Molecular Models of Metabolic Syndrome

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By: micprr4 (41 month(s) ago)

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Presentation Transcript

Normal Glucose Homeostasis : 

Normal Glucose Homeostasis

Features of The Metabolic Syndrome : 

Features of The Metabolic Syndrome Nutritionally induced IR develops as metabolic adaptation to  circulating FFAs (from intra-abdominal fat stores).  circulating FFAs force liver, muscle & other tissues to shift towards  storage & oxidation of fats for their energy production. Compensated by a  capacity of these tissues to absorb, store & metabolize glucose. Adipose tissue releases TNFα, adiponectin, leptin, and resistin. IR caused by 1)  in cellular insulin-receptor levels; 2)  responsiveness of intracellular transduction pathways.  blood glucose 2ndary to IR is compensated by  pancreatic insulin secretion.

The Metabolic Syndrome: Pathophysiology : 

The Metabolic Syndrome: Pathophysiology

Local, Portal, & Systemic Effects of Inflammation in Insulin Resistance & ASCVD : 

Local, Portal, & Systemic Effects of Inflammation in Insulin Resistance & ASCVD

Convergence of Macrophage & Adipocyte Functions in Obesity & the Metabolic Syndrome : 

Convergence of Macrophage & Adipocyte Functions in Obesity & the Metabolic Syndrome Nature Medicine  10, 126 - 127 (2004)

The Metabolic Syndrome: Adipocytes as Endocrine Cells : 

The Metabolic Syndrome: Adipocytes as Endocrine Cells

Leptin & Adiponectin as Mediators in the Adipovascular Axis : 

Leptin & Adiponectin as Mediators in the Adipovascular Axis

Obese Adipose Tissue is Characterized by Inflammation & Infiltration by Macrophages : 

Obese Adipose Tissue is Characterized by Inflammation & Infiltration by Macrophages

The Origins of Brown Adipose Tissue : 

The Origins of Brown Adipose Tissue Enerbäck S. NEJM. 360;19Volume 360:2021-2023 May 7, 2009 Number 19; 2022-2023.

Molecular Determinants Involved in White Versus Brown Adipocyte Differentiation : 

Molecular Determinants Involved in White Versus Brown Adipocyte Differentiation Biochem J. 2006 September 1; 398(Pt 2): 153–168.

4 Elements of the ARN in the Hypothalamus : 

4 Elements of the ARN in the Hypothalamus S. P. Kalra: Neuron. 19:227–230, 1997. the orexigenic & anorexigenic signal-producing networks are the 2 basic elements of the circuitry

Hypothalamic Sites Associated With Appetite-Regulating Signal Pathways : 

Hypothalamic Sites Associated With Appetite-Regulating Signal Pathways Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev. 1999 Feb;20(1):68-100. Sagittal section near midline of the rat brain

Hypothesized Adiposity Signaling Pathways in the Brain : 

Hypothesized Adiposity Signaling Pathways in the Brain Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev. 1999 Feb;20(1):68-100. Sagittal section near midline of the brain

Insulin and Leptin Increase Expression of POMC and Decrease Expression of AgRP : 

Insulin and Leptin Increase Expression of POMC and Decrease Expression of AgRP J Clin Invest. 2006 July 3; 116(7): 1761–1766. Adiposity signals (leptin and insulin) inhibit (−) and stimulate (+) NPY/AGRP and αMSH /CART neurons, respectively, in the arcuate nucleus (ARC)

Generation of PIP3 Leads to KATP Channel Opening and Consecutive Cell Hyperpolarization : 

Generation of PIP3 Leads to KATP Channel Opening and Consecutive Cell Hyperpolarization J Clin Invest. 2006 July 3; 116(7): 1761–1766.

Potential Effect of Genes and Environment on Adiposity : 

Potential Effect of Genes and Environment on Adiposity International Journal of Obesity (2008) 32, S109–S119 On the left is presented the 'traditional' environment in which food was rather scarce and energy expenditure was high, mostly related to occupational physical activity. On the right, the more recent modern 'social' and 'built' environment leads to obesogenic behaviors with plenty of cheap high-calorie density food and little need for physical activity.

