Transcript PAI-1

Ch 9, Adipocytokines and the Pathogenesis of
the Metabolism Syndrome
Geng-Ruei Chang
2006.10.26
Cardiovascular
complication
Metabolism
syndrome
Type 2 diabetes
Introduction
Adipose tissue is traditionally viewed as major site for
steroid hormone metabolism, and a passive reservoir
for energy storage to concert the disequilibrium of
energy intake and expenditure imposed by
physiological needs through removing or releasing
lipid metabolites from and to the circulation with either
loss or gain of body weight.
Adipose tissue is now recognised to be a
multifunctional organ; in addition to the central role of
lipid storage, it has a major endocrine function
secreting several hormones.
Introduction
These adipose tissue-secreted proteins, i.e. leptin,
adiponectin, resistin, pro-inflammatory cytokines,
complement factors and so on, have been given the
collective name ‘adipocytokines’ or ‘adipokines’.
However, since most are neither ‘cytokines’ nor
‘cytokine-like’, it is recommended that the term
‘adipokine’ be universally adopted to describe a
protein that is secreted from (and synthesised by)
adipocytes.
Adipokines classified by functional role.
(Trayhurn and Wood, 2004)
Adipocytokines secreted by adipose tissue.
Inflammatory and acute-phase response
proteins secreted from adipocytes.
Others: Acrylation-stimulating protein (ASP)
Plasminogen activator inhibitor-1 (PAI-1)
Protein of the renin-angiotensin system (RAS)
(Trayhurn and Wood, 2004)
Cytokine family
Leptin
Leptin
In 1994, the obese (ob) gene was first identified in
genetic obesity mouse (ob/ob mice) adipose tissue
through a positional cloning approach by Zhang et al.
Leptin, a 167 amino acid peptide hormone that is the
product of the ob gene, and released from adipose
tissue into the blood as 16-kDa protein.
Leptin has a tertiary structure strikingly resembling
the members of the long-chain cytokine family, such
as IL-6, leukaemia inhibitorr factor (LIF) and GCSF.
Domain structure of alternatively sliced
LEPR isoforms.
The long isoform, LEPRb, has intracellular motifs necessary for
JAK-STAT signaling. LEPRe lacks a transmembrane domain (TM)
and intracellular domains and circulates as a soluble receptor.
Intracellular signaling by LRb.
Leptin signalling.
Regulation of leptin
下視丘
瘦體素
接受體
白色脂肪組織中
的瘦體素
交感神經系統活性上升
脂肪組織
產熱作用
胰島素
食物攝取
( Diabetolgia et al., 1997 )
Cross-talk between insulin and leptin signalling .
Regulation of AMPK and fatty acid
oxidation by leptin in skeletal muscle.
Body weight regulation by leptin.
Causes of leptin resistance
Leptin in the immune response
Leptin-null humans and ob/ob mice manifest a
complex syndrome that is characteristic of an adaptive
response to starvation, including thymic atrophy, T cell
hyporesponsiveness and macrophage mal-phagocytic
activity.
Leptin treatment stabilizes thymic homeostasis,
restores the number and responsiveness of circulation
CD4 T cells and balances the cytokine production by T
helper 1(TH1) and TH2 cells.
Leptin together with C-reactive protein, IL-1 and IL-6
can act as an acute-phase reactant to regulate
inflammatory process.
Leptin in the cardiovascular system
Leptin signalling in vascular endothelia, stimulates the
production of monocyte chemoattractant protein-1
(MCP-1) and reactive oxygen species, leading to
increased monocyte infiltration and foam cell
accumulation in the injured arterial wall, and induces the
synthesis of endothelin-1, enhancing vasoconstriction.
Leptin signalling activation in platelets further promotes
platelet aggregation around the atherosclerotic lesion.
High leptin levels to accelerate the development of
atherothrombotic disease in obesity.
Cardiovascular actions of leptin
Interleukin 6
IL-6 is traditionally denoted as a protein secreted
by leucocytes, is now to be another adipose tissuederived cytokine that has been strongly implicated
in obesity and insulin-resistance.
IL-6 circulates in multiple glycosylated forms of
22-27 kDa and as much as 1/3 of the circulating
IL-6 in the blood circulation originates from the
adipose tissue.
Intracellular IL-6 signalling.
Interleukin 6
An increase in IL-6 gene transcription rate, is associated
with impaired energy expenditure, insulin action, and
development of type 2 diabetes.
