Adiponectin

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Adiponectin, C1Q and collagen domain containing
PBB Protein ADIPOQ image.jpg
PDB rendering based on 1c28.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADIPOQ ; ACDC; ACRP30; ADIPQTL1; ADPN; APM-1; APM1; GBP28
External IDs OMIM605441 MGI106675 HomoloGene3525 GeneCards: ADIPOQ Gene
RNA expression pattern
PBB GE ADIPOQ 207175 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 9370 11450
Ensembl ENSG00000181092 ENSMUSG00000022878
UniProt Q15848 Q60994
RefSeq (mRNA) NM_001177800 NM_009605
RefSeq (protein) NP_001171271 NP_033735
Location (UCSC) Chr 3:
186.56 – 186.58 Mb
Chr 16:
23.15 – 23.16 Mb
PubMed search [1] [2]

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.

Structure[edit]

Adiponectin is a 244-amino-acid-long polypeptide. 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[edit]

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] while 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.[6]

Transgenic mice with increased adiponectin show impaired adipocyte differentiation and increased energy expenditure associated with protein uncoupling.[7] 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.[8] Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice.[9]

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.[10]

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.[11] High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.[12] However, coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.[13]

Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin,[14] but the two hormones perform complementary actions, and can have synergistic effects.

Receptors[edit]

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:[15][16]

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.[17][18]

Discovery[edit]

Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al).[19] 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 an transcript highly expressed in preadipocytes[20] (precursors of fat cells) differentiating into adipocytes.[20][21]

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][14] 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 were 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.[14][20][22][23][24][25] 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[26] 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.[27]

Phylogenetic distribution includes expression in birds[28] and fish.[29]

Metabolic[edit]

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.[30]

Hypoadiponectinemia[edit]

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

Other[edit]

Lower levels of adiponectin associated with ADHD in adults.[31]

Adiponectin levels were found to be increased in rheumatoid arthritis patients responding to DMARDs or TNF inhibitor therapy.[32]

Adiponectin prevented leptin(obesity)-induced fibrosis in mice.[citation needed]

Administration[edit]

Because this substance is a protein, oral administration of adiponectin is not effective, as enzymes in the digestive system break it down into its constituent amino-acid parts. One way to introduce the hormone into the blood stream is intravenous administration, which itself poses significant logistical challenges due to the difficulty in producing in vitro adiponectin in its most potent, "high molecular weight" form using mammalian cells.[citation needed]

Sweet potatoes are known to contain adiponectin. A scientific study has supported the idea that extracts of sweet potatoes can raise levels of adiponectin in humans.[33] Although there is doubt in the scientific community about the reliability of this evidence.[34]

References[edit]

