Biology:Adiponectin

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.[1][2]

Structure

Adiponectin is a 244-amino-acid-long polypeptide (protein). It has four distinct regions: 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 protein shows similarity to the complement 1Q factors (C1Q), but when the three-dimensional structure of the globular region was determined, a striking similarity to TNFα was observed, despite unrelated protein sequences.[3]

Function

Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation.[4][5][6] Adiponectin is secreted from adipose tissue (and also from the placenta in pregnancy[7]) into the bloodstream and is very abundant in plasma relative to many hormones. High adiponectin levels correlate with a lower risk of diabetes mellitus type 2.[8] Plasma levels of adiponectin are lower in obese subjects than in lean subjects.[9] Many studies have found adiponectin to be inversely correlated with body mass index in patient populations.[10] However, a meta analysis was not able to confirm this association in healthy adults.[11] Circulating adiponectin concentrations increase during caloric restriction in animals and humans, such as in patients with anorexia nervosa. Furthermore, a recent study suggests that adipose tissue within bone marrow, which increases during caloric restriction, contributes to elevated circulating adiponectin in this context.[12]

Transgenic mice with increased adiponectin show reduced adipocyte differentiation and increased energy expenditure associated with mitochondrial uncoupling.[13] The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes,[10] obesity, atherosclerosis,[6] non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome.[14] Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice.[15] Adiponectin enhances insulin sensitivity primarily though regulation of fatty acid oxidation and suppression of hepatic glucose production .[16]

Adiponectin is secreted into the bloodstream, where it accounts for about 0.01% of all plasma protein at around 5-10 μg/mL. In adults, plasma concentrations are higher in females than males, and are reduced in diabetics compared to nondiabetics. Weight reduction significantly increases circulating concentrations.[17]

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.[9] High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.[18] However, coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.[19]

Adiponectin exerts some of its weight-reduction effects via the brain. This is similar to the action of leptin;[20] adiponectin and leptin can act synergistically.

Adiponectin promoted synaptic and memory function in the brain.[21] Humans with lower levels of adiponectin have reduced cognitive function.[21]

Receptors

Main page: Biology:Adiponectin receptor

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:[22][23]

These have distinct tissue specificities within the body and have different affinities to the various forms of adiponectin. AdipoR1 is enriched in skeletal muscle, whereas AdipoR2 is enriched in liver.[2] Six months of exercise has been shown in rats to double muscle AdipoR1.[2]

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.[24][25]

In 2016, the University of Tokyo announced that it would launch an investigation into claims of fabrication of AdipoR1 and AdipoR2 identification data, as accused by an anonymous person/group called Ordinary researchers.[26]

Discovery

Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al.).[27] In 1996 it was characterised in mice as the mRNA transcript most highly expressed in adipocytes.[1] In 2007, adiponectin was identified as a transcript highly expressed in preadipocytes[28] (precursors of fat cells) differentiating into adipocytes.[28][29]

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.[6][10][20][5] 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.[20][28][30][31][32][33] 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 isoquinoline alkaloid, has been shown to increase adiponectin expression,[34] 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.[35] Curcumin, capsaicin, gingerol, and catechins have also been found to increase adiponectin expression.[36]

Phylogenetic distribution includes expression in birds[37] and fish.[38]

Metabolic

Adiponectin effects:

Regulation of adiponectin

  • Obesity is associated with decreased adiponectin.[5]
    • The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.[40]

Hypoadiponectinemia

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

Other

Lower levels of adiponectin are associated with ADHD in adults.[42]

Adiponectin levels were found to be increased in rheumatoid arthritis patients responding to DMARDs or TNF inhibitor therapy.[43]

A low adiponectin to leptin ratio has been found in patients with COVID-19 pneumonia compared to healthy controls.[44]

Exercise induced release of adiponectin increased hippocampal growth and led to antidepressive symptoms in mice.[45]

Several studies have found a positive correlation in caffeine consumption and increased adiponectin levels, although the mechanism for this is unknown and requires more research.[46]

As a medication target

Circulating levels of adiponectin can indirectly be increased through lifestyle modifications and certain medications such as statins.[47]

A small molecule adiponectin receptor AdipoR1 and AdipoR2 agonist, AdipoRon, has been reported.[48] In 2016, the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on AdipoR1, AdipoR2, and AdipoRon.[26]

