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 A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output

2021 ◽  
Author(s):  
Charlotte Vanacker ◽  
R. Anthony DeFazio ◽  
Charlene M. Sykes ◽  
Suzanne M. Moenter
Keyword(s):  
Arcuate Nucleus ◽  
Designer Drugs ◽  
Neuron Activity ◽  
Gnrh Neurons ◽  
Hypothalamic Arcuate Nucleus ◽  
Lh Release ◽  
Main Regulator ◽  
Kndy Neurons

AbstractGnRH neurons are the final central neural output regulating fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (KNDy neurons) are considered the main regulator of GnRH output. GnRH and KNDy neurons are surrounded by astrocytes, which can modulate neuronal activity and communicate over distances. Prostaglandin E2 (PGE2), synthesized primarily by astrocytes, increases GnRH neuron activity and downstream pituitary release of luteinizing hormone (LH). We hypothesized GFAP-expressing astrocytes play a role regulating GnRH and/or KNDy neuron activity and LH release. We used adenoassociated viruses to target designer receptor exclusively activated by designer drugs (DREADDs) to GFAP-expressing cells to activate Gq or Gi-mediated signaling. Activating Gq signaling in the preoptic area, near GnRH neurons, but not in the arcuate, increases LH release in vivo and GnRH firing in vitro via a mechanism in part dependent upon PGE2. These data suggest astrocytes can activate GnRH/LH release in a manner independent of KNDy neurons.

scholarly journals A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output in male mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Charlotte Vanacker ◽  
Richard Anthony Defazio ◽  
Charlene M Sykes ◽  
Suzanne M Moenter
Keyword(s):  
Arcuate Nucleus ◽  
Designer Drugs ◽  
Neuron Activity ◽  
Gnrh Neurons ◽  
Hypothalamic Arcuate Nucleus ◽  
Lh Release ◽  
Main Regulator ◽  
Kndy Neurons

GnRH neurons are the final central neural output regulating fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (KNDy neurons) are considered the main regulator of GnRH output. GnRH and KNDy neurons are surrounded by astrocytes, which can modulate neuronal activity and communicate over distances. Prostaglandin E2 (PGE2), synthesized primarily by astrocytes, increases GnRH neuron activity and downstream pituitary release of luteinizing hormone (LH). We hypothesized GFAP-expressing astrocytes play a role regulating GnRH and/or KNDy neuron activity and LH release. We used adenoassociated viruses to target designer receptor exclusively activated by designer drugs (DREADDs) to GFAP-expressing cells to activate Gq or Gi-mediated signaling. Activating Gq signaling in the preoptic area, near GnRH neurons, but not in the arcuate, increases LH release in vivo and GnRH firing in vitro via a mechanism in part dependent upon PGE2. These data suggest astrocytes can activate GnRH/LH release in a manner independent of KNDy neurons.

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 In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences

2021 ◽  
pp. 0271678X2098150
Author(s):  
June van Aalst ◽  
Jenny Ceccarini ◽  
Stefan Sunaert ◽  
Patrick Dupont ◽  
Michel Koole ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Medial Temporal Lobe ◽  
Regional Differences ◽  
Specific Binding ◽  
Aerobic Glycolysis ◽  
Glucose Consumption ◽  
Brain Regions ◽  
Synaptic Density ◽  
Energy Demands

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [11C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [18F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [11C]UCB-J were indeed highly significantly correlated ( r > 0.47, p < 0.001). However, regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed, with up to 19% higher [11C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

Diet-derived nutrients mediate the inhibition of hypothalamic NPY neurons in the arcuate nucleus of mice during refeeding

2009 ◽  
Vol 297 (1) ◽  
pp. R100-R110 ◽  
Author(s):  
Csilla Becskei ◽  
Thomas A. Lutz ◽  
Thomas Riediger
Keyword(s):  
Neuropeptide Y ◽  
Arcuate Nucleus ◽  
Peptide Yy ◽  
Small Reduction ◽  
Hypothalamic Arcuate Nucleus ◽  
Ad Libitum ◽  
Fos Expression

Fasting activates orexigenic neuropeptide Y neurons in the hypothalamic arcuate nucleus (ARC) of mice, which is reversed by 2 h refeeding with standard chow. Here, we investigated the contribution of diet-derived macronutrients and anorectic hormones to the reversal of the fasting-induced ARC activation during 2 h refeeding. Refeeding of 12-h-fasted mice with a cellulose-based, noncaloric mash induced only a small reduction in c-Fos expression. Refeeding with diets, containing carbohydrates, protein, or fat alone reversed it similar to chow; however, this effect depended on the amount of intake. The fasting-induced ARC activation was unchanged by subcutaneously injected amylin, CCK (both 20 μg/kg), insulin (0.2 U/kg and 0.05 U/kg) or leptin (2.6 mg/kg). Insulin and leptin had no effect on c-Fos expression in neuropeptide Y or proopiomelanocortin-containing ARC neurons. Interestingly, CCK but not amylin reduced the ghrelin-induced c-Fos expression in the ARC in ad libitum-fed mice, suggesting that CCK may inhibit orexigenic ARC neurons when acting together with other feeding-related signals. We conclude that all three macronutrients and also non-nutritive, ingestion-dependent signals contribute to an inhibition of orexigenic ARC neurons after refeeding. Similar to the previously demonstrated inhibitory in vivo action of peptide YY, CCK may be a postprandial mediator of ARC inhibition.

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.

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

2006 ◽  
Vol 291 (5) ◽  
pp. E1131-E1140 ◽  
Author(s):  
Michael Christopher ◽  
Christian Rantzau ◽  
Zhi-Ping Chen ◽  
Rodney Snow ◽  
Bruce Kemp ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Fatty Acid Oxidation ◽  
Low Dose ◽  
Whole Body ◽  
Glucose Turnover ◽  
Acid Oxidation ◽  
Metabolic Clearance ◽  
The Impact

AMPK plays a central role in influencing fuel usage and selection. The aim of this study was to analyze the impact of low-dose AMP analog 5-aminoimidazole-4-carboxamide-1-β-d-ribosyl monophosphate (ZMP) on whole body glucose turnover and skeletal muscle (SkM) glucose metabolism. Dogs were restudied after prior 48-h fatty acid oxidation (FAOX) blockade by methylpalmoxirate (MP; 5 × 12 hourly 10 mg/kg doses). During the basal equilibrium period (0–150 min), fasting dogs ( n = 8) were infused with [3-3H]glucose followed by either 2-h saline or AICAR (1.5–2.0 mg·kg−1·min−1) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FAOX blockade. The AICAR and AICAR + MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (Rd tissue), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCRg) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACC∼pSer221) increased by 50%. In the AICAR + MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and Rd tissue responses were markedly attenuated, but MCRg and GF increased significantly. SkM substrates were unchanged, but ACC∼pSer221 rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FAox blockade.

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