner ◽  
Chronic Unpredictable Mild Stress ◽  
Antidepressant Effects

Accumulating evidence indicates that dysfunction of the glutamatergic neurotransmission has been widely involved in the pathophysiology and treatment of depression. Photobiomodulation therapy (PBMT) has been demonstrated to regulate neuronal function both in vitro and in vivo. Herein, we aim to investigate whether the antidepressant phenotype of PBMT is associated with the improvement of glutamatergic dysfunction and to explore the mechanisms involved. Results showed that PBMT decreased extracellular glutamate levels via upregulation of glutamate transporter-1 (GLT-1) and rescued astrocyte loss in the cerebral cortex and hippocampus, which also alleviated dendritic atrophy and upregulated the expression of AMPA receptors on the postsynaptic membrane, ultimately exhibiting behaviorally significant antidepressant effects in mice exposed to chronic unpredictable mild stress (CUMS). Notably, PBMT also obtained similar antidepressant effects in a depressive mouse model subcutaneously injected with corticosterone (CORT). Evidence from in vitro mechanistic experiments demonstrated that PBMT treatment significantly increased both the GLT-1 mRNA and protein levels via the Akt/NF-κB signaling pathway. NF-κB-regulated transcription was in an Akt-dependent manner, while inhibition of Akt attenuated the DNA-binding efficiency of NF-κB to the GLT-1 promoter. Importantly, in vitro, we further found that PKA activation was responsible for phosphorylation and surface levels of AMPA receptors induced by PBMT, which is likely to rescue excitatory synaptic transmission. Taken together, our research suggests that PBMT as a feasible therapeutic approach has great potential value to control the progression of depression.

scholarly journals DNA methylation and demethylation underlie the sex difference in estrogen receptor alpha in the arcuate nucleus

2021 ◽  
Author(s):  
Laura R. Cortes ◽  
Carla D. Cisternas ◽  
Iagn N.K.V. Cabahug ◽  
Damian Mason ◽  
Emma K. Ramlall ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Estrogen Receptor ◽  
Sex Difference ◽  
Dna Methyltransferase ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Methylation Status ◽  
Ventromedial Hypothalamus ◽  
Cell Number ◽  
Small Interfering Rnas

AbstractIntroductionNeurons expressing estrogen receptor (ER) α in the arcuate nucleus (ARC) of the hypothalamus sex-specifically control energy homeostasis and bone density. Females have more of these neurons than do males, but how this sex difference develops is unknown.ObjectiveWe tested the hypothesis that DNA methylation and/or demethylation control the development of a sex difference in ERα in the ARC.MethodsERα immunoreactive neurons were quantified at birth and at weaning in male, female and testosterone-treated female mice that received neonatal, intracerebroventricular injections of vehicle or zebularine, a DNA methyltransferase inhibitor. Methylation status of Esr1 was determined in the ARC and ventromedial hypothalamus (VMH) using bisulfite conversion of DNA followed by pyrosequencing. Small interfering RNAs against ten-eleven translocases were used to examine effects of demethylation on ERα cell number.ResultsA sex difference in ERα cell number in the ARC, favoring females, developed between birth and weaning and was due to programming effects of testosterone. Zebularine treatment eliminated the sex difference in ERα in the ARC at weaning by decreasing ERα in females to male-like levels. Previously, the same treatment increased ERα in males in the VMH. A promoter region of Esr1 exhibited sex differences in opposite directions in percent of total methylation in the ARC (females > males) and VMH (males > females). Moreover, neonatal inhibition of demethylation increased ERα in the ARC of males.ConclusionDNA methylation and demethylation regulate ERα cell number in the ARC, and methyl marks may paradoxically activate Esr1 in this region.

Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

1996 ◽  
Vol 76 (01) ◽  
pp. 111-117 ◽  
Author(s):  
Yasuto Sasaki ◽  
Junji Seki ◽  
John C Giddings ◽  
Junichiro Yamamoto
Keyword(s):  
Blood Flow ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Red Cell ◽  
Cell Velocity ◽  
Red Cell Velocity ◽  
The Mean ◽  
Wall Shear ◽  
Dose Dependent

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

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