Molecular Mechanism of Metabolic disorders Shinichi Oka Ph

Molecular Mechanism of Metabolic disorders Shinichi Oka, Ph. D Department of Cell Biology and Molecular Medicine Rutgers New Jersey Medical School MSB-I 543 okash@njms. rutgers. edu

Objectives To understand molecular pathology of obesity and diabetes 1. Leptin Resistance as a mechanism of obesity 2. Insulin Resistance as a mechanism of diabetes 3. Metaflammation link between obesity and diabetes Obese Leptin Resistance Metaflammation Diabetes Insulin Resistance

Leptin resistance causes obesity control ob/ob; Letpin mutant db/db; Letpin receptor mutant

Leptin Brain Leptin Excessive food intake Bloodstream Orexigenic peptide hormone Adipose tissue Anorexigenic peptide hormone Reduction of appetite Leptin (Greek λεπτός (leptos) meaning "thin") is a 16 -k. Da adipokine

Leptin signaling Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus STAT 3 P Orexigenic peptide hormone Anorexigenic peptide hormone

Leptin function and signaling Excessive food intake Bloodstream Reduction of appetite Leptin Adipose tissue Brain Leptin Plasma membrane JAK 2 P STAT 3 P Nucleus P STAT 3 Orexigenic peptide hormone Anorexigenic peptide hormone

Molecular pathology of Leptin Resistance Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Leptin Resistance Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus P STAT 3 Orexigenic peptide hormone Anorexigenic peptide hormone

Leptin-induced JAK 2 activation is impaired in Leptin Resistance Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus P STAT 3 Leptin Resistance Orexigenic peptide hormone Anorexigenic peptide hormone Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005

Leptin-induced STAT 3 phosphorylation is impaired in Leptin Resistance Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus P STAT 3 Orexigenic peptide hormone Anorexigenic peptide hormone Leptin Resistance

Orexigenic peptide hormones are elevated in Leptin Resistance Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus P STAT 3 P Orexigenic peptide hormone STAT 3 Anorexigenic peptide hormone Leptin Resistance Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005

Food intake is enhanced in Leptin Resistance Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus P STAT 3 Orexigenic peptide hormone Anorexigenic peptide hormone Leptin Resistance

Plasma Leptin is elevated in Leptin Resistance Leptin Plasma membrane JAK 2 P STAT 3 P Appetite Nucleus P STAT 3 Orexigenic peptide hormone Anorexigenic peptide hormone Leptin Resistance Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005

Summary Leptin Plasma membrane JAK 2 Leptin Resistance Impaired cellular Leptin signaling Increased orexinenic peptide hormones Reduced anorexigenic peptide hormones Increased plasma leptin Increased food intake Gain body weight P STAT 3 P Appetite Nucleus P STAT 3 Orexigenic peptide hormone Anorexigenic peptide hormone

Objectives To understand molecular pathology of obesity and diabetes 1. Leptin Resistance as a mechanism of obesity 2. Insulin Resistance as a mechanism of diabetes 3. Metaflammation link between obesity and diabetes Obese Leptin Resistance Metaflammation Diabetes Insulin Resistance

Diabetes is a metabolic diseases in which a person has high blood glucose. Diabetes causes heart diseases, kidney failure and eye problem.

Insulin Resistance causes type II diabetes Insulin resistance is defined as a deteriorated response to insulin action. Individuals with insulin resistance are predisposed to developing type 2 diabetes. Insulin resistance is a crucial pathological feature in the type 2 diabetes.

Insulin A peptide hormone secreted from the Pancreas

Insulin action Glucose http: //trialx. com/curetalk/2011/01/risk-of-cvd-in-diabetes-mellitus-pateints/

Molecular pathology of insulin resistance Insulin Glucose Insulin Receptor P IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER

Hyperglycemia in insulin resistance Insulin Glucose Insulin Receptor P IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER Insulin Resistance Duan et al, MCB, 2004

Glucose tolerance and insulin sensitivity are impaired in insulin resistance Glucose Insulin Receptor P Insulin Resistance IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Insulin Resistance Glut 4 ER Duan et al, MCB, 2004

Insulin-induced insulin receptor phosphorylation is impaired in insulin resistance Insulin Glucose Insulin Receptor P IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER Insulin Resistance Duan et al, MCB, 2004

Insulin-induced insulin receptor substrate (IRS) phosphorylation is impaired in insulin resistance Insulin Glucose Insulin Receptor P IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER Insulin Resistance Duan et al, MCB, 2004

Insulin-induced PI 3 K activation is impaired in insulin resistance Insulin Glucose Insulin Receptor PIP 3 P IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER Insulin Resistance PIP 3: Phosphatidylinositol triphosphate Duan et al, MCB, 2004

Insulin-induced Akt phosphorylation is impaired in insulin resistance Insulin Glucose Insulin Receptor P (-) Insulin IRS P PIP 3 PI 3 K Insulin Resistance Insulin (-) P AKT Plasma membrane PDK 1 P Glut 4 ER Duan et al, MCB, 2004

Plasma insulin is elevated in insulin resistance Insulin Glucose Insulin Receptor P IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER Insulin Resistance Duan et al, MCB, 2004

Summary Insulin Glucose Insulin Receptor P Insulin Resistance Impaired cellular Insulin signaling Impaired insulin-induced glucose uptake Impaired glucose tolerance Increased plasma Insulin IRS P PIP 3 PI 3 K P AKT Plasma membrane PDK 1 P Glut 4 ER

Objectives To understand molecular pathology of obesity and diabetes 1. Leptin Resistance as a mechanism of obesity 2. Insulin Resistance as a mechanism of diabetes 3. Metaflammation link between obesity and diabetes Obese Leptin Resistance Metaflammation Diabetes Insulin Resistance

Inflammatory Reaction http: //jem. rupress. org/content/203/2/269/F 2. large. jpg

Inflammatory Signaling http: //atlasgeneticsoncology. org/Deep/NFKBID 20033. html

Metaflammation link between obese and diabetes Metabolically driven, chronic low-grade of inflammation, termed metaflammation, takes place in obese conditions. Inflammatory reactions Host Defense Inflammatory cytokines e. g. TNF-a, IL-6 Receptors JNK Stress response Plasma membrane Nucleus NFk. B Proinflammatory genes

Inflammatory reaction inhibits insulin signaling Hirosumi et al, Nature, 420, 333 Obese conditions ? Inflammatory cytokines e. g. TNF-a, IL-6 Insulin Glucose Insulin Receptors P IRS P PIP 3 PI 3 K P AKT PDK 1 P P Inhibitory phosphorylation JNK Glut 4 ER

Summary Metaflammation Chronic low-grade of inflammation, termed metaflammation, takes place in obese conditions. Obese conditions The metaflammation causes insulin resistance partly through inhibitory phosphoryalation of IRS ? Inflammatory cytokines e. g. TNF-a, IL-6 Insulin Glucose Insulin Receptors P IRS P PIP 3 PI 3 K P AKT PDK 1 P P Inhibitory phosphorylation JNK Glut 4 ER