Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

Cholesterol is important for normal brain function. The brain synthesizes its own cholesterol, presumably in astrocytes. We have previously shown that diabetes results in decreased brain cholesterol synthesis by a reduction in sterol regulatory element-binding protein 2 (SREBP2)-regulated transcription. Here we show that coculture of control astrocytes with neurons enhances neurite outgrowth, and this is reduced with SREBP2 knockdown astrocytes. In vivo, mice with knockout of SREBP2 in astrocytes have impaired brain development and behavioral and motor defects. These mice also have altered energy balance, altered body composition, and a shift in metabolism toward carbohydrate oxidation driven by increased glucose oxidation by the brain. Thus, SREBP2-mediated cholesterol synthesis in astrocytes plays an important role in brain and neuronal development and function, and altered brain cholesterol synthesis may contribute to the interaction between metabolic diseases, such as diabetes and altered brain function.

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Adipokines as key players in β cell function and failure

Clinical Science ◽

10.1042/cs20190523 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2317-2327 ◽

Cited By ~ 3

Author(s):

Nicolás Gómez-Banoy ◽

James C. Lo

Keyword(s):

Metabolic Diseases ◽

Cell Function ◽

Whole Body ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Axis ◽

Β Cell Function ◽

Prevalence Of Obesity ◽

Specific Factors ◽

Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

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Implantable neural interfaces

10.1093/oso/9780199674923.003.0050 ◽

2018 ◽

Author(s):

Stefano Vassanelli

Keyword(s):

Brain Function ◽

Large Scale ◽

Ionic Channels ◽

Patch Clamp Technique ◽

Advantages And Disadvantages ◽

Optogenetic Stimulation ◽

Physical Interfaces ◽

The Brain

Establishing direct communication with the brain through physical interfaces is a fundamental strategy to investigate brain function. Starting with the patch-clamp technique in the seventies, neuroscience has moved from detailed characterization of ionic channels to the analysis of single neurons and, more recently, microcircuits in brain neuronal networks. Development of new biohybrid probes with electrodes for recording and stimulating neurons in the living animal is a natural consequence of this trend. The recent introduction of optogenetic stimulation and advanced high-resolution large-scale electrical recording approaches demonstrates this need. Brain implants for real-time neurophysiology are also opening new avenues for neuroprosthetics to restore brain function after injury or in neurological disorders. This chapter provides an overview on existing and emergent neurophysiology technologies with particular focus on those intended to interface neuronal microcircuits in vivo. Chemical, electrical, and optogenetic-based interfaces are presented, with an analysis of advantages and disadvantages of the different technical approaches.

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What is the effect of body’s chemical messengers in the brain?

Letters in Applied NanoBioScience ◽

10.33263/lianbs83.613618 ◽

2019 ◽

Vol 8 (3) ◽

pp. 613-618

Keyword(s):

Language Learning ◽

Brain Function ◽

Physicochemical Parameters ◽

Active Sites ◽

Geometry Optimization ◽

Normal Brain ◽

Delivery Technique ◽

Normal Brain Function ◽

Practical Model ◽

The Brain

Neurochemical transmitters in the brain are fundamental to normal brain function and this investigation aims to introduce a study on the center of neuroscientific through an account of language development which conducts human speech mechanism using theoretical methods. In the process of this work, new understanding has been gained from the neurochemistry of several important neurotransmitters of dopamine (DA), epinephrine (EN), norepinephrine (NE), histamine (HA) and serotonin (ST) in brain by Monte Carlo simulation (MC) which uses the increased temperature to the potential energy of the neurochemicals in the brain considering the geometry optimization of the compounds as an additional conformational level. Moreover, the results of optimized DA, EN, NE, HA, ST neurochemical transmitters by running the physicochemical parameters as a practical model using Gaussian 09 program package can approve the twisting of language-brain due to these structures using density electron deliverers. The most stable of these compounds through the active sites of nitrogen and oxygen atoms has illustrated the best optimized position for localizing the structure through delivery technique in the brain to activate the center of learning a language as a simulated model. So, the best results with the calculated amounts conduct us to analyze the perspective of language learning process and enhancing this ability.

