ADIPONECTIN
BY: DR VARUN GUPTA JR-2 DEPT. OF PHARMACOLOGY RMCH BAREILLY
CONTENTS •
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HISTORY INTRODUCTION ADIPONECTIN AS A HORMON WHY IS IT IMPORTANT TO STUDY ADIPONECTIN? CORRELATION BETWEEN ADIPONECTIN AND INSULIN RESISTANCE RESISTANCE ADIPONECTIN RECEPTORS DRUGS AFFECTING ADIPONECTIN LEVELS SUMMARY
HISTORY[1] •
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Adiponectin was first identified in 1995 in differentiating adipocytes. In 1996 it was identified in mice as the mRNA transcript most highly expressed in adipocytes. In 2007, adiponectin was identified as a transcript highly expressed in pre-adipocytes (precursors of fat cells) differentiating into adipocytes.
INTRODUCTION •
Adiponectin is a protein which in humans is encoded by the ADIPOQ gene.[2]
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Composed of 247 amino acids.
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Accounts for 0.05 % of total serum protein.
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Concentration: 2- 20 μg/mL in the blood.
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adiponectin also gaining recognition as a hormone.
ADIPONECTIN AS A HORMONE[3] •
Adiponectin is a white and brown adipose tissue hormone. circulates in the bloodstream in trimeric, hexameric, and high-molecular-mass species. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2 & T-cadherin.
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Adiponectin enhances AMPK ( 5' adenosine monophosphate-activated protein kinase) [4] and the PPARα [5] pathway in the liver and skeletal muscle. Adiponectin can exist in two different forms as-
1. a full-length protein or 2. as a globular form. •
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The globular form of adiponectin appears to stimulate β oxidation in muscle while the full-length form appears to decrease glucose output by the liver
WHY IS IT IMPORTANT TO STUDY ADIPONECTIN? •
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Evidence strongly suggests that adiponectin plays a role in the pathophysiology of type 2 diabetes and other metabolic syndrome diseases!!
CORRELATION BETWEEN ADIPONECTIN AND INSULIN RESISTANCE •
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Obesity and type 2 diabetes are associated with decreased adiponectin levels Reduced plasma adiponectin is also seen in people with conditions such as cardiovascular disease and hypertension, diseases that are often associated with insulin resistance. In a study conducted by Hotta et al., (2001), plasma adiponectin levels dropped in parallel to the observation of decreased insulin sensitivity in rhesus monkeys. [6] Monkeys with decreased insulin sensitivity developed type 2 diabetes.[6]
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Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states.[7] Plasma concentrations reveal a dimorphism, with females having higher levels than males. Weight reduction significantly increases circulating levels.
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Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. [7] Adiponectin has been reported to exert an antiatherosclerotic effect. [8] It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, insulin resistance, nonalcoholic fatty liver disease.[9]
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The physiological role of adiponectin has not yet been fully elucidated, but it is believed that it has the ability to reduce glucose, triglycerides, and free fatty acids. it plays a major role in the pathogenesis of metabolic syndrome. Metabolic syndrome comprises a cluster of metabolic disorders that give rise to such metabolic risk factors [10] Such as visceral obesity, insulin resistance, hyperglycaemia ,dyslipidaemia, and hypertensi
ADIPONECTIN RECEPTORS [12] •
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There are two known ones: AdipoR1 and AdipoR2 & Tcadherin. They are integral membrane proteins that have seven transmembrane domains where the N terminus is located within the cell, and the C terminus is external. AdipoR1 is a receptor that mainly binds globular adiponectin, while AdipoR2 binds to full-length adiponectin AdipoR1 is abundant in skeletal muscle. On the other hand, AdipoR2 is most expressed in the liver.
RECEPTOR •
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T-cadherin can bind to the hexameric and HMW forms of adiponectin but not to monomer globular and trimeric forms. T-cadherin is ubiquitously expressed, with the highest expression found in the heart and the aortic, carotid, iliac, and kidney arteries.
Osmotin [13] •
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potential agonist for adiponectin!! It is a plant protein that is implicated in the plant defense system. Causes apoptosis in yeast. adiponectin and osmotin were able to induce phosphorylation of AMP kinase in C2C12 myocytes.
DRUGS AFFECTING ADIPONECTIN LEVELS •
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Thiazolidinediones [14] increases adiponectin levels in all subjects, including normal subjects in which no other effects of TZDs are observed.
Insulin also appears to suppress adiponectin levels. Disease-modifying antirheumatic drugs( DMARDs) [15] increase serum adiponectin levels in patients with rheumatoid arthritis.
SUMMARY 1. adiponectin is a potent insulin sensitizing molecule. 2. The two forms (globular and full-length) bind to different receptors and have different effects. 3. Decreased levels of adiponectin induced by genetic mutations, obesity, and high fat diets lead to insulin resistance and pathological conditions such as type 2 diabetes. 4. Adiponectin activates signaling cascades that eventually increase glucose uptake by muslce, increase fatty acid oxidation by muscle and liver, and decrease gluconeogenesis in the liver. 5. In the future, Osmotin could be used as a novel therapeutic method for hypoadiponectinemia.
