Adiponectin also known as AdipoQ ,AcrP30, apM1 or gelatin binding protein-28 (GBP-28), is an adipose tissue-specific collagen-like molecule described in 1996, Biochem Biophys Res Commun. 1996 Apr 16;221(2):286-9 and expressed exclusively in adipocytes. It is present in human circulation in high levels (5-30mcg/ml) accounting for 0.01% of plasma proteins. Biochem Biophys Res Commun. 1999 Apr 2;257(1):79-83 , with slightly higher levels in women than men. Diabetes. 2002 Sep;51(9):2734-41. It has been shown to have anti-diabetic, anti-atherosclerotic and anti-inflammatory functions. Adiponectin is presently understood to be closely related to the development/perpetuation of the metabolic syndrome and may turn out to be a promising insulin sensitizing agent.
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Adiponectin and Visceral Fat
The fat cell or adipocyte has conventionally been thought of as an energy storing cell. But in recent times, with the recognition of hormones, cytokines, growth factors and other bioactive substances being secreted by the adipocytes, the view has changed dramatically. Secretion of peptides into blood which are effective at a distant region raised the status of the fat cell to that of an endocrine organ. The metabolic morbidities of obesity are often not necessarily proportional to the extent or degree of fat accumulation. Instead, the distribution of body fat (visceral vs. subcutaneous) might be more crucial to the development of these complications. Intra abdominal fat may predominantly influence the propensity to develop complications including diabetes Metabolism. 1987 Jan;36(1):54-9.hypertension Hypertension. 1990 Nov;16(5):484-90 dyslipidaemia Arteriosclerosis. 1989 Mar-Apr;9(2):203-10 and in turn atherosclerosis. Atherosclerosis. 1994 Jun;107(2):239-46. |
It is likely that substances secreted by visceral fat might be responsible for clustering of the components of the metabolic syndrome in any one subject. The human Adiponectin gene has been localized to chromosome 3q27 which has a susceptibility locus for the metabolic syndrome Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14478-83. which could suggest an influence of Adiponectin on the initiation or perpetuation of the syndrome. Plasma levels of Adiponectin, a 244 amino acid protein, have been shown to negatively correlate with visceral adiposity. Adiponectin gene expression is lower in visceral fat compared to subcutaneous fat in both lean and obese humans. Mol Cell Endocrinol. 2004 Apr 30;219(1-2):9-15 TNF α, a strong inhibitor of Adiponectin promoter activity is secreted from visceral fat in increased quantities Diabetes. 2001 Sep;50(9):2094-9 and might explain this negative correlation. |
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Adiponectin and Insulin resistance
Obese patients tend to have lower adiponectin levels probably due to feedback inhibition by fat accumulation. Adiponectin levels are also lower in patients with the metabolic syndrome Diabetes Care. 2003 Aug;26(8):2442-50. including diabetes, hypertension and hypertriglyceridaemia; states which are characterised by insulin resistance. Adiponectin levels strongly correlate with insulin sensitivity. Diabetes. 2002 Jun;51(6):1884-8. In fact, circulating adiponectin levels seem to correlate more with hyperinsulinaemia and insulin resistance than with obesity or body fat. J Clin Endocrinol Metab. 2001 May;86(5):1930-5 Adiponectin may decrease circulating free fatty acids by increasing NEFA oxidation in the skeletal muscle, Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2005-10 thus decreasing the triglyceride content of muscles and reducing hepatic triglyceride deposition with resultant improved insulin sensitivity. A direct effect of adiponectin on hepatic FFA uptake is also possible. Adiponectin infusion produces suppression of hepatic glucose production. J Clin Invest. 2001 Dec;108(12):1875-81. ; Nat Med. 2001 Aug;7(8):947-53. Adiponectin Knock-out mice are insulin resistant. J Biol Chem. 2002 Jul 19;277(29):25863-6 Adiponectin knock-out mice show delayed clearance of free fatty acids from plasma. Nat Med. 2002 Jul;8(7):731-7. Insulin resistant mice have restored insulin sensitivity when infused intravenously with recombinant Adiponectin Nat Med. 2001 Aug;7(8):941-6. Transgenic mice over-expressing adiponectin show amelioration of insulin resistance. J Biol Chem. 2003 Jan 24;278(4):2461-8 Recombinant Adiponectin reduces serum glucose in normal and diabetic rodents without stimulating insulin secretion. Nat Med. 2001 Aug;7(8):947-53 The improved glycaemia may be mediated partly through suppression of hepatic glucose production. J Clin Invest. 2001 Dec;108(12):1875-81. Two distinct adiponectin receptors (Adipo R1 and R2) have been cloned which may mediate the specific anti-diabetic actions of adiponectin on liver and the muscle. Nature. 2003 Jun 12;423(6941):762-9 |
