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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 obesity2. Insulin Resistance as a mechanism of diabetes3. 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 obesity2. Insulin Resistance as a mechanism of diabetes3. 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 adipokine
Adipose tissue
Leptin
Excessive food intake
Brain
Bloodstream
Anorexigenic peptide hormone
Orexigenic peptide hormone
Reduction of appetite
Leptin signalingLeptin
JAK2
Anorexigenic peptide hormone
Orexigenic peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Leptin
JAK2
Anorexigenic peptide hormone
Orexigenic peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
PP
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
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Ren et al, JCI, 2007Ren 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
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Ren et al, JCI, 2007Ren et al, Cell Metabolism, 2005
Leptin Resistance
Leptin
JAK2
Anorexigenic peptide hormone
Orexigenic peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Ren et al, JCI, 2007Ren 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
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Ren et al, JCI, 2007Ren et al, Cell Metabolism, 2005
Orexigenic peptide hormones are elevated in Leptin Resistance
Leptin Resistance
Leptin
JAK2
Anorexigenic peptide hormone
Orexigenic peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Ren et al, JCI, 2007Ren et al, Cell Metabolism, 2005
Food intake is enhanced in Leptin Resistance
Leptin Resistance
Leptin
JAK2
Anorexigenic peptide hormone
Orexigenic peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Ren et al, JCI, 2007Ren et al, Cell Metabolism, 2005
Plasma Leptin is elevated in Leptin Resistance
Leptin Resistance
Leptin
JAK2
Anorexigenic peptide hormone
Orexigenic peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
PP
P
P
Nucleus
Appetite
Impaired cellular Leptin signalingIncreased orexinenic peptide hormonesReduced anorexigenic peptide hormonesIncreased plasma leptinIncreased food intakeGain 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 obesity2. Insulin Resistance as a mechanism of diabetes3. 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.
InsulinA peptide hormone secreted from the Pancreas
Insulin actionGlucose
http://trialx.com/curetalk/2011/01/risk-of-cvd-in-diabetes-mellitus-pateints/
Molecular pathology of insulin resistance
Insulin
IRSPI3K
Plasma membrane
P P AKT
Insulin Receptor
P PDK1
PIP3
P
Glut4
ER
Glucose
Hyperglycemia in insulin resistanceInsulin
IRS
PI3K
Plasma membrane
P P AKT
Insulin Receptor
P PDK1
PIP3
P
Glut4
ER
Glucose
Duan et al, MCB, 2004
Insulin Resistance Insulin Resistance
Glucose tolerance and insulin sensitivity are 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 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
PIP3
P
Glut4
ER
Glucose
Duan et al, MCB, 2004
Insulin ResistanceInsulin Insulin(-)(-)
Insulin-induced Akt phosphorylation is impaired in insulin resistance
Plasma insulin is elevated in insulin resistanceInsulin
IRS
PI3K
Plasma membrane
P P AKT
Insulin Receptor
P PDK1
PIP3
P
Glut4
ER
Glucose
Duan et al, MCB, 2004
Insulin ResistanceInsulin Resistance
Insulin
IRS
PI3K
Plasma membrane
P P AKT
Insulin Receptor
P PDK1
PIP3
P
Glut4
ER
Glucose
Impaired cellular Insulin signalingImpaired insulin-induced glucose uptakeImpaired glucose toleranceIncreased 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 obesity2. Insulin Resistance as a mechanism of diabetes3. Metaflammation link between obesity and diabetes
Metaflammation
Inflammatory Reaction
http://jem.rupress.org/content/203/2/269/F2.large.jpg
Inflammatory Signaling
http://atlasgeneticsoncology.org/Deep/NFKBID20033.html
Metaflammation link between obese and diabetes
Metabolically driven, chronic low-grade of inflammation, termed metaflammation, takes place in obese conditions.
JNK
Plasma membrane
Inflammatory cytokinese.g. TNF-a, IL-6
Proinflammatory genes
NFkB
Stress response
Receptors
Nucleus
Inflammatory reactionsHost Defense
Inflammatory reaction inhibits insulin signaling
Insulin
IRSPI3KP P AKT
Insulin Receptor
P PDK1
PIP3
P
Glut4
ER
Glucose
JNK
Inflammatory cytokinese.g. TNF-a, IL-6
Inhibitory phosphorylation
Receptors
P
Obese conditions
?
Hirosumi et al, Nature, 420, 333
Metaflammation
Insulin
IRSPI3KP P AKT
Insulin Receptor
P PDK1
PIP3
P
Glut4
ER
Glucose
JNK
Inflammatory cytokinese.g. TNF-a, 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