Adiponectin as a hormone refrence •
HORMONES 2012, 11(1):8-20
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DOI:
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Review
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Adiponectin: Regulation of its production and its role in human diseases
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Adeeb Shehzad,1 Waqas Iqbal,1 Omer Shehzad,2 Young Sup Lee1
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1School
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Abstract
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of Life Sciences, College of Natural Sciences, Kyungpook National University, Daegu, 2Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea Adiponectin is a white and brown adipose tissue hormone, also known as gelatin-binding protein-28 (GBP28), AdipoQ, adipocyte complement-related protein (ACRP30), or apM1. Adiponectin circulates in the bloodstream in trimeric, hexameric, and high-molecularmass species, while different forms of adiponectin have been found to play distinct roles in the balance of energy homoeostasis. Adiponectin is an insulin sensitizing hormone that exerts its action through its receptors AdipoR1, AdipoR2, and T-cadherin . AdipoR1 is expressed abundantly in muscle, whereas AdipoR2 is predominantly expressed in the liver. Adiponectin is inversely proportional to obesity, diabetes, and other insulin-resistant states. In this review w e present the current findings regarding the regulation of its production and several new findings pertaining to its biological effects. Adiponectin enhances AMPK and the PPARα pathway in the liver and skeletal muscle. Adiponectin increases fatty acids oxidation, which lowers circulating free fatty acids and prevents insulin resistance. Adiponectin has been reported to exert an antiatherosclerotic effect. It inhibits macrophage activation and foam cell accumulation, while it also augments endothelial nitrous oxide production and protects the vasculature by reducing platelet aggregation and vasodilation. Apart from causing metabolic dysfunction, adiponectin deficiency may also contribute to coronary heart disease, steatohepatitis, insulin resistance, nonalcoholic fatty liver disease, and a wide array of cancers. In this study, we present ample evidence that adiponectin mediates multiple molecular pathways. We therefore support the concept that it shows distinct potential for being of therapeutic value in the treatment of obesity related diseases, ranging from metabolic syndrome to malignancies.
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Keywords
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Adiponectin, Regulation, Insulin, Inflammation, Atherosclerosis, Fatty acid, Obesity, Liver disease
REFERENCE 1. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995 Nov 10;270(45):26746-9. PMID 7592907 · Lara-Castro C, Fu Y, Chung BH, Garvey WT (2007). "Adiponectin and the metabolic syndrome : mechanisms mediating risk for metabolic and cardiovascular disease". Curr. Opin. Lipidol. 18 (3): 263 –70. doi:10.1097/MOL.0b013e32814a645f . PMID 17495599. · Matsuzawa Y, Funahashi T, Kihara S, Shimomura I (2004). "Adiponectin and metabolic syndrome". Arterioscler. Thromb. Vasc. Biol. 24 (1): 29 –33. doi:10.1161/01.ATV.0000099786.99623.EF. PMID 14551151.
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2. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K (1996). "cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1)". Biochem. Biophys. Res. Commun. 221 (2): 286 –9. doi:10.1006/bbrc.1996.0587 . PMID 8619847. 3. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF, 2004 T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. Proc Natl Acad Sci USA 101: 10308-10313.
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4. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, et al. (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 13: 332 – 339. doi: 10.1038/nm1557 – – –
•
View Article PubMed/NCBI Google Scholar
5. Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, et al. (2004) Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem 279: 30817 – 30822. doi: 10.1074/jbc.m402367200 – – –
View Article PubMed/NCBI Google Scholar
6. Hotta K., et al. (2001) Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes. 50:1126 –1133 7. Cnop M. et al. (2003) Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 46: 459 –469. 8.
12. . Dalamaga M, Diakopoulos KN, Mantzoros CS (2012) The Role of Adiponectin in Cancer: A Review of Current Evidence. Endocr Rev. (ADIPONECTIN RECEPTORS) 13. Narasimhan M.L. et al. (2005) Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptors. Molecular Cell. 17(2): 171-180. 14. Diabetes. 2002 Oct;51(10):2968-74. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Yu JG1, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M, Olefsky JM.
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15. J Clin Rheumatol. 2011 Jan;17(1):14-7. doi: 10.1097/RHU.0b013e318204a587. Disease-modifying antirheumatic drugs increase serum adiponectin levels in patients with rheumatoid arthritis. Cansu B1, Cansu DU, Kaşifoğlu T, Gülbas Z, Korkmaz C. Author information Abstract BACKGROUND: Adiponectin is an adipocyte-derived adipokine with immunosuppressive and anti-inflammatory properties. It also decreases expression of adhesion molecules. In terms of its relationship with acute-phase reactants, there are conflicting results in patients with rheumatoid arthritis (RA).
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