Extracts of sweet potatoes have been reported to increase levels of adiponectin and thereby improve glycemic control in humans.[49] However, a systematic review concluded there is insufficient evidence to support the consumption of sweet potatoes to treat type 2 diabetes mellitus.[50]

Adiponectin is apparently able to cross the blood-brain-barrier.[45] However, conflicting data on this issue exist.[51] Adiponectin has a half-life of 2.5 hours in humans.[52]

References

  1. ↑ 1.0 1.1 "cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1)". Biochemical and Biophysical Research Communications 221 (2): 286–289. April 1996. doi:10.1006/bbrc.1996.0587. PMID 8619847. 
  2. ↑ 2.0 2.1 2.2 "Skeletal muscle adiponectin induction in obesity and exercise". Metabolism 102: 154008. January 2020. doi:10.1016/j.metabol.2019.154008. PMID 31706980. 
  3. ↑ "The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor". Current Biology 8 (6): 335–338. March 1998. doi:10.1016/S0960-9822(98)70133-2. PMID 9512423. 
  4. ↑ 4.0 4.1 4.2 "Adiponectin Genetic Variant and Expression Coupled with Lipid Peroxidation Reveal New Signatures in Diabetic Dyslipidemia". Biochemical Genetics 59 (3): 781–798. June 2021. doi:10.1007/s10528-021-10030-5. PMID 33543406. 
  5. ↑ 5.0 5.1 5.2 5.3 "Adiponectin: Probe of the molecular paradigm associating diabetes and obesity". World J Diabetes 15 (6(1)): 151–166. February 2015. doi:10.4239/wjd.v6.i1.151. PMID 25685286. 
  6. ↑ 6.0 6.1 6.2 6.3 "The role of the novel adipocyte-derived hormone adiponectin in human disease". European Journal of Endocrinology 148 (3): 293–300. March 2003. doi:10.1530/eje.0.1480293. PMID 12611609. 
  7. ↑ "Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines". Diabetologia 49 (6): 1292–1302. June 2006. doi:10.1007/s00125-006-0194-7. PMID 16570162. 
  8. ↑ "Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis". JAMA 302 (2): 179–188. July 2009. doi:10.1001/jama.2009.976. PMID 19584347. 
  9. ↑ 9.0 9.1 "Adiponectin in health and disease". Diabetes, Obesity & Metabolism 9 (3): 282–289. May 2007. doi:10.1111/j.1463-1326.2006.00610.x. PMID 17391153. 
  10. ↑ 10.0 10.1 10.2 "Adiponectin: a link between excess adiposity and associated comorbidities?". Journal of Molecular Medicine 80 (11): 696–702. November 2002. doi:10.1007/s00109-002-0378-7. PMID 12436346. 
  11. ↑ "Lack of association between body mass index and plasma adiponectin levels in healthy adults". International Journal of Obesity 35 (12): 1487–1494. December 2011. doi:10.1038/ijo.2011.20. PMID 21364526. 
  12. ↑ "Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction". Cell Metabolism 20 (2): 368–375. August 2014. doi:10.1016/j.cmet.2014.06.003. PMID 24998914. 
  13. ↑ 13.0 13.1 "Overexpression of adiponectin targeted to adipose tissue in transgenic mice: impaired adipocyte differentiation". Endocrinology 148 (4): 1539–1549. April 2007. doi:10.1210/en.2006-0838. PMID 17204560. 
  14. ↑ 14.0 14.1 "Hypoadiponectinemia: a risk factor for metabolic syndrome". Acta Medica Indonesiana 41 (1): 20–24. January 2009. PMID 19258676. 
  15. ↑ "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity". Nature Medicine 7 (8): 941–946. August 2001. doi:10.1038/90984. PMID 11479627. 
  16. ↑ "Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease?". Cardiovascular Diabetology 13 (1): 103. June 2014. doi:10.1186/1475-2840-13-103. PMID 24957699. 
  17. ↑ "Effect of weight loss on coronary circulation and adiponectin levels in obese women". International Journal of Cardiology 134 (3): 414–416. May 2009. doi:10.1016/j.ijcard.2007.12.087. PMID 18378021. 
  18. ↑ "High-molecular-weight adiponectin and the risk of type 2 diabetes in the ARIC study". The Journal of Clinical Endocrinology and Metabolism 95 (11): 5097–5104. November 2010. doi:10.1210/jc.2010-0716. PMID 20719834. 