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Resolving rates of mutation in the brain using single-neuron genomics

eLife ◽

10.7554/elife.12966 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 97

Author(s):

Gilad D Evrony ◽

Eunjung Lee ◽

Peter J Park ◽

Christopher A Walsh

Keyword(s):

Single Cell ◽

Somatic Mutation ◽

Brain Function ◽

Single Neuron ◽

Bioinformatic Analysis ◽

Normal Brain ◽

Neuronal Function ◽

Human Neurons ◽

Normal Brain Function ◽

The Brain

Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (<xref ref-type="bibr" rid="bib65">Upton et al., 2015</xref>) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies.

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Perspective: Mitochondria-ER Contacts in Metabolic Cellular Stress Assessed by Microscopy

Cells ◽

10.3390/cells8010005 ◽

2018 ◽

Vol 8 (1) ◽

pp. 5 ◽

Cited By ~ 13

Author(s):

Alessandra Stacchiotti ◽

Gaia Favero ◽

Antonio Lavazza ◽

Raquel Garcia-Gomez ◽

Maria Monsalve ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Calcium Ions ◽

Metabolic Diseases ◽

Cellular Stress ◽

Pivotal Role ◽

Whole Body ◽

Oxygen Species ◽

Whole Body Metabolism

The interplay of mitochondria with the endoplasmic reticulum and their connections, called mitochondria-ER contacts (MERCs) or mitochondria-associated ER membranes (MAMs), are crucial hubs in cellular stress. These sites are essential for the passage of calcium ions, reactive oxygen species delivery, the sorting of lipids in whole-body metabolism. In this perspective article, we focus on microscopic evidences of the pivotal role of MERCs/MAMs and their changes in metabolic diseases, like obesity, diabetes, and neurodegeneration.

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Effects on Liver Lipid Metabolism of the Naturally Occurring Dietary Flavone Luteolin-7-glucoside

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/647832 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Carla Sá ◽

Ana Rita Oliveira ◽

Cátia Machado ◽

Marisa Azevedo ◽

Cristina Pereira-Wilson

Keyword(s):

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Regulatory Element ◽

Lipid Lowering ◽

Whole Body ◽

Mrna Levels ◽

Dependent Manner ◽

Hepatic Expression

Disruptions in whole-body lipid metabolism can lead to the onset of several pathologies such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs). The present study aimed at elucidating the molecular mechanisms behind the lipid-lowering effects of the flavone luteolin-7-glucoside (L7G) which we previously showed to improve plasma lipid profile in rats. L7G is abundant in plant foods of Mediterranean diet such as aromatic plants used as herbs. Results show that dietary supplementation with L7G for one week induced the expression of peroxisome proliferator-activated receptor-alpha (PPAR-α) and of its target gene carnitine palmitoyl transferase 1 (CPT-1) in rat liver. L7G showed a tendency to decrease the hepatic expression of sterol regulatory element-binding protein-1 (SREBP-1), without affecting fatty acid synthase (FAS) protein levels. Although SREBP-2 and LDLr mRNA levels did not change, the expression of HMG CoA reductase (HMGCR) was significantly repressed by L7G. L7G also inhibited this enzyme’sin vitroactivity in a dose dependent manner, but only at high and not physiologically relevant concentrations. These results add new evidence that the flavone luteolin-7-glucoside may help in preventing metabolic diseases and clarify the mechanisms underlying the beneficial health effects of diets rich in fruits and vegetables.

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Glucocorticoid receptor action in metabolic and neuronal function

F1000Research ◽

10.12688/f1000research.11375.1 ◽

2017 ◽

Vol 6 ◽

pp. 1208 ◽

Cited By ~ 19

Author(s):

Michael J. Garabedian ◽

Charles A. Harris ◽

Freddy Jeanneteau

Keyword(s):

Gene Expression ◽

Glucocorticoid Receptor ◽

Metabolic Diseases ◽

Cell Types ◽

Health And Disease ◽

And Behavior ◽

External Signals ◽

The Brain

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this “brain-fat axis” will enable a more complete understanding of metabolic diseases and inform new ways to target them.

