Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons

2015 ◽  
Vol 309 (4) ◽  
pp. E320-E333 ◽  
Author(s):  
Hideharu Kurita ◽  
Kai Y. Xu ◽  
Yuko Maejima ◽  
Masanori Nakata ◽  
Katsuya Dezaki ◽  
...  
Keyword(s):  
Feeding Behavior ◽  
Energy State ◽  
Glucose Lowering ◽  
First Order ◽  
Obesity And Diabetes ◽  
Metabolic States ◽  
Pump Activity ◽  
Single Arc ◽  
Energy States ◽  
Agouti Related Protein

Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na+,K+-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na+ concentration in single ARC neurons that subsequently exhibited [Ca2+]i responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca2+]i in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca2+]i increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKAα3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes.

The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia

2021 ◽  
Vol 13 (590) ◽  
pp. eabd6434
Author(s):  
Patrick Sweeney ◽  
Michelle N. Bedenbaugh ◽  
Jose Maldonado ◽  
Pauline Pan ◽  
Katelyn Fowler ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Feeding Behavior ◽  
Critical Role ◽  
Brain Regions ◽  
Sexually Dimorphic ◽  
Male And Female ◽  
Female Mice ◽  
Bidirectional Regulation ◽  
Fear And Anxiety ◽  
Agouti Related Protein

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.

scholarly journals The Function of Paraventricular Thalamic Circuitry in Adaptive Control of Feeding Behavior

2021 ◽  
Vol 15 ◽  
Author(s):  
Gorica D. Petrovich
Keyword(s):  
Feeding Behavior ◽  
Cognitive Processes ◽  
Energy Use ◽  
Hippocampal Formation ◽  
Energy State ◽  
Energy Resources ◽  
Behavioral Choice ◽  
Cortical Areas ◽  
Prefrontal Cortical ◽  
Set Up

The paraventricular nucleus of the thalamus (PVT) is a complex area that is uniquely embedded across the core feeding, reward, arousal, and stress circuits. The PVT role in the control of feeding behavior is discussed here within a framework of adaptive behavioral guidance based on the body’s energy state and competing drives. The survival of an organism depends on bodily energy resources and promotion of feeding over other behaviors is adaptive except when in danger or sated. The PVT is structurally set up to respond to homeostatic and hedonic needs to feed, and to integrate those signals with physiological and environmental stress, as well as anticipatory needs and other cognitive inputs. It can regulate both food foraging (seeking) and consumption and may balance their expression. The PVT is proposed to accomplish these functions through a network of connections with the brainstem, hypothalamic, striatal, and cortical areas. The connectivity of the PVT further indicates that it could broadcast the information about energy use/gain and behavioral choice to impact cognitive processes—learning, memory, and decision-making—through connections with the medial and lateral prefrontal cortical areas, the hippocampal formation, and the amygdala. The PVT is structurally complex and recent evidence for specific PVT pathways in different aspects of feeding behavior will be discussed.

scholarly journals Amino acids, taste circuits, and feeding behavior in Drosophila: towards understanding the psychology of feeding in flies and man

2007 ◽  
Vol 192 (3) ◽  
pp. 467-472 ◽  
Author(s):  
Christoph Melcher ◽  
Ruediger Bader ◽  
Michael J Pankratz
Keyword(s):  
Feeding Behavior ◽  
Functional Characterization ◽  
Relevant Information ◽  
Sensory Stimuli ◽  
Major Health ◽  
Obesity And Diabetes ◽  
The Central Nervous System ◽  
Complex Regulatory Network

Feeding can be regulated by a variety of external sensory stimuli such as olfaction and gustation, as well as by systemic internal signals of feeding status and metabolic needs. Faced with a major health epidemic in eating-related conditions, such as obesity and diabetes, there is an ever increasing need to dissect and understand the complex regulatory network underlying the multiple aspects of feeding behavior. In this minireview, we highlight the use of Drosophila in studying the neural circuits that control the feeding behavior in response to external and internal signals. In particular, we outline the work on the neuroanatomical and functional characterization of the newly identified hugin neuronal circuit. We focus on the pivotal role of the central nervous system in integrating external and internal feeding-relevant information, thus enabling the organism to make one of the most basic decisions – to eat or not to eat.

scholarly journals Genomics of estradiol-3-sulfate action in the ovine fetal hypothalamus

2012 ◽  
Vol 44 (13) ◽  
pp. 669-677 ◽  
Author(s):  
Maria Belen Rabaglino ◽  
Elaine Richards ◽  
Nancy Denslow ◽  
Maureen Keller-Wood ◽  
Charles E. Wood
Keyword(s):  
Feeding Behavior ◽  
Transforming Growth Factor ◽  
Fetal Brain ◽  
Ovis Aries ◽  
Late Gestation ◽  
Postnatal Life ◽  
Growth Factor Signaling ◽  
Fetal Sheep ◽  
Ovine Fetal ◽  
Agouti Related Protein

