Physiological Consequences of Brain Insulin Action

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Half Title
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Title Page
Copyright Page
Table of Contents
Series Preface
Preface
Acknowledgements
Editor
Contributors
Abbreviations
1 MOLECULAR MECHANISMS OF BRAIN INSULIN SIGNALING
	Interaction between Metabolism and Insulin
	Insulin and Insulin Growth Factor 1 Receptor
	Insulin Signaling Cascade in the Brain
	Downstream Signaling from the Insulin and Insulin Growth Factor 1 Receptor
		Insulin Signaling through the AKT Pathway
	Extracellular Signal-Regulated Protein Kinases Isoforms
		Negative Modulation of the Insulin Signaling Pathway
		Genetic Mutations Associated with Insulin Resistance
		Dephosphorylation of Proteins and Metabolites Involved in the Insulin Signaling Pathway
		Inhibitory Phosphorylations of Proteins in the Insulin Signaling Pathway
	Insulin and Insulin Growth Factor 1 Receptor
	IR Expression in the Brain
	Insulin Growth Factor 1 Receptor
	Insulin and Insulin Growth Factor 1 Receptor Heterodimers
	Insulin Receptor Substrate 1 Expression in the Brain
	Insulin Receptor Substrate 2 Expression in the Brain
	Insulin Receptor Substrate 4 Expression in the Brain
	AKT Isoforms and Their Expression in the Brain
	Extracellular Signal-Regulated Protein Kinases Isoforms and Their Expression in the Brain
	Concluding Remarks
	Acknowledgments
	References
2 INSULI/IGF SIGNALING IN EARLY BRAIN DEVELOPMENT
	Effects on the Developing Central Nervous System
	First Steps in Central Nervous System Development: Neurulation
	Expanding Central Nervous System Cells: Neurogenesis
	Neuronal Survival and Development
	Cellular Differentiation
	Brain Region Specific Effects in Development
	The Cortex
	The Hippocampus
	The Hypothalamus
	Insulin Dependent Diseases and Brain Development Effects
	Gestational Diabetes and Decreased Maternal Insulin Sensitivity
	Malnutrition and Maternal Undernutrition
	Polycystic Ovarian Syndrome (PCOS)
	Concluding Remarks
	References
3 INSULIN SIGNALING MODULATES NEURONAL METABOLISM
	Introduction
	Overview of Neuronal Metabolism and Bioenergetics
	Insulin Regulates Neuronal Glucose Metabolism
	Insulin Signaling and Astrocyte-Neuron Lactate Shuttling
	Insulin Signaling and Ketone Body Metabolism in Neurons
	Insulin and Glycogen Metabolism in Neurons
	Insulin and Lipid Metabolism in Neurons
	Insulin Signaling Contributes to Mitochondrial Function and Homeostasis in Neurons
		Insulin Signaling Regulates Mitochondrial Bioenergetic Capacity
		Insulin Signaling Regulates Mitochondrial Mass by Supporting Mitochondrial Biogenesis
		Insulin Signaling Modulates Mitochondrial Stress Response Network
		Potential Link between Impaired Insulin/IGF-1 Signaling and Mitochondrial Dysfunction in Neurodegenerative Diseases
	Insulin Signaling Contributes to Intracellular Ca[sup(2+)] Homeostasis in Neurons
	Concluding Remarks
	Acknowledgements
	References
4 REGULATION OF GLIAL FUNCTION BY INSULIN PEPTIDES
	Introduction
	Astroglia
		Physiology
		Pathology
	Microglia
		Physiology
		Pathology
	Oligodendroglia
		Physiology
		Pathology
	Concluding Remarks
	Acknowledgments
	References
5 NEUROENDOCRINE INTERACTIONS IN THE CONTROL OF GLUCOSE- AND ENERGY HOMEOSTASIS
	Regulation of Energy Homeostasis by Insulin
	Regulation of Energy Homeostasis by Leptin
	Leptin Homeostasis and Its Relevance for Insulin Action
	The Glucoregulatory Role of Leptin