PPAR-gamma (peroxisome proliferator activated receptor) is abundant in the adipose tissue, and is responsible for the induction of adipocyte differentiation, and controls many adipocyte genes. Thiazolidinediones which are PPAR-gamma agonists with the ability to improve insulin resistance, increase Adiponectin mRNA expression in the adipose tissue of obese and lean rodents. Diabetes. 2001 Sep;50(9):2094-9. ; Endocrinology. 2002 Mar;143(3):998-1007. Thiazolidinediones also reverse the inhibitory effect of TNF-alpha on Adiponectin expression in the adipocytes. 3-month Thiazolidinedione (troglitazone) treatment of glucose intolerant overweight subjects,Diabetes. 2001 Sep;50(9):2094-9. diabetic subjects, as well as lean and obese non-diabetic subjects Diabetes. 2002 Oct;51(10):2968-74. resulted in significantly increased plasma Adiponectin levels. Similar positive effects on plasma Adiponectin levels in type 2 diabetics with both rosiglitazone Diabetes Care. 2002 Feb;25(2):376-80. and pioglitazone Metabolism. 2002 Mar;51(3):314-7 have been demonstrated. Lower levels of Adiponectin have been observed in subjects with dominant-negative PPAR-gamma mutationsEndocrinology. 2002 Mar;143(3):998-1007 as well as those with polymorphisms of the PPAR-gamma2 gene. Metabolism. 2002 Nov;51(11):1407-9 On a similar note, polymorphisms of the adiponectin gene could help predict the response of diabetic patients to thiazolidinediones. Diabetes Care. 2005 May;28(5):1139-44. |
The sympathetic system via catecholamines might facilitate insulin resistance. Sympathetic stimulation with the beta-adrenergic agonist isoproterenol resulted in decrease in Adiponectin mRNA levels, Biochem J. 2002 Nov 1;367(Pt 3):677-85 an effect that was prevented by pre-treatment with the beta-blocker propranolol. Adiponectin seems to have anti-inflammatory actions on the vessel walls as well as in adipose tissue and may inhibit vascular smooth muscle proliferation. It seems to protect endothelium from macrophage adhesion and macrophage-induced injury Circulation. 2001 Feb 27;103(8):1057-63. while increasing fatty acid oxidation in peripheral tissues Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2005-10. thus preventing ectopic fat storage. Mutations resulting in hypo-adiponectinaemia have been identified, Int J Obes Relat Metab Disord. 2000 Jul;24(7):861-8. which were accompanied by hypertension, hyperlipidaemia, glucose intolerance and coronary artery disease. Diabetes. 2002 Jul;51(7):2325-8. Adiponectin deficiency as demonstrated in the Adiponectin Knock-out mice resulted in insulin resistance and hyperglycaemia when rats were fed on high fat and high sucrose diets. The insulin resistance was reversed on treatment with Adiponectin. Nat Med. 2002 Jul;8(7):731-7 Vascular damage with intimal smooth muscle proliferation in these Adiponectin deficient mice was also corrected with Adiponectin treatment. J Biol Chem. 2002 Oct 4;277(40):37487-91. |
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Adiponectin and Type 2 Diabetes
Type 2 diabetics have lower Adiponectin levels. Type 2 diabetics with macrovascular disease have lower Adiponectin levels than those without. Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1595-9. Low plasma adiponectin levels are an independent risk factor for future development of diabetes, but not for obesity itself. Conversely, high Adiponectin levels have been shown to be protective against glucose intolerance developing in Pima Indians who are at high risk for diabetes as a group. Lancet. 2002 Jul 6;360(9326):57-8. Thiazolidinediones (while reducing the adipocyte secretion of resistin) increases secretion of Adiponectin. Adiponectin levels have also been noted to correlate with hepatic fat Curr Mol Med. 2005 May;5(3):287-95 and might explain the variation of hepatic fatty infiltration between equally obese individuals and the resultant variations in insulin resistance. Small studies have shown that type I diabetics have elevated plasma Adiponectin levels compared to healthy controls, which did not change with insulin therapy. Diabetes Care. 2002 Sep;25(9):1665-6 First degree relatives of type 2 diabetic patients have normal levels of circulating Adiponectin but lower expression of Adiponectin mRNA in adipose tissue suggesting a dysregulation in this group. Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E443-8. |
Adiponectin and Obesity
