Molecular Mechanism of Metabolic disorders Shinichi Oka, PhD Department of Cell Biology and Molecular Medicine Rutgers New Jersey Medical School MSB-I543

Objectives Leptin Resistance Obese Insulin Resistance Diabetes 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 Metaflammation

Objectives Leptin Resistance Obese Insulin Resistance Diabetes 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 Metaflammation

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

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

Leptin signaling Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite

Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Leptin function and signaling Adipose tissue Excessive food intake Brain Leptin Reduction of appetite Bloodstream

Molecular pathology of Leptin Resistance Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Leptin Resistance

Leptin-induced JAK2 activation is impaired in Leptin Resistance Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Leptin Resistance

Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Leptin Resistance Leptin-induced STAT3 phosphorylation is impaired in Leptin Resistance

Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Orexigenic peptide hormones are elevated in Leptin Resistance Leptin Resistance

Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Food intake is enhanced in Leptin Resistance Leptin Resistance

Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Ren et al, JCI, 2007 Ren et al, Cell Metabolism, 2005 Plasma Leptin is elevated in Leptin Resistance Leptin Resistance

Leptin JAK2 Anorexigenic peptide hormone Orexigenic peptide hormone STAT3 Plasma membrane P P P P Nucleus Appetite Impaired cellular Leptin signaling Increased orexinenic peptide hormones Reduced anorexigenic peptide hormones Increased plasma leptin Increased food intake Gain body weight Summary Leptin Resistance

Objectives Leptin Resistance Obese Insulin Resistance Diabetes 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 Metaflammation

Diabetes 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

Molecular pathology of insulin resistance Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP3 P Glut4 ER Glucose

Hyperglycemia in insulin resistance Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP 3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance

Glucose tolerance and insulin sensitivity are impaired in insulin resistance Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP 3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance Insulin Resistance Glucose

Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance Insulin-induced insulin receptor phosphorylation is impaired in insulin resistance

Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance Insulin-induced insulin receptor substrate (IRS) phosphorylation is impaired in insulin resistance

Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance Insulin-induced PI3K activation is impaired in insulin resistance PIP3: Phosphatidylinositol triphosphate PIP3

Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP 3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance Insulin (-) Insulin-induced Akt phosphorylation is impaired in insulin resistance

Plasma insulin is elevated in insulin resistance Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP 3 P Glut4 ER Glucose Duan et al, MCB, 2004 Insulin Resistance

Insulin IRS PI3K Plasma membrane P P AKT Insulin Receptor P PDK1 PIP 3 P Glut4 ER Glucose Impaired cellular Insulin signaling Impaired insulin-induced glucose uptake Impaired glucose tolerance Increased plasma Insulin Summary Insulin Resistance

Objectives Leptin Resistance Obese Insulin Resistance Diabetes 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 Metaflammation

Inflammatory Reaction

Inflammatory Signaling

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

Inflammatory reaction inhibits insulin signaling Insulin IRSPI3K P P AKT Insulin Receptor P PDK1 PIP3 P Glut4 ER Glucose JNK Inflammatory cytokines e.g. TNF- , IL-6 Inhibitory phosphorylation Receptors P Obese conditions Hirosumi et al, Nature, 420, 333

Metaflammation Insulin IRSPI3K P P AKT Insulin Receptor P PDK1 PIP3 P Glut4 ER Glucose JNK Inflammatory cytokines e.g. TNF- , IL-6 Inhibitory phosphorylation Receptors P Obese conditions Summary Chronic low-grade of inflammation, termed metaflammation, takes place in obese conditions. The metaflammation causes insulin resistance partly through inhibitory phosphoryalation of IRS