Peripgeral administration of IL-6 induces
hyperlipidaemia, hyperglycaemia and other markers of
insulin resistance.
Lack of IL-6 may induce mature-onset obesity and
disturbed carbohydrate and lipid metabolism in IL-6
null mice.
Interleukin 6
IL-6 reduces gene expression and activity of
insulin signalling molecules and induces
expression of SOCS-3 with consequently impaired
insulin and leptin signalling.
Increased IL-6 release from visceral adipose tissue
in abdominal obesity may constantly stimulate
acute-phase protein production from the liver.
Very high interstitial concentrations of IL-6 have
been demonstrated in human subcutaneous
adipose tissue, where adiponectin is highly
expressed, and IL-6 at similar concentrations in
vitro reduces adiponectin gene expression.
Tumour necrosis factor alpha (TNF-α)
TNF-αis initially identified as an endotoxin-indeced factor
identical to cachectin that causes necrosis of tumours and
plays a role in the metabolic disturbances and chronic
inflammation.
TNF-αis synthesized as a 26-kDa transmembrane
monomer, and proteolytic cleavage of the membranebound precursors prodeces biologically active trimer
protein that exerts it effects via type ⅠandⅡ TNFαreceptors.
TNF-αis expressed both in adipocyte and stromovascular
cells, which enables TNF-α to regulate locally both
adipogenesis and adipose tissue function.
TNF-α
Treatment with neutralizing soluble TNF-α receptors
has been found beneficial in improving insulin
sensitivity in obese rodents.
Targeted gene deletion of either TNF-α or TNF-α
receptors significantly improves insulin sensitivity and
circulating NEFAs in obese rodents.
TNF-α
TNF-αreduces expression levels of the genes encoding
transcription factors and components essential for
adipogenesis and lipogenesis, and alters the balance of
adipocytokines such as adiponectin and IL-6.
In the liver, TNF-αproduces a gene expression that may
lead to reduced glucose utilization and fatty acid
oxidation while increasing synthesis of cholesterol and
fatty acids; it also impairs insulin action.
Mechanisms of TNF-α-induced insulin resistance
The relationship between TNF-α and type 2 diabetes
Adiponectin
Adiponectin, also termed adipose most abundant gene
transcript 1(apM1), adipocyte complement related protein
of 30 kDa (Acrp30) , AdipoQ, or gelatine binding protein
28 kDa (GBP28).
Adiponectin is composed of an N-terminal signal sequence,
a variable domain, a collagen-like domain and C-terminal
globular domain, which structurally, adiponectin belongs
to the collagen superfamily sharing homologies with
collagens (type Ⅷ and Ⅹ), complement factors (C1 q)and
TNFa.
Structure of adiponectin receptors.
AdipoR1 and AdipoR2 (66.7% amino acid identity with AdipoR1) are predicted to
contain 7 transmembrane domains but are structurally and topologically distinct
from GPCRs.
The role of adiponectin
(Saltiel, 2001 )
Adiponectin for insulin resistance, the metabolic
syndrome, and atherosclerosis.
TZDs ameliorate diabetes by adiponectindependent and -independent pathways.
Adiponectin in the cardiovascular system
Human subjects harbouring adiponectin gene mutations
associated with reduced plasma adiponectin levels seem
to have a higher risk to develop hypertension and
coronary heart disease.
Adiponectin reduces monocyte adhesion by inhibiting
endothelial expression of cell adhesion molecules and
release of reactive oxygen species.
Adiponectin increases endothelial production of nitric
oxide and inhibits GF-induced vascular smooth muscle
cell proliferation.
Adiponectin signal transduction.
Resistin
Resistin is a 12.5-kDa cysteine-rich peptide that as a
novel factor secreted by adipocytes with an impact on
insulin sensitivity was proposed as a new mechanism to
explain the pathogenic sequence of adipocyte-obesityinsulin resistance.
Resistin inhibits the release of dopamine and
norepinephrine while having no effect on serotonin
release,
Similar to Leptin, to regulate appetite by acting on the
hypothalamic satiety centre.
Resistin
Serum resistin levels are increased in mice with genetic
(ob/ob mice or db/db mice) or diet-induced obesity,
which is associated with impaired glucose metabolism
and insulin resistance.
Resistin suppresses insulin-stimulated glucose uptake in
vitro, and this effect is prevented by anti-resistin
antibodies.
These data suggest that resistin induces insulin resistance
and that hyperresistinemia contributes to impaired insulin
sensitivity.
