Transcript Adiponectin

ADIPONECTIN
Its emerging role in Atherosclerosis,
Metabolic Syndrome and Insulin
Resistance
RT ERASMUS
Chemical Pathology, Tygerberg Hospital,
NHLS &University of Stellenbosch
[email protected]
Discovery and Structure (1)
●
●
Discovered by 4 independent researchers in 1996
More than 1000 papers published mostly from
Japan
●
Specific and most abundant in adipocytes
●
Part of adipokine family (TNFalpha, leptin)
●
●
30 kDa protein; 247 amino acids coded by apM1
gene
Member of collagen family, shares homology with
collagen VIII & X and complement C1q
FIG. 1. Structure and domains of adiponectin
Kadowaki, T. et al. Endocr Rev 2005;26:439-451
Copyright ©2005 The Endocrine Society
Physiology(1)
●
●
●
●
●
Expressed and secreted only in adipose tissue
Endogenous adiponectin post translationally modified into 8
isoforms
Globular portion as efficient as full length adiponectin at
lowering glucose & FFA
Pulsatile & diurnal secretion similar to other hormones
Secretion hormone regulated: ↓levels with insulin&
glucocorticoids
●
TNFα decreases adiponectin transcription
●
Elisa &RIA methods available : 5-10 ug/ml
Physiology (2)
●
●
Correlates negatively with BMI & more –
vely with visceral than subcut fat
High levels in plasma (3 x normal conc of
other hormones)
●
Low levels seen in obesity, type 2 DM, IHD
●
Levels correlate with insulin sensitivity
Biological Effects (1)
●
●
●
Insulin- sensitizing actions
Adiponectin reduces tissue TG content and up
regulates insulin signaling through ↑CD36,
↑combustion of fatty acids →↑GLUT4 ( Rx of
obese diabetic mice with adiponectin
→↑phosphorylation of IRS-1 & insulin receptor)
Activation of PPARα leading to ↑ fatty acid
combustion → ↓tissue FA → ↑ insulin sensitivity
(C2C12 myocytes with adiponectin)
Biological effects (2)
●
●
●
No adiponectin found in normal vessels but
in balloon injured vascular walls
Inhibits adhesion molecules eg E selectin,
vascular adhesion mol 1, intracellular
adhesion 1
Inhibits SR-A class of macrophages –
decreases uptake of oxidised LDL & thus
inhibiting foam cell formation
Polymorphisms in Gene ass with hypoadiponectinaemia, Type
2 DM and Insulin Resistance
●
●
●
Adiponectin gene, chrom 3, spans 17kb, 3
exons & 2 introns
Several SNP polymorphisms in Japanese,
German and Americans have been identified
and ass with Type 2 DM and IR eg SNP 276
and SNP 45(many ass with abnormal forms
of adiponectin or low levels)
This strongly suggests pivotal role of
Adiponectin in dev of type DM
Adiponectin Receptors
●
●
●
●
●
●
2003 : 2 receptors identified:Adipo R1 & R2
Expressed in skeletal muscle and liver
7 transmembrane proteins
Receptors for both full length & globular
adiponectin
Recently receptors also found in pancreas β
cells
Receptors mediate ↑AMP kinase & PPARγ
activity→ FA oxidation & ↑glucose uptake
Regulation of Adiponectin Receptors
●
●
●
Fasting upregulates expression and refeeding
restores them
Insulin negative regulator – low levels in
insulin resistance
Decreased expression in obesity leading to
decreased adiponectin sensitivity and
adiponectin resistance and subsequent
insulin resistance setting up a “vicious
cycle”
Obesity, adiponectin and insulin resistance
Adiponectin and atherosclerosis
●
●
In cultured cells, human recombinant
adiponectin suppresses endothelial
expression of adhesion molecules,
proliferation of vascular smooth muscle cells
& transformation of macrophages to foam
cells: adiponectin may thus protect vascular
wall against atherogenic changes
In mice overexpression of adiponectin
reduced atherosclerotic plaques
Adiponectin and Insulin Resistance
●
●
●
Low adiponectin levels seen in obese humans,
cardiovascular diseases, hypertension or metablocs
syndrome – all of which are ass with IR
Whether there is cause and effect relationship not
known
Several exp in mice have clearly established the
insulin sensitizing effects of adiponectin (along
with leptin) as well as the reversal of IRS with
recombinant adiponectin – could this be used to
treat IR and type 2 DM ?
Adiponectin Hypothesis
●
●
Reduced levels may occur due to
genetic(polymorphisms, SNP 276) or
environmental factors(obesity,HF diet) and
or reduced actions due to down regulation of
receptors (obesity)
These reduced levels may play a causal role
in dev IR, MS & progress to atherosclerosis
Conclusion
●
●
●
●
Adiponectin specific adipokine produced by
adipocytes in large amounts
Has potent antinflammatory and
atheroprotective properties
Has insulin sensitizing effect influencing
glucose and lipid metabolism
Is associated with insulin resistance and the
metabolic syndrome