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Adiponectin

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Adiponectin

Adiponectin, C1Q and collagen domain containing
PDB rendering based on 1c28.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; ACDC; ACRP30; ADIPQTL1; ADPN; APM-1; APM1; GBP28
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein which in humans is encoded by the ADIPOQ gene.[1] It is involved in regulating glucose levels as well as fatty acid breakdown.

Contents

  • Structure 1
  • Function 2
  • Receptors 3
  • Discovery 4
  • Metabolic 5
  • Hypoadiponectinemia 6
  • Other 7
    • As a drug target 7.1
  • References 8

Structure

Adiponectin is a 244-amino-acid-long polypeptide (protein). There are four distinct regions of adiponectin. The first is a short signal sequence that targets the hormone for secretion outside the cell; next is a short region that varies between species; the third is a 65-amino acid region with similarity to collagenous proteins; the last is a globular domain. Overall this gene shows similarity to the complement 1Q factors (C1Q). However, when the 3-dimensional structure of the globular region was determined, a striking similarity to TNFα was observed, despite unrelated protein sequences.[2]

Function

Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation.[3] Adiponectin is exclusively secreted from adipose tissue (and also from the placenta in pregnancy[4]) into the bloodstream and is very abundant in plasma relative to many hormones. Levels of the hormone are inversely correlated with body fat percentage in adults; [5] however, a meta analysis was not able to confirm this association in healthy adults.[6] The association in infants and young children is less clear. Similarly, circulating adiponectin concentrations increase during caloric restriction in animals and humans, such as in patients with anorexia nervosa. This observation is surprising, given that adiponectin is produced by adipose tissue; however, a recent study suggests that adipose tissue within bone marrow, which increases during caloric restriction, contributes to elevated circulating adiponectin in this context.[7]

Transgenic mice with increased adiponectin show impaired adipocyte differentiation and increased energy expenditure associated with protein uncoupling.[8] The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes,[5] obesity, atherosclerosis,[3] non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome.[9] Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice.[10]

Adiponectin is secreted into the bloodstream where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL. Plasma concentrations reveal a sexual dimorphism, with females having higher levels than males. Levels of adiponectin are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating levels.[11]

Adiponectin automatically self-associates into larger structures. Initially, three adiponectin molecules bind together to form a homotrimer. The trimers continue to self-associate and form hexamers or dodecamers. Like the plasma concentration, the relative levels of the higher-order structures are sexually dimorphic, where females have increased proportions of the high-molecular weight forms. Recent studies showed that the high-molecular weight form may be the most biologically active form regarding glucose homeostasis.[12] High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.[13] However, coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.[14]

Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin,[15] but the two hormones perform complementary actions, and can have synergistic effects.

Receptors

Adiponectin binds to a number of receptors. So far, two receptors have been identified with homology to G protein-coupled receptors, and one receptor similar to the cadherin family:[16][17]

These have distinct tissue specificities within the body and have different affinities to the various forms of adiponectin. The receptors affect the downstream target AMP kinase, an important cellular metabolic rate control point. Expression of the receptors is correlated with insulin levels, as well as reduced in mouse models of diabetes, particularly in skeletal muscle and adipose tissue.[18][19]

Discovery

Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al).[20] In 1996 it was characterised in mice as the mRNA transcript most highly expressed in adipocytes (Maeda, 1996 (citation #1, below)). In 2007, adiponectin was identified as a transcript highly expressed in preadipocytes[21] (precursors of fat cells) differentiating into adipocytes.[21][22]

The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in adipose tissue, adiponectin was found to be decreased in obesity.[3][5][15] This downregulation has not been fully explained. The gene was localised to chromosome 3q27, a region highlighted as affecting genetic susceptibility to type 2 diabetes and obesity. Supplementation by differing forms of adiponectin was able to improve insulin control, blood glucose and triglyceride levels in mouse models.