Major Components of Body Weight Regulation in an Obesogenic Environment : 

Major Components of Body Weight Regulation in an Obesogenic Environment International Journal of Obesity (2008) 32, S109–S119 Changes in the environment of subsequent generations that influence genetic and epigenetic propensity for weight gain. Current habitual lifestyle that promotes sedentary behaviors and provides an oversupply of energy dense foods.

Major Components of Body Weight Regulation in an Obesogenic Environment : 

Major Components of Body Weight Regulation in an Obesogenic Environment International Journal of Obesity (2008) 32, S109–S119 Monozygotic twins reared apart indicate that approximately 33% of the variability in body mass index (BMI) is attributable to nongenetic factors and 67% to genetic factors.

Leptin and the Regulation of Adipose Tissue Mass : 

Leptin and the Regulation of Adipose Tissue Mass Nature. 404, 632-634 (6 April 2000) The cloning of the ob gene and the characterization of leptin has indicated that body fat content is under homeostatic control. The available data suggest that leptin is the afferent signal in a feedback loop regulating adipose tissue mass.

Leptin Receptor Expression inthe Arcuate Nucleus of the Hypothalamus : 

Leptin Receptor Expression inthe Arcuate Nucleus of the Hypothalamus Nature. 404, 632-634 (6 April 2000) In arcuate nucleus of hypothalamus, leptin receptor is expressed in 2 different classes of neurons. 1 class expresses NPY and AGRP; 2 neuropeptides that  food intake. Another class expresses POMC, the precursor of -MSH, and CART.

Role of Adiponectin in Hypertension : 

Role of Adiponectin in Hypertension Wang ZV, Scherer PE. Adiponectin, cardiovascular function, and hypertension. Hypertension. 2008 Jan;51(1):8-14.

Altered Secretory Profile Associated with Terminal Fat Cell Differentiation : 

Altered Secretory Profile Associated with Terminal Fat Cell Differentiation (Hypothesis)

Adiponectin in Metabolic Versus Autoimmune/Chronic Inflammatory Disease : 

Adiponectin in Metabolic Versus Autoimmune/Chronic Inflammatory Disease Adiponectin and inflammation: Consensus and controversy. Journal of Allergy and Clinical Immunology - Volume 121, Issue 2 (February 2008)

Adiponectin as a Molecular Regulator of Atherosclerosis : 

Adiponectin as a Molecular Regulator of Atherosclerosis Szmitko PE, Teoh H, Stewart DJ, Verma S. Adiponectin and cardiovascular disease: state of the art? Am J Physiol Heart Circ Physiol. 2007 Apr;292(4):H1655-63.

Main Effects Exerted by the More Relevant Adipokines at the Cardiovascular Level : 

Main Effects Exerted by the More Relevant Adipokines at the Cardiovascular Level Trends in Cardiovascular Medicine. Volume 17, Issue 8, November 2007, Pages 275-283

Crosstalk Between Adipocytes and Macrophages in Obese Adipose Tissue : 

Crosstalk Between Adipocytes and Macrophages in Obese Adipose Tissue (Hypothesis)

Hypothetical Model of Chronic Inflammation and Adipocyte Insulin Resistance : 

Hypothetical Model of Chronic Inflammation and Adipocyte Insulin Resistance Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112:12

Insulin: 2 Potential Insulin Receptor-Dependent Signal Transduction Pathways : 

Insulin: 2 Potential Insulin Receptor-Dependent Signal Transduction Pathways

Natural History of Insulin Resistance and Type 2 Diabetes : 

Natural History of Insulin Resistance and Type 2 Diabetes

Hormonal and Cellular Mechanisms of Atherosclerosis within the Vessel Wall : 

Hormonal and Cellular Mechanisms of Atherosclerosis within the Vessel Wall

Slide 31: 

Development of Type 2 Diabetes: Metabolic Pathways in the Liver

Slide 32: 

Pentose Phosphate Pathway Glycolysis Gluconeogenesis - Development of Type 2 Diabetes: Metabolic Pathways in the Liver

Slide 33: 

  Insulin-independent glucose uptake Glucagon Insulin Glucose FFA Leptin Insulin-independent glucose uptake Insulin Skeletal muscle Fat Adiponecin TNF- Non-glucose secretagogues Plasma glucose

Insulin Signaling in Cells : 

Insulin Signaling in Cells J. Clin. Invest. 116:1756-1760 (2006).