  1. ^ Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K (April 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. 
  2. ^ Shapiro L, Scherer PE (March 1998). "The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor". Curr. Biol. 8 (6): 335–8. doi:10.1016/S0960-9822(98)70133-2. PMID 9512423. 
  3. ^ a b c d Díez JJ, Iglesias P (March 2003). "The role of the novel adipocyte-derived hormone adiponectin in human disease". Eur. J. Endocrinol. 148 (3): 293–300. doi:10.1530/eje.0.1480293. PMID 12611609. 
  4. ^ Chen J, et al. (June 2006). "Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines.". Diabetalogica 49 (6): 1292–302. doi:10.1007/s00125-006-0194-7. PMID 16570162. 
  5. ^ a b c Ukkola O, Santaniemi M (November 2002). "Adiponectin: a link between excess adiposity and associated comorbidities?". J. Mol. Med. 80 (11): 696–702. doi:10.1007/s00109-002-0378-7. PMID 12436346. 
  6. ^ 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 (July 2014). "Bone Marrow Adipose Tissue Is an Endocrine Organ that Contributes to Increased Circulating Adiponectin during Caloric Restriction.". Cell Metab 20 (2): 368–375. doi:10.1016/j.cmet.2014.06.003. PMID 24998914. 
  7. ^ a b Bauche IB, El Mkadem SA, Pottier AM, Senou M, Many MC, Rezsohazy R, Penicaud L, Maeda N, Funahashi T, Brichard SM (April 2007). "Overexpression of adiponectin targeted to adipose tissue in transgenic mice: impaired adipocyte differentiation". Endocrinology 148 (4): 1539–49. doi:10.1210/en.2006-0838. PMID 17204560. 
  8. ^ a b Renaldi O, Pramono B, Sinorita H, Purnomo LB, Asdie RH, Asdie AH (January 2009). "Hypoadiponectinemia: a risk factor for metabolic syndrome". Acta Med Indones 41 (1): 20–4. PMID 19258676. 
  9. ^ 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 (August 2001). "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity". Nat. Med. 7 (8): 941–6. doi:10.1038/90984. PMID 11479627. 
  10. ^ Coppola A, Marfella R, Coppola L, Tagliamonte E, Fontana D, Liguori E, Cirillo T, Cafiero M, Natale S, Astarita C (March 2008). "Effect of weight loss on coronary circulation and adiponectin levels in obese women". Int. J. Cardiol. 134 (3): 414–6. doi:10.1016/j.ijcard.2007.12.087. PMID 18378021. 
  11. ^ Oh DK, Ciaraldi T, Henry RR Adiponectin in health and disease. Diabetes Obes Metab 2007:9:282–289
  12. ^ Zhu N, Pankow JS, Ballantyne CM, Couper D, Hoogeveen RC, Pereira M, Duncan BB, Schmidt MI (November 2010). "High-molecular-weight adiponectin and the risk of type 2 diabetes in the ARIC study". J. Clin. Endocrinol. Metab. 95 (11): 5097–104. doi:10.1210/jc.2010-0716. PMC 2968724. PMID 20719834. 
  13. ^ 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". JOURNAL OF THE AMERICAN GERIATRIC SOCIETY 58 (4): 702–706. doi:10.1111/j.1532-5415.2010.02773.x. PMID 20398150. 
  14. ^ a b c d e f g Nedvídková J, Smitka K, Kopský V, Hainer V (2005). "Adiponectin, an adipocyte-derived protein". Physiol Res 54 (2): 133–40. PMID 15544426. 
  15. ^ 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 (June 2003). "Cloning of adiponectin receptors that mediate antidiabetic metabolic effects". Nature 423 (6941): 762–9. doi:10.1038/nature01705. PMID 12802337. 
  16. ^ 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. doi:10.1073/pnas.0403382101. PMC 478568. PMID 15210937. 
  17. ^ Fang X, Sweeney G (November 2006). "Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes". Biochem. Soc. Trans. 34 (Pt 5): 798–801. doi:10.1042/BST0340798. PMID 17052201. 
  18. ^ Bonnard C, Durand A, Vidal H, Rieusset J (February 2008). "Changes in adiponectin, its receptors and AMPK activity in tissues of diet-induced diabetic mice". Diabetes Metab. 34 (1): 52–61. doi:10.1016/j.diabet.2007.09.006. PMID 18222103. 
  19. ^ 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
  20. ^ a b c d Lara-Castro C, Fu Y, Chung BH, Garvey WT (June 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. 
  21. ^ Matsuzawa Y, Funahashi T, Kihara S, Shimomura I (January 2004). "Adiponectin and metabolic syndrome". Arterioscler. Thromb. Vasc. Biol. 24 (1): 29–33. doi:10.1161/01.ATV.0000099786.99623.EF. PMID 14551151. 
  22. ^ a b Hara K, Yamauchi T, Kadowaki T (April 2005). "Adiponectin: an adipokine linking adipocytes and type 2 diabetes in humans". Curr. Diab. Rep. 5 (2): 136–40. doi:10.1007/s11892-005-0041-0. PMID 15794918. 
  23. ^ a b c d Vasseur F, Leprêtre F, Lacquemant C, Froguel P (April 2003). "The genetics of adiponectin". Curr. Diab. Rep. 3 (2): 151–8. doi:10.1007/s11892-003-0039-4. PMID 12728641. 
  24. ^ a b Hug C, Lodish HF (April 2005). "The role of the adipocyte hormone adiponectin in cardiovascular disease". Curr Opin Pharmacol 5 (2): 129–34. doi:10.1016/j.coph.2005.01.001. PMID 15780820. 
  25. ^ 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. doi:10.1017/S1462399406000147. PMID 17112391. 
  26. ^ 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. doi:10.4162/nrp.2009.3.2.84. PMC 2788178. PMID 20016706. 
  27. ^ Grimshaw CE, Matthews DA, Varughese KI, Skinner M, Xuong NH, Bray T, Hoch J, Whiteley JM (August 1992). "Characterization and nucleotide binding properties of a mutant dihydropteridine reductase containing an aspartate 37-isoleucine replacement". J. Biol. Chem. 267 (22): 15334–9. PMID 1639779. 
  28. ^ 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. doi:10.1159/000087527. PMID 16276104. 
  29. ^ 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. doi:10.1002/dvdy.21559. PMID 18489000. 
  30. ^ Liu, M; Liu, F (2012). "Up- and down-regulation of adiponectin expression and multimerization: Mechanisms and therapeutic implication". Biochimie 94 (10): 2126–30. doi:10.1016/j.biochi.2012.01.008. PMC 3542391. PMID 22342903.  edit
  31. ^ Mavroconstanti T, Halmøy A, Haavik J (2014). "Decreased serum levels of adiponectin in adult attention deficit hyperactivity disorder". Psychiatry Research 215. doi:10.1016/j.psychres.2014.01.025. 
  32. ^ Kim KS (Jan 2014). "Serum adipokine levels in rheumatoid arthritis patients and their contributions to the resistance to treatment". J Mol Med Rep 9 (1): 255–60. doi:10.3892/mmr.2013.1764. PMID 24173909. 
  33. ^ http://www.ncbi.nlm.nih.gov/pubmed/17645559
  34. ^ http://www.ncbi.nlm.nih.gov/pubmed/24000051