In fetal sheep during late gestation sulfoconjugated estrogens in plasma reach a concentration 40–100 times greater than unconjugated estrogens. The objective of the present study was to determine the genomics of estradiol-3-sulfate (E2S) action in the ovine fetal brain. The hypothesis was that E2S stimulates genes involved in the neuroendocrine pathways that direct or facilitate fetal development at the end of gestation. Four sets of chronically catheterized ovine twin fetuses were studied (gestational age: 120–127 days gestation) with one infused with E2S intracerebroventricularly (1 mg/day) and the other remaining untreated (control). After euthanasia, mRNA samples were extracted from fetal brains. Only hypothalamic samples were employed for this study given the important function of this brain region in the control of the hypothalamus-pituitary-adrenal axis. Microarray analysis was performed following the Agilent protocol for one-color 8 × 15 microarrays, designed for Ovis aries. A total of 363 known genes were significantly upregulated by the E2S treatment ( P < 0.05). Network and enrichment analyses were performed using the Cytoscape/Bingo software, and the results validated by quantitative real-time PCR. The main overrepresented biological processes resulting from this analysis were feeding behavior, hypoxia response, and transforming growth factor signaling. Notably, the genes involved in the feeding behavior (neuropeptide Y and agouti-related protein) were the most strongly induced by the E2S treatment. In conclusion, E2S may be an important component of the mechanism for activating orexigenic, hypoxia responsiveness and neuroprotective pathways in the lamb as it approaches postnatal life.

scholarly journals Structural basis for ligand binding to an enzyme by a conformational selection pathway

2017 ◽  
Vol 114 (24) ◽  
pp. 6298-6303 ◽  
Author(s):  
Michael Kovermann ◽  
Christin Grundström ◽  
A. Elisabeth Sauer-Eriksson ◽  
Uwe H. Sauer ◽  
Magnus Wolf-Watz
Keyword(s):  
Ligand Binding ◽  
Adenylate Kinase ◽  
Energy State ◽  
High Energy ◽  
Structural Basis ◽  
Fast Time ◽  
X Ray ◽  
Conformational Selection ◽  
High Energy State ◽  
Energy States

Proteins can bind target molecules through either induced fit or conformational selection pathways. In the conformational selection model, a protein samples a scarcely populated high-energy state that resembles a target-bound conformation. In enzymatic catalysis, such high-energy states have been identified as crucial entities for activity and the dynamic interconversion between ground states and high-energy states can constitute the rate-limiting step for catalytic turnover. The transient nature of these states has precluded direct observation of their properties. Here, we present a molecular description of a high-energy enzyme state in a conformational selection pathway by an experimental strategy centered on NMR spectroscopy, protein engineering, and X-ray crystallography. Through the introduction of a disulfide bond, we succeeded in arresting the enzyme adenylate kinase in a closed high-energy conformation that is on-pathway for catalysis. A 1.9-Å X-ray structure of the arrested enzyme in complex with a transition state analog shows that catalytic sidechains are properly aligned for catalysis. We discovered that the structural sampling of the substrate free enzyme corresponds to the complete amplitude that is associated with formation of the closed and catalytically active state. In addition, we found that the trapped high-energy state displayed improved ligand binding affinity, compared with the wild-type enzyme, demonstrating that substrate binding to the high-energy state is not occluded by steric hindrance. Finally, we show that quenching of fast time scale motions observed upon ligand binding to adenylate kinase is dominated by enzyme–substrate interactions and not by intramolecular interactions resulting from the conformational change.

scholarly journals AMPfret: synthetic nanosensor for cellular energy states

2020 ◽  
Vol 48 (1) ◽  
pp. 103-111
Author(s):  
Hannah Crocker ◽  
Martin Pelosse ◽  
Uwe Schlattner ◽  
Imre Berger
Keyword(s):  
Energy State ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Therapeutic Interventions ◽  
Cell Physiology ◽  
Dna Assembly ◽  
Cellular Energy ◽  
Energy States

Cellular energy is a cornerstone of metabolism and is crucial for human health and disease. Knowledge of the cellular energy states and the underlying regulatory mechanisms is therefore key to understanding cell physiology and to design therapeutic interventions. Cellular energy states are characterised by concentration ratios of adenylates, in particular ATP:ADP and ATP:AMP. We applied synthetic biology approaches to design, engineer and validate a genetically encoded nano-sensor for cellular energy state, AMPfret. It employs the naturally evolved energy sensing of eukaryotic cells provided by the AMP-activated protein kinase (AMPK). Our synthetic nano-sensor relies on fluorescence resonance energy transfer (FRET) to detect changes in ATP:ADP and ATP:AMP ratios both in vitro and in cells in vivo. Construction and iterative optimisation relied on ACEMBL, a parallelised DNA assembly and construct screening technology we developed, facilitated by a method we termed tandem recombineering (TR). Our approach allowed rapid testing of numerous permutations of the AMPfret sensor to identify the most sensitive construct, which we characterised and validated both in the test tube and within cells.