The role of resistin.
Resistin acts on skeletal muscle to cause
insulin resistance
Acylation Stimulating Protein (ASP)
ASP is a small basic protein synthesized from complement
factor C3, which was isolated from the human plasma and
which has been shown to be the most potent stimulant yet
discovered of triglyceride synthesis.
ASP is not an active immune modular and binds to a Gprotein-coupled receptor in adipocytes to stimulate glucose
uptake and diacylglycerol acyltransferase activity and to
inhibit hormone sensitive lipase.
The involvement of ASP in metabolic syndrome has been
showing the correlations of ASP or ASP precursors with
body fat mass and levels of circulating hormones,
carbohydrates and lipids.
ASP
ASP and ASP precursors are increased in obese and diabetic
subjects and decreased in individuals with anorexia nervosa
and lipodystrophies; they correlate with plasma insulin,
glycosylated haemoglobin, triglycerides, fatty acids and
disease, i.e. hypertension and cardiovascular disease.
Gene ablation of C3 and ASP in mice has found to increase
fatty acid oxidation in the liver and skeletal mucle.
The mechanisms whereby ASP deficiency and/or ASP
resistance induce metabolism and vascular disorders remain
to be determined.
Macrophage and monocyte chemoattractant
protein-1 (MCP-1)
MCP-1 is a chemokine that recruits monocytes to sites
of inflammation and, in adipose tissue is primarily
expressed.
MCP-1 are increased in rodent obesity, which is
associated with increased infiltration of macrophage in
the adipose tissue and increased release of proinflammatory cytokines such as IL-6 and TNF- α.
MCP-1 may potentially induce insulin resistance by
impairing insulin-stimulated insulin receptor tyrosine
phosphorylation and insulin-stimulated glucose uptake
by the adipose cells, and also impair adipogenesis.
Plasminogen activator inhibitor-1 (PAI-1)
PAI-1 is a member of the serine protease inhibitor
family that inhibits the fibrinolysis system with
reduced intravascular thrombolysis by inactivating
urokinase-type and tissue-type plasminogen activator.
Adipose tissue gene expression and plasma
concentrations of PAI-1 are elevated in obesity and
insulin resistance and correlated with visceral fat
accumulation and levels of insulin and triglycerides.
PAI-1
Targeted deletion of PAI-1 in mice reduces dietinduced weight gain and enhances energy
expenditure, accompanied by improved glucose
tolerance and insulin sensitivity.
Therefore, increased PAI-1 production in obesity
may thus play an important role in the metabolic
syndrome, type 2 DM, and atherosclerotic
cardiovascular disease.
PAI-1 in the obesity and diabetes.
Factors contributing to increased
PAI-1 production in obesity.
Proteins of the renin-angiotensin system (RAS)
Cardiovascular risk factors are associated with activation of
the tissue RAS that mediates vascular tone, aldosterone
secretion and sodium and water re-absorption.
New findings have been reported concerning the metabolic
syndrome in relation to the renin-angiotensin system, ie, that
treatment with inhibitors of the angiotensin-converting
enzyme (ACE) not only decreases blood pressure levels but
prevents the development of diabetes mellitus.
Adipiose tissue expresses angiotensinogen and enzymes
required for angiotensin synthesis, including angiotensinconverting enzyme, chymase, cathepsins D and G and tonin,
and is a major source of the vasoactive peptides in obesity.
Renin-angiotensin system
RAS
Increasing adipose tissue expression of angiotensinogen by
glucocorticoids activates the RAS with increased plasma
levels of angiotensinogen, angiotensin Ⅱ and aldosterone,
together with increased blood pressure.
Angiotensin has been found to stimulate hapatic
gluconeogenesis and glycogenolysis and to inhibit insulinstimulated glucose uptake.
Increased RAS activity disturbs the balance of adipocytokine
secretion, i. e. leptin, pAI-1…..
Inhibition of the RAS significantly reduces the risk of
cardiovascular death and the progression of atherosclerosis,
and improves metabolic disorders.
Pathophysiology of cardiovascular disease in RAS, ICAM-1, VCAM-1..
Ang II on human adipogenesis
and insulin resistance
Summary and perspective
Discordant genetic-environmental interaction
obesity
adipocytokines
Energy
metabolism
Vascular
haemostasis
The metabolic syndrome
Inflammation
Q &A
舉例說明adipocytokine在metabolic
syndrome中扮演的角色？
Thanks for your attention！