Evolving View of the Biological Functions of the Adipocyte : 

Evolving View of the Biological Functions of the Adipocyte

Leptin and Regulation of Glucose Homeostasis : 

Leptin and Regulation of Glucose Homeostasis

Leptin as an Adipocytokine That Regulates Food Intake and Energy Expenditure : 

Leptin as an Adipocytokine That Regulates Food Intake and Energy Expenditure

Energy Homeostasis and Balance Between Caloric Intake and Energy Expenditure : 

Energy Homeostasis and Balance Between Caloric Intake and Energy Expenditure Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53.

Adipocytes Regulate Energy Balance by Endocrine and Nonendocrine Mechanisms : 

Adipocytes Regulate Energy Balance by Endocrine and Nonendocrine Mechanisms Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53.

Glucose Homeostasis Requires the Coordinated Actions of Various Organs : 

Glucose Homeostasis Requires the Coordinated Actions of Various Organs Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53.

Adipocytes Secrete Proteins with Varied Effects on Glucose Homeostasis : 

Adipocytes Secrete Proteins with Varied Effects on Glucose Homeostasis Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53.

Adipocyte Derived Nonesterified FFA’s Effects on Glucose Homeostasis : 

Adipocyte Derived Nonesterified FFA’s Effects on Glucose Homeostasis Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53.

Peripheral Signaling and Ongoing Energy Balance and Metabolic Homeostasis : 

Peripheral Signaling and Ongoing Energy Balance and Metabolic Homeostasis Castañeda TR, et al. Obesity and the neuroendocrine control of energy homeostasis: the role of spontaneous locomotor activity. J Nutr. 2005 May;135(5):1314-9.

Antiobesity Drug Targets of the GI/CNS and Neurotransmitter/Neuronal Pathways : 

Antiobesity Drug Targets of the GI/CNS and Neurotransmitter/Neuronal Pathways Obesity Research (2004) 12, 1197–1211

Antiobesity Drug Targets of the Leptin/Insulin/CNS Pathways : 

Antiobesity Drug Targets of the Leptin/Insulin/CNS Pathways Obesity Research (2004) 12, 1197–1211

Examples of Antiobesity Agents in Development : 

Examples of Antiobesity Agents in Development CNS agents that affect neurotransmitters or neural ion channels Antidepressants (bupropion) Noradrenaline reuptake inhibitors (GW320659) Selective 5HT 2c receptor agonists Antiseizure agents (topiramate, zonisamide) Some dopamine antagonists CB-1 receptor antagonists (rimonabant) Leptin/insulin/CNS pathway agents Leptin analogues Leptin transport and/or receptor promoters CNTF (Axokine) NPY antagonists AgRP antagonists POMC promoters CART promoters MSH analogues MC4 receptor agonists Obesity Research (2004) 12, 1197–1211

Examples of Antiobesity Agents in Development : 

Examples of Antiobesity Agents in Development Agents that affect insulin metabolism/activity [PTP-1B inhibitors, PPAR receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin/Acrp30 (Famoxin or Fatty Acid Metabolic OXidation INducer)] Gastrointestinal-neural pathway agents Agents that increase CCK and PYY activity Agents that increase GLP-1 activity (extendin 4, liraglutide, DPP IV inhibitor) Agents that decrease ghrelin activity Amylin (pramlinitide) Agents that may increase RMR "Selective" -3 stimulators/agonist UCP homologues Thyroid receptor agonists Obesity Research (2004) 12, 1197–1211

