Shinichi Oka PhD Department of Cell Biology and Molecular Medicine Rutgers New Jersey Medical School MSBI543 okashnjmsrutgersedu Objectives Leptin Resistance Obese Insulin Resistance ID: 341379
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Slide1
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.eduSlide2
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
MetaflammationSlide3
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
MetaflammationSlide4
Leptin resistance causes obesity
ob
/
ob
ob
/
ob; Letpin
mutant
db/d
b; Letpin receptor mutant
controlSlide5
Leptin
Leptin
(Greek
λε
πτός
(leptos) meaning "thin") is a 16-kDa
adipokine
Adipose tissue
Leptin
Excessive food intake
Brain
Bloodstream
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
Reduction
of appetiteSlide6
Leptin
signaling
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
P
P
P
P
Nucleus
AppetiteSlide7
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
P
P
P
P
Nucleus
Leptin
function and signaling
Adipose tissue
Excessive food intake
Brain
Leptin
Reduction
of appetite
BloodstreamSlide8
Molecular pathology of Leptin
Resistance
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
P
P
P
P
Nucleus
Appetite
Ren et al, JCI, 2007
Ren et al, Cell Metabolism, 2005
Leptin
ResistanceSlide9
Leptin-induced JAK2 activation is impaired in
Leptin
Resistance
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
STAT3
Plasma membrane
P
P
P
P
Nucleus
Appetite
Ren et al, JCI, 2007
Ren et al, Cell Metabolism, 2005
Leptin
ResistanceSlide10
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
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
ResistanceSlide11
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
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
ResistanceSlide12
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
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
ResistanceSlide13
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
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
ResistanceSlide14
Leptin
JAK2
Anorexigenic
peptide hormone
Orexigenic
peptide hormone
STAT3
STAT3
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
ResistanceSlide15
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
MetaflammationSlide16
Diabetes
Diabetes is a metabolic diseases in which a person has high blood glucose.
Diabetes causes heart diseases, kidney failure and eye problem.Slide17
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.Slide18
Insulin
A peptide hormone secreted from the PancreasSlide19
Insulin action
Glucose
http://trialx.com/curetalk/2011/01/risk-of-cvd-in-diabetes-mellitus-pateints/Slide20
Molecular pathology of insulin resistance
Insulin
IRS
PI3K
Plasma membrane
P
P
AKT
Insulin Receptor
P
PDK1
PIP3
P
Glut4
ER
GlucoseSlide21
Hyperglycemia 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 ResistanceSlide22
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
GlucoseSlide23
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 resistanceSlide24
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 resistanceSlide25
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
PIP3Slide26
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
Insulin
(-)
(-)
Insulin-induced
Akt
phosphorylation is impaired in insulin resistanceSlide27
Plasma insulin is elevated 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 ResistanceSlide28
Insulin
IRS
PI3K
Plasma membrane
P
P
AKT
Insulin Receptor
P
PDK1
PIP3
P
Glut4
ER
Glucose
Impaired cellular Insulin signaling
Impaired insulin-induced glucose uptake
Impaired glucose tolerance
Increased plasma Insulin
Summary
Insulin ResistanceSlide29
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
MetaflammationSlide30
Inflammatory Reaction
http://jem.rupress.org/content/203/2/269/F2.large.jpgSlide31
Inflammatory Signaling
http://atlasgeneticsoncology.org/Deep/NFKBID20033.htmlSlide32
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-
a
, IL-6
Proinflammatory
genes
NF
k
B
Stress response
Receptors
Nucleus
Inflammatory reactions
Host DefenseSlide33
Inflammatory reaction inhibits insulin signaling
Insulin
IRS
PI3K
P
P
AKT
Insulin Receptor
P
PDK1
PIP3
P
Glut4
ER
Glucose
JNK
Inflammatory cytokines
e.g. TNF-
a
, IL-6
Inhibitory phosphorylation
Receptors
P
Obese conditions
?
Hirosumi
et al, Nature, 420, 333Slide34
Metaflammation
Insulin
IRS
PI3K
P
P
AKT
Insulin Receptor
P
PDK1
PIP3
P
Glut4
ER
Glucose
JNK
Inflammatory cytokines
e.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