Download Metabolic Stress Signaling by the JNK Pathway

Roger J. Davis
Metabolic Stress Signaling
by the JNK Pathway
Age-adjusted Percentage of U.S. Adults with
Diagnosed Diabetes or Obesity
Diabetes
2000
1994
<4.5%
4.5-5.9%
6.0-7.4%
2007
7.5-8.9%
>9.0%
Obesity (BMI ≥30 kg/m2)
1994
<14.0%
2000
14.0-17.9%
18.0-21.9%
2007
22.0-25.9%
>26.0%
see WWW.CDC.GOV/Diabetes
Diabetes: Problem Scope

USA:
*Dall TM. Health Affairs, 2010
• ~24 million Americans afflicted (>8%), incidence increasing
• Expensive! In 2007- $218B*
1 in 3 Americans born in 2000 are expected to develop
• Compared to those without the disease, patients with T2D and T1D see physicians 2.9 and 3.5
diabetes
during
their lifetime…
times more
frequently
•
Leading cause of kidney failure, blindness, amputations, and a major contributor to
Narayan
et almortality
Diabetes Care 29: 2114–2116, 2006
premature
JNK, Obesity & Insulin Resistance
JNK is activated by eating a high fat diet
JNK-deficient mice are resistant to the effects of a high fat diet
The Jackson Labs
PP2A
PP6
PP2A
PP2C
MKP
Obesity-induced insulin resistance
- Role of MLK
Scaffold proteins can assemble a
JNK signaling module
MKKK
MLK
MKK
MAPK
JIP1 MKK7
JNK
JIP1 and the metabolic stress response
Diabetes:
MLK
JIP1 MKK7
JNK
 The human JIP1Ser59Asn allele segregates
with diabetes.
 JIP1-deficient mice are resistant to obesity
-induced JNK activation and insulin resistance.
 Response to obesity requires MLK, MKK7 & JNK.
JIP1 scaffold protein
1) JIP1 scaffold protein contributes to JNK-mediated
metabolic stress responses
2) JIP1 organizes large multi-protein complexes
3) JIP1 complexes are dynamically regulated
- Phosphorylation
- Kinesin-mediated transport
Mechanism of JNK-regulated
Obesity and Insulin Resistance
 JNK in peripheral tissues regulates insulin sensitivity.
 A central mechanism accounts for JNK-regulated obesity.
How does JNK make you obese ?
JNK and the hypothalamic-pituitary axis
Mechanism of JNK-regulated Obesity
JNK in the anterior pituitary gland causes obesity
without changing food consumption
1H-MRS
Analysis
JNK causes decreased energy expenditure
Gene Expression Analysis
 Differentially expressed genes - liver and brown fat
 significant enrichment of thyroid hormone responsive genes
 Anterior pituitary gland
 Increased Thyroid Stimulating Hormone (TSH) expression
JNK suppresses the thyroid hormone axis
Pharmacological inhibition of Thyroid hormone release
prevents the effects of JNK-deficiency on obesity
JNK suppresses TSH expression
No change in pitiuitary transcription factors known to regulate TSH expression
JNK promotes AP1-dependent gene expression
What is Dio2 ?
 Dio2 converts the pro-hormone T4 to the active form T3
 Critically required for local thyroid hormone signaling.
 Dio2 is required for feed-back inhibiton of TSH expression in
the anterior pituitary gland by T4.
 Increased TSH expression by the anterior pituitary gland may be
caused by failure of T4-mediated repression of TSH expression.
JNK is required for T4-mediated repression of
TSH expression by the anterior pituitary gland
JNK in the hypothalamus
also regulates the thyroid
hormone axis.
JNK is required for T4mediated repression of
thyroglobulin releasing
hormone (TRH).
JNK-regulated Dio2
expression in the
hypothalamus (tanycytes)
may provide a mechanism.
Dio2
TRH
JNK and
Obesity
JNK promotes diet-induced
obesity by suppressing the
hypothalamic-pituitarythyroid axis
How does JNK promote insulin resistance
?
Insulin Resistance: tissue interactions
Obesity-induced chronic diseases
Handschin et al, Nature 2008; 454:463-469
Obesity-induced inflammation in adipose tissue
Adipocyte
ATM; Adipose
Tissue
Macrophage
Odegaard et al, Annu Rev Patol Mech Dis 2011; 6:275
Jnk1-/- Jnk2-/- Macrophages
Control
LPS
FWT
FKO
pSer63-cJun
Macrophage JNK-deficiency does not prevent obesity
Macrophage-specific JNK deficiency prevents
diet-induced hyperglycemia & hyperinsulinemia
Macrophage JNK causes glucose and insulin intolerance
Glucose
injection
Glucose tolerance test
Insulin
injection
Insulin tolerance test
Macrophage JNK promotes insulin resistance
GIR; Glucose infusion rate
HIA; Hepatic insulin action
HGP; Hepatic glucose production
Macrophage JNK suppresses insulin-stimulated AKT
JNK Promotes Macrophage Infiltration of Adipose Tissue
Macrophage JNK promotes
chemokine signaling
Obesity-induced inflammation in adipose tissue
Adipocyte
ATM; Adipose
Tissue
Macrophage
Odegaard et al, Annu Rev Patol Mech Dis 2011; 6:275
Macrophage Polarization
M1
M2
(Classically activated macrophages)
(Alternatively activated macrophages)
IFN-g and endotoxin
IL4 or IL13 (M2a)
Immune Complex (M2b)
IL10 or TGFb (M2c)
IL12-mediated
Th1 immune response
Th2 immune response
Pro-inflammatory cytokines
Resolution of acute inflammation
Regulation of tissue homeostasis
CD11C, TNF
Arg-1, Mgl1, Mrc1, IL10
JNK Promotes Macrophage Infiltration of Adipose Tissue
M1
M2
Macrophage polarization in vitro
GM-CSF
BMDM
IFNg, LPS
M1
IL4, IL13 IC+LPS
M2a
M2b
FACS
CD11c
CD206,CD301
CD86
Gene
Expression
Ccr7, Cd11c, Il1b,
Tnfa, Il6,Ccl2, Ccl5
Arg1,
CD206,
CD301
Il1b, Tnfa,
Il6, Il10
IL10
M2c
Macrophage JNK is not required for M2a polarization
Macrophage JNK is required for M1 polarization
JNK controls M1 Macrophage Polarization
Adipocyte
ATM; Adipose
Tissue
Macrophage
Odegaard et al, Annu Rev Patol Mech Dis 2011; 6:275
Metabolic stress
signaling by JNK
1) JNK targets Dio2 to regulate obesity.
2) JNK1 in peripheral tissues (fat, muscle) controls
insulin sensitivity.
3) JNK promotes macrophage-mediated inflammation.
- M1 polarization
- Tissue infiltration
Metabolic Stress
1) JNK responds to metabolic stress
2) JNK-mediated inflammation contributes to disease:
- Diabetes
- Cardiovascular disease
- Cancer
3) Opportunity for therapeutic intervention
Acknowledgments
Tammy Barrett
Seda Barutcu
Vicky Benoit
Shashi Kant
Julie Cavanagh-Kyro
Nomeda Girnius
Myoung Sook Han
Norm Kennedy
Caroline Morel
Kasmir Ramo
Santiago Vernia
Ping Xu
Clamp assays
Jason Kim