ADIPONECTIN Its emerging role in Atherosclerosis, Metabolic Syndrome and Insulin Resistance RT ERASMUS Chemical Pathology, Tygerberg Hospital, NHLS &University of Stellenbosch

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

Copyright ©2005 The Endocrine Society Kadowaki, T. et al. Endocr Rev 2005;26: FIG. 1. Structure and domains of adiponectin

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