	WNT/β-Catenin Signalling as an Integrator of Central Insulin and Leptin Action on Energy Homeostasis
	Incretins and Energy Homeostasis
	Concluding Remarks
	Acknowledgements
	References
6 HYPOTHALAMIC NEURONAL CIRCUITS ARE MODULATED BY INSULIN AND IMPACT METABOLISM
	Introduction
	The Hypothalamic Relevance of Insulin
	How Insulin Targets the Hypothalamus
	Insulin and the Hypothalamic Neuronal Circuits
		The Arcuate Nucleus, Key Hypothalamic Region in the Insulin Signalling
	Other Hypothalamic Circuits Modulated by Insulin
	Non-Neuronal Insulin Targeting Places in the Hypothalamus
		Astrocytes
		Pericytes
	Insulin Receptor Signalling in the Hypothalamus
	The Canonical Insulin Signalling Pathway: PI3K-AKT Pathway
		The PI3K K-ATP Downstream Pathway
		mTOR/S6K Downstream Pathway
		AMPK Downstream Pathway
	The MAPK/ERK Pathway
	Hypothalamic Insulin Signalling Impact Peripheral Metabolism
		Neuronal Insulin Signalling Regulates Peripheral Metabolism
		Brain Insulin Action in Hepatic Glucose Production and Triglyceride Export
		Brain Insulin and White Adipose Tissue Metabolism
		Brain Insulin and Brown Adipose Tissue Thermogenesis
	Hypothalamic Insulin Resistance Impact Peripheral Metabolism
		Proposed Mechanism by Which Brain Insulin Resistance Occurs
		Brain Insulin Resistance and Its Metabolic Sequelae
		Hypothalamic Insulin Resistance, a Maladaptive Response
	Concluding Remarks
	Acknowledgements
	References
7 INSULIN AND BRAIN REWARD SYSTEMS
	Introduction
	Historical Perspective
	Peripheral Insulin
	The Insulin Receptor
	Targeted Deletion of IRs in the CNS versus Peripheral Sites
	Insulin in the Central Nervous System
	Brain IRs and Insulin Signaling
	Leptin
	Ghrelin
	Insulin, Dopamine, Feeding Behavior and the Hypothalamus
	Central Insulin and Mood Disorders
	Central Insulin as a Driver of Reward-Associated Behavior
		The Reward System
		Dopamine
		Glutamate
		GABA
	The Mesolimbic Dopamine System and Central Insulin
	Nucleus Accumbens
	Mechanisms of Insulin Regulation of Dopamine Release
	Insulin and Substance Use Disorders
	Eating Disorders
	Insulin and Parkinson\'s Disease
	Concluding Remarks
	Acknowledgements
	References
8 THE IMPACT OF INSULIN ON BRAIN SEROTONERGIC SYSTEM: CONSEQUENCES ON DIABETESASSOCIATED MOOD DISORDERS
	Introduction: The Comorbidity Diabetes-Depression
	Overview of Brain Insulin Signaling
	Effects of Brain Insulin on Emotionality
	Evidence of the Impact of Insulin onto Serotonergic Neurotransmission
		Overview of the Role of DRN 5-HT Neurons in Mood
		Evidence of Insulin Action on the 5-HT Neurons
		Effects of Insulin on 5-HT Sensitive Cells – Crosstalk between Insulin and Serotonin Signaling Pathways
	Concluding Remarks
	Acknowledgments
	References
9 ORGAN CROSS-TALK REGULATES (BRAIN) INSULIN ACTION
	Introduction
	Adipose Tissue
	Leptin
	Adiponectin
	Liver
	Regulation of Fibroblast Growth Factor 21
	Glucose Tolerance Is Improved by a Dietary Protein Restriction in Response to a High-Fat Diet
	Dietary Amino Acid Restriction Protects from Type 2 Diabetes by FGF21 Secretion
	Perspective
	Insulin-Like Growth Factors
	IGF1
	IGF2
	Gastrointestinal Tract and GLP-1
	Concluding Remarks
	Acknowledgments
	References
10 INSULIN RESISTANCE AS A RISK FACTOR FOR ALZHEIMER\'S DISEASE
	Introduction
	Peripheral Insulin Resistance as Risk Factor of Cognitive Alteration in Late Onset Alzheimer\'s Disease
	Physiological Roles of Insulin in the Brain and in Late Onset Alzheimer\'s Disease
	Late Onset Alzheimer\'s Disease and Brain Insulin Resistance
