1. Molecular Mechanism of Metabolic disorders Shinichi Oka, PhD Department of Cell Biology and Molecular Medicine Rutgers New Jersey Medical School MSB-I543 okash@njms.rutgers.edu

2. 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

3. 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

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

5. 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

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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

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

17. 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.

18. Insulin A peptide hormone secreted from the Pancreas

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

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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. Inflammatory Reaction http://jem.rupress.org/content/203/2/269/F2.large.jpg

31. Inflammatory Signaling http://atlasgeneticsoncology.org/Deep/NFKBID20033.html

32. 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

33. 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

34. 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