scholarly journals Protein Malnutrition during Pregnancy in C57BL/6J Mice Results in Offspring with Altered Circadian Physiology before Obesity

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1570-1580 ◽  
Author(s):  
Gregory M. Sutton ◽  
Armand V. Centanni ◽  
Andrew A. Butler
Keyword(s):  
Feeding Behavior ◽  
Energy Homeostasis ◽  
Control Diet ◽  
Whole Body ◽  
Deficient Diet ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Obesity And Diabetes ◽  
Fetal Malnutrition ◽  
Circadian Physiology

The mechanisms linking intrauterine growth retardation (IUGR) with adulthood obesity and diabetes are unclear. These studies investigated energy homeostasis in 8- and 20-wk-old male and female mice subjected to protein deficiency in utero. Pregnant C57BL/6J female mice were fed a protein-deficient diet (6% protein). Undernourished offspring (UO) and controls (CO) were cross-fostered to lactating dams fed a 20% control diet. The 24-h profiles of energy expenditure, feeding behavior, physical activity, and whole-body substrate preference was assessed using 8-wk UO and CO weaned onto control diet. Blood chemistries, glucose tolerance, and expression of genes involved in hepatic lipid and glucose metabolism were analyzed in 8- and 20-wk-old CO and UO fed control or a high-fat diet. UO exhibited IUGR with catch-up growth at 8 wk of age and increased severity of diet-induced obesity and insulin resistance by 20 wk of age. Therefore, fetal malnutrition in the C57BL/6J mouse increases sensitivity to diet-induced obesity. Abnormal daily rhythms in food intake and metabolism, increased lipogenesis, and inflammation preceded obesity in the UO group. Arrhythmic expression of circadian oscillator genes was evident in brain, liver, and muscle of UO at 8 and 20 wk of age. Expression of the clock-associated nuclear receptor and transcription repressor Rev-erbα was reduced in liver and muscle of UO. Altered circadian physiology may be symptomatic of the metabolic dysregulation associated with IUGR, and altered feeding behavior and substrate metabolism may contribute to the obese phenotype.

scholarly journals On the absorption of light by gaseous, liquid and solid xenon

1930 ◽  
Vol 129 (810) ◽  
pp. 266-283 ◽  
Keyword(s):  
Vibrational Energy ◽  
Solid Phase ◽  
Energy State ◽  
Energy Levels ◽  
Electronic Energy ◽  
Rotational States ◽  
Absorption Of Light ◽  
Energy States ◽  
The One ◽  
Vibrational Energy Levels

The result of studies made by McLennan and McLeod and by McLennan, Smith and Wilhelm on the Raman effects obtained with liquid hydrogen have made it abundantly clear that molecules of hydrogen in the liquid phase exist or can exist in electronic, vibrational and rotational states that are exactly the same as states that are available for them to assume in the form of a gas or as isolated units. The same is true in regard to energy states that molecules of oxygen or of nitrogen may take up when existing as isolated entities on the one hand or when existing as a gas or a liquid on the other. In so far as oxygen is concerned, it is known from the work of Babcock that practically all the molecules of oxygen in the earth’s atmosphere are in the electronic state of lowest energy possible for them to assume. Only a very small percentage of them, namely, 0·04 per cent., have even one quantum of vibrational energy. It has been shown by McLennan, Smith and Wilhelm that a similar statement applies in a description of the energy states of the molecules of oxygen as they exist in the liquid or in the solid phase. The band systems and the structures of the band system that characterise the absorption spectra of gaseous, liquid and solid oxygen are identical. These bands all originate in transitions to higher energy states from rotational vibrational energy levels associated with a fundamental 3 Ʃ electronic energy state that can be shown by the theory of Hund and Mullikan to be the most stable one that molecules of oxygen can assume.

scholarly journals Extended stable equilibrium invaded by an unstable state

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Camila Castillo-Pinto ◽  
Marcel G. Clerc ◽  
Gregorio González-Cortés
Keyword(s):  
Domain Walls ◽  
Stable Equilibrium ◽  
Energy State ◽  
Front Propagation ◽  
Unstable State ◽  
Dimensional Model ◽  
One Dimensional ◽  
First Order ◽  
Contagious Diseases ◽  
Pattern Forming

Abstract Coexistence of states is an indispensable feature in the observation of domain walls, interfaces, shock waves or fronts in macroscopic systems. The propagation of these nonlinear waves depends on the relative stability of the connected equilibria. In particular, one expects a stable equilibrium to invade an unstable one, such as occur in combustion, in the spread of permanent contagious diseases, or in the freezing of supercooled water. Here, we show that an unstable state generically can invade a locally stable one in the context of the pattern forming systems. The origin of this phenomenon is related to the lower energy unstable state invading the locally stable but higher energy state. Based on a one-dimensional model we reveal the necessary features to observe this phenomenon. This scenario is fulfilled in the case of a first order spatial instability. A photo-isomerization experiment of a dye-dopant nematic liquid crystal, allow us to observe the front propagation from an unstable state.

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