Obese rats have lower Adiponectin mRNA levels. It is possible that adipogenic gene expression and Adiponectin production which is activated during adipogenesis undergoes feedback inhibition resulting in lower levels of Adiponectin in the obese state. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11371-6 Obese humans have lower levels of Adiponectin. J Clin Endocrinol Metab. 2001 May;86(5):1930-5 . with mean plasma Adiponectin levels of 3.7 mcg/ml as opposed to the higher mean level of 8.9 mcg/ml in lean subjects. Biochem Biophys Res Commun. 1999 Apr 2;257(1):79-83. In obese subjects, plasma Adiponectin levels negatively correlate with BMI, body fat mass, fasting insulin, leptin and insulin resistance. Eur J Endocrinol. 2002 Aug;147(2):173-80. Even in subjects with normal BMI, plasma Adiponectin levels negatively correlated with BMI, systolic and diastolic BP, fasting glucose, insulin, total and LDL cholesterol, triglycerides, and uric acid. Clin Sci (Lond). 2002 Aug;103(2):137-42.Weight loss in obese humans undergoing gastric surgery resulted in an increase in plasma Adiponectin levels. J Clin Endocrinol Metab. 2001 Aug;86(8):3815-9. |
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Adiponectin and Vascular Disease
Adiponectin levels are lower in ischaemic heart disease Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):85-9. and in hypertensive patients. J Nephrol. 2002 Sep-Oct;15(5):507-11. Cardiac events are more likely in patients with renal insufficiency and lower Adiponectin levels. Nephrol Dial Transplant. 2004 Aug;19 Suppl 5:V67-72 Adiponectin strongly inhibits expression of adhesion molecules including ICAM-1, vascular cellular adhesion molecule 1 and E-selectin. Circulation. 1999 Dec 21-28;100(25):2473-6. Inflammation is implicated in vascular damage in atherosclerosis. Adiponectin has been shown to have anti-inflammatory activity with inhibition of myelomonocytic and phagocytic activity. Adiponectin also inhibits Nuclear factor Kappa B activation through inhibition of TNF-alpha. Circulation. 2000 Sep 12;102(11):1296-301. This may in turn prevent the monocyte adhesion to endothelial cells - a mechanism which contributes to the atherosclerotic cellular changes. Adiponectin inhibits synthesis and release of IL-8 (a pro-inflammatory chemokine with a role in atherogenesis) from endothelial cells, through inhibition of a PKA-dependent NF-kappa B signalling pathway, and thus might prevent atherosclerosis. Circ Res. 2005 Dec 9;97(12):1245-52 The uptake of oxidized LDL by macrophages to form foam cells resulting in atherosclerotic changes is also decreased by Adiponectin through inhibition of expression of the scavenger receptor class A1 macrophages (SR-A) Circulation. 2001 Feb 27;103(8):1057-63 Thus, Adiponectin may protect injured arterial walls against development of atherogenic changes. Adiponectin treatment of Apolipoprotein E-deficient mice decreased aortic plaque formation, and reduced the size of the lipid droplets compared to untreated mice. Circulation. 2002 Nov 26;106(22):2767-70. |
Adiponectin and its Regulators
I125 labelled Adiponectin localises to the skeletal muscle suggesting that adiponectin receptors might be present in muscle. In vitro Insulin treatment suppresses Adiponectin gene expression in adipocytes. Insulin reduces the level of Adiponectin mRNA in a dose dependent fashion. Hyperinsulinaemic euglycaemic clamp study showed Adiponectin level suppression in both diabetic and non-diabetic subjects. TNF-alpha reduces the expression and secretion of Adiponectin from adipocytes. Horm Metab Res. 2000 Nov-Dec;32(11-12):548-54. Adiponectin may in turn regulate TNF-alpha with the duo acting against each other to modulate insulin sensitivity and vascular atherogenicity. IL-6 also reduces adiponectin gene expression and secretion from adipocytes. Am J Physiol Endocrinol Metab. 2003 Sep;285(3):E527-33 Testosterone therapy reduces plasma Adiponectin and may well explain the sex difference in plasma Adiponectin levels. Diabetes. 2002 Sep;51(9):2734-41. Other candidate regulators of Adiponectin gene expression and secretion are beta- adrenergic agonists, Biochem J. 2002 Nov 1;367(Pt 3):677-85 (see above as well as Biochim Biophys Acta. 2002 Oct 10;1584(2-3):115-22 ) glucocorticoids, Biochem Biophys Res Commun. 2001 Nov 16;288(5):1102-7 and IGF-1. Thus while multiple factors regulate adiponectin, it may be affected by as well as influence development of obesity and insulin resistance. Its modulation might provide newer options to treat this metabolic condition. |
Patients with anorexia nervosa Clin Endocrinol (Oxf). 2003 Jan;58(1):22-9. and renal failure on dialysis J Am Soc Nephrol. 2002 Jan;13(1):134-41. were shown to have high plasma Adiponectin levels compared to healthy controls. The clearance and metabolism of Adiponectin remains to be clarified.