The gene was investigated for variants that predispose to type 2 diabetes.[15][21][23][24][25][26] Several single nucleotide polymorphisms in the coding region and surrounding sequence were identified from several different populations, with varying prevalences, degrees of association and strength of effect on type 2 diabetes. Berberine, an herbal folk medicine, has been shown to increase adiponectin expression[27] which partly explains its beneficial effects on metabolic disturbances. Mice fed the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown increased plasma adiponectin.[28]

Phylogenetic distribution includes expression in birds[29] and fish.[30]

Metabolic

Adiponectin effects:

Regulation of adiponectin

  • Obesity is associated with decreased adiponectin.
    • The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.[31]

Hypoadiponectinemia

A low level of adiponectin is an independent risk factor for developing:

Other

Lower levels of adiponectin are associated with ADHD in adults.[32]

Adiponectin levels were found to be increased in rheumatoid arthritis patients responding to DMARDs or TNF inhibitor therapy.[33]

Exercise induced release of adiponectin increased hippocampal growth and led to antidepressive symptoms in mice.[34]

As a drug target

Circulating levels of adiponectin can indirectly be increased through lifestyle modifications and certain drugs such as statins.[35]

A small molecule adiponectin receptor (ADIPOR1 and ADIPOR2) agonist (AdipoRon) has been reported.[36]

Extracts of sweet potatoes have been reported to increase levels of adiponectin and thereby improve glycemic control in humans.[37] However, a systematic review concluded there is insufficient evidence to support the consumption of sweet potatoes to treat type 2 diabetes mellitus.[38]