Examples of Antiobesity Agents in Development : 

Examples of Antiobesity Agents in Development Other agents MCH antagonists Phytostanol analogues Functional oils P57 Amylase inhibitors Growth hormone fragments Synthetic analogues of DHEAS (fluasterone) Antagonists of adipocyte 11B-hydroxysteroid dehydrogenase type 1 activity CRH agonists Carboxypeptidase inhibitors Inhibitors of fatty acid synthesis (cerulenin and C75) Indanones/indanols Aminosterols (Trodusquemine/trodulamine) Other gastrointestinal lipase inhibitors (ATL962) Obesity Research (2004) 12, 1197–1211

Photomicrograph of a Macrophage Foam Cell Isolated From a Hypercholesterolemic Mouse : 

Photomicrograph of a Macrophage Foam Cell Isolated From a Hypercholesterolemic Mouse

Macrophage Itinerary in Adipose Tissue Infiltration : 

Macrophage Itinerary in Adipose Tissue Infiltration

Integration of Metabolic & Immune Responses in Adipocytes & Macrophages : 

Integration of Metabolic & Immune Responses in Adipocytes & Macrophages

Nutrient and Pathogen Sensing or Response Systems: Important Overlapping Features : 

Nutrient and Pathogen Sensing or Response Systems: Important Overlapping Features

Overlapping Metabolic & Inflammatory Pathways in Adipocytes or Macrophages : 

Overlapping Metabolic & Inflammatory Pathways in Adipocytes or Macrophages

Potential Cellular Mechanisms for Activating Inflammatory Signaling : 

Potential Cellular Mechanisms for Activating Inflammatory Signaling

Potential Mechanisms for Activation of Inflammation in Adipose Tissue : 

Potential Mechanisms for Activation of Inflammation in Adipose Tissue

Potential Mechanisms for Adiposity-induced Inflammation in the Liver : 

Potential Mechanisms for Adiposity-induced Inflammation in the Liver

Adipocytes as Endocrine Cells: Adipose Tissue-derived Proteins : 

Adipocytes as Endocrine Cells: Adipose Tissue-derived Proteins

Chronic Exposure to High-fat Diet Induces Leptin Resistance in CNS : 

Chronic Exposure to High-fat Diet Induces Leptin Resistance in CNS

Major Disease Areas Affected by Adipocyte-derived Factors : 

Major Disease Areas Affected by Adipocyte-derived Factors

Major Organ Systems Affected by Adipocyte-derived Factors : 

Major Organ Systems Affected by Adipocyte-derived Factors

Involvement of Adiponectin in Pathological Sequelae of Various Diseases : 

Involvement of Adiponectin in Pathological Sequelae of Various Diseases

Major Extracellular Targets Derived From the Adipocyte Currently Under Study : 

Major Extracellular Targets Derived From the Adipocyte Currently Under Study

Stress and The Metabolic Syndrome : 

Stress and The Metabolic Syndrome

Interactions Between Stress & Immune System : 

Interactions Between Stress & Immune System

The Effects of Stress on GI Function : 

The Effects of Stress on GI Function

Stress and The Metabolic Syndrome : 

Stress and The Metabolic Syndrome

Stress and The Metabolic Syndrome : 

Stress and The Metabolic Syndrome

Stress and The Metabolic Syndrome : 

Stress and The Metabolic Syndrome

Hormonal and Cellular Mechanisms of Atherosclerosis within the Vessel Wall : 

Hormonal and Cellular Mechanisms of Atherosclerosis within the Vessel Wall

Slide 70: 

Copyright ©2006 American Heart Association Waxman, S. et al. Circulation 2006;114:2390-2411 Culprit and Suspected Vulnerable Atherosclerotic Lesions

Mechanisms Relating Adiposity to Cancer Risk : 

Mechanisms Relating Adiposity to Cancer Risk

Effects of Obesity on Hormone Production : 

Effects of Obesity on Hormone Production

Obesity, Hormones and Endometrial Cancer : 

Obesity, Hormones and Endometrial Cancer