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The Neuroactivation of Cognitive Processes Investigated with SPECT

Behavioural Neurology ◽

10.1155/2000/525163 ◽

2000 ◽

Vol 12 (1-2) ◽

pp. 53-67 ◽

Cited By ~ 1

Author(s):

Daniela Montaldi ◽

Andrew R. Mayes

Keyword(s):

Human Brain ◽

Cognitive Processes ◽

Brain Function ◽

Healthy Subjects ◽

Functional Mapping ◽

Normal Brain ◽

Memory Processing ◽

Yield Information ◽

Normal Brain Function ◽

The Brain

The last ten years have seen the development and expansion of an exciting new field of neuroscientific research; functional mapping of the human brain. Whilst many of the questions addressed by this area of research could be answered using SPECT, relatively few SPECT activation studies of this kind have been carried out. The present paper combines an evaluation of SPECT procedures used for neuroactivation studies, and their comparison with other imaging modalities (i.e., PET and fMRI), with a review of SPECT neuroactivation studies that yield information concerning normal brain function with a particular emphasis on the brain activations produced by memory processing. The paper aims to describe and counter common misunderstandings regarding potential limitations of the SPECT technique, to explain and illustrate which SPECT procedures best fulfill the requirements of a neuroactivation study, and how best to obtain information about normal brain function (whether using normal healthy subjects or patients) and finally to highlight SPECT’s potential future role in the functional mapping of the human brain.

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Enhanced glycogen metabolism in adipose tissue decreases triglyceride mobilization

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00741.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. E117-E125 ◽

Cited By ~ 6

Author(s):

Kathleen R. Markan ◽

Michael J. Jurczak ◽

Margaret B. Allison ◽

Honggang Ye ◽

Maria M. Sutanto ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Lactate Production ◽

Transgenic Animals ◽

Whole Body ◽

Nonesterified Fatty Acids ◽

Transgenic Mouse Line ◽

Whole Body Metabolism

Adipose tissue is a primary site for lipid storage containing trace amounts of glycogen. However, refeeding after a prolonged partial fast produces a marked transient spike in adipose glycogen, which dissipates in coordination with the initiation of lipid resynthesis. To further study the potential interplay between glycogen and lipid metabolism in adipose tissue, the aP2-PTG transgenic mouse line was utilized since it contains a 100- to 400-fold elevation of adipocyte glycogen levels that are mobilized upon fasting. To determine the fate of the released glucose 1-phosphate, a series of metabolic measurements were made. Basal and isoproterenol-stimulated lactate production in vitro was significantly increased in adipose tissue from transgenic animals. In parallel, basal and isoproterenol-induced release of nonesterified fatty acids (NEFAs) was significantly reduced in transgenic adipose tissue vs. control. Interestingly, glycerol release was unchanged between the genotypes, suggesting that enhanced triglyceride resynthesis was occurring in the transgenic tissue. Qualitatively similar results for NEFA and glycerol levels between wild-type and transgenic animals were obtained in vivo during fasting. Additionally, the physiological upregulation of the phospho enolpyruvate carboxykinase cytosolic isoform (PEPCK-C) expression in adipose upon fasting was significantly blunted in transgenic mice. No changes in whole body metabolism were detected through indirect calorimetry. Yet weight loss following a weight gain/loss protocol was significantly impeded in the transgenic animals, indicating a further impairment in triglyceride mobilization. Cumulatively, these results support the notion that the adipocyte possesses a set point for glycogen, which is altered in response to nutritional cues, enabling the coordination of adipose glycogen turnover with lipid metabolism.

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Cholesterol: Its Regulation and Role in Central Nervous System Disorders

Cholesterol ◽

10.1155/2012/292598 ◽

2012 ◽

Vol 2012 ◽

pp. 1-19 ◽

Cited By ~ 128

Author(s):

Matthias Orth ◽

Stefano Bellosta

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Metabolic Pathways ◽

Cholesterol Metabolism ◽

Major Constituent ◽

Normal Brain ◽

Lipoprotein Receptors ◽

Brain Cholesterol ◽

Brain Functions ◽

The Brain

Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer’s disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

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