References

  1. ^ 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.  
  2. ^ Shapiro L, Scherer PE (1998). "The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor". Curr. Biol. 8 (6): 335–8.  
  3. ^ a b c d Díez JJ, Iglesias P (2003). "The role of the novel adipocyte-derived hormone adiponectin in human disease". Eur. J. Endocrinol. 148 (3): 293–300.  
  4. ^ Chen J, Tan B, Karteris E, Zervou S, Digby J, Hillhouse EW, Vatish M, Randeva HS (2006). "Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines". Diabetologia 49 (6): 1292–302.  
  5. ^ a b c Ukkola O, Santaniemi M (2002). "Adiponectin: a link between excess adiposity and associated comorbidities?". J. Mol. Med. 80 (11): 696–702.  
  6. ^ Kuo SM, Halpern MM (2011). "Lack of association between body mass index and plasma adiponectin levels in healthy adults". Int J Obes (Lond) 35 (12): 1487–94.  
  7. ^ Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, Ning X, Bree AJ, Schell B, Broome DT, Soliman SS, DelProposto JL, Lumeng CN, Mitra A, Pandit SV, Gallagher KA, Miller JD, Krishnan V, Hui SK, Bredella MA, Fazeli PK, Klibanski A, Horowitz MC, Rosen CJ, MacDougald OA (2014). "Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction". Cell Metab. 20 (2): 368–375.  
  8. ^ a b Bauche IB, El Mkadem SA, Pottier AM, Senou M, Many MC, Rezsohazy R, Penicaud L, Maeda N, Funahashi T, Brichard SM (2007). "Overexpression of adiponectin targeted to adipose tissue in transgenic mice: impaired adipocyte differentiation". Endocrinology 148 (4): 1539–49.  
  9. ^ a b Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, Asdie AH (2009). "Hypoadiponectinemia: a risk factor for metabolic syndrome". Acta Med Indones 41 (1): 20–4.  
  10. ^ Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T (2001). "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity". Nat. Med. 7 (8): 941–6.  
  11. ^ Coppola A, Marfella R, Coppola L, Tagliamonte E, Fontana D, Liguori E, Cirillo T, Cafiero M, Natale S, Astarita C (2009). "Effect of weight loss on coronary circulation and adiponectin levels in obese women". Int. J. Cardiol. 134 (3): 414–6.  
  12. ^ Oh DK, Ciaraldi T, Henry RR Adiponectin in health and disease. Diabetes Obes Metab 2007:9:282–289
  13. ^ Zhu N, Pankow JS, Ballantyne CM, Couper D, Hoogeveen RC, Pereira M, Duncan BB, Schmidt MI (2010). "High-molecular-weight adiponectin and the risk of type 2 diabetes in the ARIC study". J. Clin. Endocrinol. Metab. 95 (11): 5097–104.  
  14. ^ Rizza S, Gigli F, Galli A, Micchelini B, Lauro D, Lauro R, Federici M (2010). "Adiponectin isoforms in elderly patients with or without coronary artery disease". J Am Geriatr Soc 58 (4): 702–706.  
  15. ^ a b c d e f g Nedvídková J, Smitka K, Kopský V, Hainer V (2005). "Adiponectin, an adipocyte-derived protein" (PDF). Physiol Res 54 (2): 133–40.  
  16. ^ Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T (2003). "Cloning of adiponectin receptors that mediate antidiabetic metabolic effects". Nature 423 (6941): 762–9.  
  17. ^ 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. U.S.A. 101 (28): 10308–13.  
  18. ^ Fang X, Sweeney G (2006). "Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes". Biochem. Soc. Trans. 34 (Pt 5): 798–801.  
  19. ^ Bonnard C, Durand A, Vidal H, Rieusset J (2008). "Changes in adiponectin, its receptors and AMPK activity in tissues of diet-induced diabetic mice". Diabetes Metab. 34 (1): 52–61.  
  20. ^ 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
  21. ^ a b c d 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.  
  22. ^ Matsuzawa Y, Funahashi T, Kihara S, Shimomura I (2004). "Adiponectin and metabolic syndrome". Arterioscler. Thromb. Vasc. Biol. 24 (1): 29–33.  
  23. ^ a b Hara K, Yamauchi T, Kadowaki T (2005). "Adiponectin: an adipokine linking adipocytes and type 2 diabetes in humans". Curr. Diab. Rep. 5 (2): 136–40.  
  24. ^ a b c d Vasseur F, Leprêtre F, Lacquemant C, Froguel P (2003). "The genetics of adiponectin". Curr. Diab. Rep. 3 (2): 151–8.  
  25. ^ a b Hug C, Lodish HF (2005). "The role of the adipocyte hormone adiponectin in cardiovascular disease". Curr Opin Pharmacol 5 (2): 129–34.  
  26. ^ a b Vasseur F, Meyre D, Froguel P (2006). "Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies". Expert Rev Mol Med 8 (27): 1–12.  
  27. ^ Choi BH, Kim YH, Ahn IS, Ha JH, Byun JM, Do MS (2009). "The inhibition of inflammatory molecule expression on 3T3-L1 adipocytes by berberine is not mediated by leptin signaling". Nutr Res Pract 3 (2): 84–8.  
  28. ^ Grimshaw CE, Matthews DA, Varughese KI, Skinner M, Xuong NH, Bray T, Hoch J, Whiteley JM (1992). "Characterization and nucleotide binding properties of a mutant dihydropteridine reductase containing an aspartate 37-isoleucine replacement". J. Biol. Chem. 267 (22): 15334–9.  
  29. ^ Yuan J, Liu W, Liu ZL, Li N (2006). "cDNA cloning, genomic structure, chromosomal mapping and expression analysis of ADIPOQ (adiponectin) in chicken". Cytogenet. Genome Res. 112 (1-2): 148–51.  
  30. ^ Nishio S, Gibert Y, Bernard L, Brunet F, Triqueneaux G, Laudet V (2008). "Adiponectin and adiponectin receptor genes are coexpressed during zebrafish embryogenesis and regulated by food deprivation". Dev. Dyn. 237 (6): 1682–90.  
  31. ^ Liu M, Liu F (2012). "Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication". Biochimie 94 (10): 2126–30.  
  32. ^ Mavroconstanti T, Halmøy A, Haavik J (2014). "Decreased serum levels of adiponectin in adult attention deficit hyperactivity disorder". Psychiatry Res 216 (1).  
  33. ^ Kim KS, Choi HM, Ji HI, Song R, Yang HI, Lee SK, Yoo MC, Park YB (2014). "Serum adipokine levels in rheumatoid arthritis patients and their contributions to the resistance to treatment". Mol Med Rep 9 (1): 255–60.  
  34. ^ Yau SY, Li A, Hoo RL, Ching YP, Christie BR, Lee TM, Xu A, So KF (2014). "Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin". Proc. Natl. Acad. Sci. U.S.A. 111 (44): 15810–15815.  
  35. ^ Lim S, Quon MJ, Koh KK (Apr 2014). "Modulation of adiponectin as a potential therapeutic strategy". Atherosclerosis 233 (2).  
  36. ^ Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M, Ogata H, Tokuyama K, Ueki K, Nagano T, Tanaka A, Yokoyama S, Kadowaki T (Nov 2013). "A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity". Nature 503 (7477).  
  37. ^ Ludvik B, Hanefeld M, Pacini G (2008). "Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects". Diabetes Obes Metab 10 (7): 586–92.  
  38. ^ Ooi CP, Loke SC (2013). "Sweet potato for type 2 diabetes mellitus". Cochrane Database Syst Rev 9: CD009128.  
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