Transcript Molecular Mechanism of Metabolic disorders

Molecular Mechanism of
Metabolic disorders
Shinichi Oka, PhD
Department of Cell Biology and Molecular
Medicine
Rutgers New Jersey Medical School
MSB-I543
[email protected]
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
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
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-kDa adipokine
Leptin signaling
Leptin
Plasma membrane
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
STAT3
Orexigenic peptide
hormone
Anorexigenic peptide
hormone
Leptin function and signaling
Excessive
food intake
Bloodstream
Reduction
of appetite
Leptin
Adipose tissue
Brain
Leptin
Plasma membrane
JAK2
P
P
STAT3
Nucleus
P
STAT3
P
STAT3
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
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
STAT3
Orexigenic peptide
hormone
Anorexigenic peptide
hormone
Leptin-induced JAK2 activation is impaired in
Leptin Resistance
Leptin
Plasma membrane
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
STAT3
Leptin Resistance
Orexigenic peptide
hormone
Anorexigenic peptide
hormone
Ren et al, JCI, 2007
Ren et al, Cell Metabolism, 2005
Leptin-induced STAT3 phosphorylation is impaired in
Leptin Resistance
Ren et al, JCI, 2007
Ren et al, Cell Metabolism, 2005
Leptin
Plasma membrane
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
STAT3
Orexigenic peptide
hormone
Anorexigenic peptide
hormone
Leptin Resistance
Orexigenic peptide hormones are elevated in Leptin
Resistance
Leptin
Plasma membrane
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
Orexigenic peptide
hormone
STAT3
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
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
STAT3
Orexigenic peptide
hormone
Anorexigenic peptide
hormone
Leptin Resistance
Plasma Leptin is elevated in Leptin Resistance
Leptin
Plasma membrane
JAK2
P
P
STAT3
Appetite
Nucleus
P
STAT3
P
STAT3
Orexigenic peptide
hormone
Anorexigenic peptide
hormone
Leptin Resistance
Ren et al, JCI, 2007
Ren et al, Cell Metabolism, 2005
Summary
Leptin
Plasma membrane
JAK2
P
P
STAT3
Appetite
Leptin Resistance
Impaired cellular Leptin signaling
Increased orexinenic peptide hormones
Reduced anorexigenic peptide hormones
Increased plasma leptin
Increased food intake
Gain body weight
Nucleus
P
STAT3
P
STAT3
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
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
PIP3
PI3K
P
AKT
Plasma membrane
PDK1
P
Glut4
ER
Hyperglycemia in insulin resistance
Insulin
Glucose
Insulin
Receptor
P
IRS
P
PIP
3
PI3K
P
AKT
Plasma
membrane
PDK1
P
Glut4
ER
Insulin Resistance
Insulin Resistance
Duan et al, MCB, 2004
Glucose tolerance and insulin sensitivity are
impaired in insulin resistance
Glucose
Insulin
Glucose
Insulin
Receptor
P
IRS
Insulin
Resistance
P
PIP
3
PI3K
P
AKT
Plasma
membrane
PDK1
P
Insulin
Resistance
Glut4
ER
Duan et al, MCB, 2004
Insulin-induced insulin receptor phosphorylation is
impaired in insulin resistance
Insulin
Glucose
Insulin
Receptor
P
IRS
P
Plasma
membrane
PIP3
PI3K
P
AKT
PDK1
P
Glut4
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
Plasma
membrane
PIP3
PI3K
P
AKT
PDK1
P
Glut4
ER
Insulin Resistance
Duan et al, MCB, 2004
Insulin-induced PI3K activation is impaired in insulin
resistance
Insulin
Glucose
Insulin
Receptor
P
PIP3
IRS
P
Plasma
membrane
PIP3
PI3K
P
AKT
PDK1
P
Glut4
ER
Insulin Resistance
PIP3: Phosphatidylinositol triphosphate
Duan et al, MCB, 2004
Insulin-induced Akt phosphorylation is impaired in insulin
resistance
Insulin
Glucose
Insulin
Receptor
P
IRS
P
PIP
3
PI3K
P
AKT
Plasma
membrane
PDK1
P
Glut4
(-)
Insulin
Insulin Resistance
Insulin
(-)
ER
Duan et al, MCB, 2004
Plasma insulin is elevated in insulin resistance
Insulin
Glucose
Insulin
Receptor
P
IRS
P
PIP
3
PI3K
P
AKT
Plasma
membrane
PDK1
P
Glut4
ER
Insulin Resistance
Insulin Resistance
Duan et al, MCB, 2004
Summary
Insulin
Glucose
Insulin
Receptor
P
IRS
Insulin Resistance
Impaired cellular Insulin signaling
Impaired insulin-induced glucose uptake
Impaired glucose tolerance
Increased plasma Insulin
P
PIP
3
PI3K
P
AKT
Plasma
membrane
PDK1
P
Glut4
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/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.
Inflammatory reactions
Host Defense
Inflammatory cytokines
e.g. TNF-a, IL-6
Receptors
Plasma membrane
Nucleus
JNK
Stress
response
NFkB
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
Receptor
Receptors
P
IRS
P
PIP3
PI3K
P
AKT
PDK1
P
P
Inhibitory
phosphorylation
JNK
Glut4
ER
Summary
Metaflammation
Chronic low-grade of inflammation, termed
metaflammation, takes place in obese conditions.
Obese conditions
Inflammatory cytokines
e.g. TNF-a, IL-6
The metaflammation causes insulin resistance
partly through inhibitory phosphoryalation of IRS
Insulin
Glucose
Insulin
Receptor
Receptors
P
IRS
P
PIP3
PI3K
P
AKT
PDK1
P
P
Inhibitory
phosphorylation
JNK
Glut4
ER