	Molecular Pathways Involved in Central Insulin Resistance Associated with Late Onset Alzheimer\'s Disease Neurodegeneration
	Amyloid as a Responsible of Brain Insulin Resistance in Late Onset Alzheimer\'s Disease
	The Role of Tau in the Brain Insulin Resistance in the Late Onset Alzheimer\'s Disease
	Apolipoprotein-ε4 and Insulin Resistance
	PTP-1B as the Link between Brain Insulin Resistance Associated with Cognitive Loss and Late Onset Alzheimer\'s Disease
	Neuroinflammation as a Link between Brain Insulin Resistance and Alzheimer\'s Disease
	Glutamate Excitotoxicity as a Responsible for Brain Insulin Resistance
	Mitochondrial Dysfunction Is Responsible for Brain Insulin Resistance
	Mammalian Target of Rapamycin Signalling Modulates Insulin Resistance
	Ceramides Regulate Insulin Resistance and Increase the Risk of Late Onset Alzheimer\'s Disease
	Concluding Remarks
	Acknowledgements
	References
11 BRAIN INSULIN ACTION IN THE CONTROL OF METABOLISM IN HUMANS
	Introduction
	Investigating Central Insulin Action in Humans
	Intranasal Insulin
	Methods to Investigate Peripheral and Whole-Body Insulin Sensitivity
		Glucose Challenge
		Hyperinsulinemic-Euglycemic Glucose Clamp
	Neuroimaging Methods to Quantify Central Insulin Action in Humans
		Electroencephalography/Magnetoencephalography
		Nuclear Tomographical Imaging Techniques
		Functional Magnetic Resonance Imaging (fMRI)
	Central Insulin Action- Evidence of EEG and MEG Studies
	Regional Specific Central Insulin Action-Evidence of PET and fMRI Studies
	Central Effects of Insulin Action on Behavior
	Central Effects of Insulin Action on Systemic Metabolism
	Definition of Brain Insulin Resistance in Humans
	Concluding Remarks
	Acknowledgements
	References
12 IMPACT OF DIETARY AND EXERCISE INTERVENTIONS ON BRAIN INSULIN ACTION AND BRAIN FUNCTION
	The Diet-Insulin-Brain Axis in Humans
	Associations between General Dietary Factors and Neurological Outcomes
	Epidemiological Impact of Lifestyle Factors on Obesity, Insulin Resistance and T2DM
	Lifestyle and Dementia
	Lifestyle and Depression
	Metabolic Impact of Different Lifestyle Interventions on Obesity, Glycemia, and Insulin Resistance
	Effects of Metabolically Beneficial Complex Lifestyle Changes on Cognition
	Interventional Effects of Specific Lifestyle Components on Glycemic Metabolism and Cognition
	Effects of Specific Dietary Interventions on Glycemic Metabolism and Mood
	Concluding Remarks
	References
13 PHARMACOLOGICAL AND SURGICAL INTERVENTIONS TO IMPROVE BRAIN INSULIN RESISTANCE
	GLP-1 Agonist Treatment and Brain Insulin Resistance
	Preclinical Evidence
		Alzheimer\'s Disease Rodent Models
		Alzheimer\'s Disease Cell Models
		Parkinson\'s Disease (PD) Rodent Models
	Clinical Evidence
		AD Clinical Evidence
		PD Clinical Evidence
	Intranasal GLP-1 Application
	Other Anti-Diabetic Drugs and Brain Insulin Resistance
		Insulin
			Peripheral Insulin
			Intranasal Insulin
		Insulin Sensitizers
			Metformin
			Peroxisome Proliferator-Activated Receptor Agonists (PPARs)
		Incretin Analogues
			Glucose-Dependent Insulinotropic Polypeptide (GIP) Analogues
			Dual/Triple Agonists
	Other Therapeutic Agents
		Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors
		Sodium Dependent Glucose Co-Transporter 2 (SGLT-2) Inhibitors
	Brain Insulin Sensitivity and Bariatric Surgery
		Brain Insulin Sensitivity in Obesity
	Brain Insulin Sensitivity, Conventional Weight Loss and Bariatric Surgery
	Concluding Remarks
	Literature
Index