  19. ↑ "Adiponectin isoforms in elderly patients with or without coronary artery disease". Journal of the American Geriatrics Society 58 (4): 702–706. April 2010. doi:10.1111/j.1532-5415.2010.02773.x. PMID 20398150. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 "Adiponectin, an adipocyte-derived protein". Physiological Research 54 (2): 133–140. 2005. doi:10.33549/physiolres.930600. PMID 15544426. http://www.biomed.cas.cz/physiolres/pdf/54/54_133.pdf. 
  21. ↑ 21.0 21.1 "The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer's Disease". Frontiers in Neuroscience 12: 1027. 2019. doi:10.3389/fnins.2018.01027. PMID 30692905. 
  22. ↑ "Cloning of adiponectin receptors that mediate antidiabetic metabolic effects". Nature 423 (6941): 762–769. June 2003. doi:10.1038/nature01705. PMID 12802337. Bibcode: 2003Natur.423..762Y. 
  23. ↑ "T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin". Proceedings of the National Academy of Sciences of the United States of America 101 (28): 10308–10313. July 2004. doi:10.1073/pnas.0403382101. PMID 15210937. Bibcode: 2004PNAS..10110308H. 
  24. ↑ "Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes". Biochemical Society Transactions 34 (Pt 5): 798–801. November 2006. doi:10.1042/BST0340798. PMID 17052201. 
  25. ↑ "Changes in adiponectin, its receptors and AMPK activity in tissues of diet-induced diabetic mice". Diabetes & Metabolism 34 (1): 52–61. February 2008. doi:10.1016/j.diabet.2007.09.006. PMID 18222103. 
  26. ↑ 26.0 26.1 University of Tokyo to investigate data manipulation charges against six prominent research groups ScienceInsider, Dennis Normile, Sep 20, 2016
  27. ↑ "A novel serum protein similar to C1q, produced exclusively in adipocytes". The Journal of Biological Chemistry 270 (45): 26746–26749. November 1995. doi:10.1074/jbc.270.45.26746. PMID 7592907. 
  28. ↑ 28.0 28.1 28.2 28.3 "Adiponectin and the metabolic syndrome: mechanisms mediating risk for metabolic and cardiovascular disease". Current Opinion in Lipidology 18 (3): 263–270. June 2007. doi:10.1097/MOL.0b013e32814a645f. PMID 17495599. 
  29. ↑ "Adiponectin and metabolic syndrome". Arteriosclerosis, Thrombosis, and Vascular Biology 24 (1): 29–33. January 2004. doi:10.1161/01.ATV.0000099786.99623.EF. PMID 14551151. 
  30. ↑ 30.0 30.1 "Adiponectin: an adipokine linking adipocytes and type 2 diabetes in humans". Current Diabetes Reports 5 (2): 136–140. April 2005. doi:10.1007/s11892-005-0041-0. PMID 15794918. 
  31. ↑ 31.0 31.1 31.2 31.3 "The genetics of adiponectin". Current Diabetes Reports 3 (2): 151–158. April 2003. doi:10.1007/s11892-003-0039-4. PMID 12728641. 
  32. ↑ 32.0 32.1 "The role of the adipocyte hormone adiponectin in cardiovascular disease". Current Opinion in Pharmacology 5 (2): 129–134. April 2005. doi:10.1016/j.coph.2005.01.001. PMID 15780820. https://zenodo.org/record/895583. 
  33. ↑ 33.0 33.1 "Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies". Expert Reviews in Molecular Medicine 8 (27): 1–12. November 2006. doi:10.1017/S1462399406000147. PMID 17112391. 
  34. ↑ "The inhibition of inflammatory molecule expression on 3T3-L1 adipocytes by berberine is not mediated by leptin signaling". Nutrition Research and Practice 3 (2): 84–88. 2009. doi:10.4162/nrp.2009.3.2.84. PMID 20016706. 
  35. ↑ "Characterization and nucleotide binding properties of a mutant dihydropteridine reductase containing an aspartate 37-isoleucine replacement". The Journal of Biological Chemistry 267 (22): 15334–15339. August 1992. doi:10.1016/S0021-9258(19)49538-0. PMID 1639779. 
  36. ↑ "New insight into adiponectin role in obesity and obesity-related diseases". BioMed Research International 2014: 658913. 2014. doi:10.1155/2014/658913. PMID 25110685. 
  37. ↑ "cDNA cloning, genomic structure, chromosomal mapping and expression analysis of ADIPOQ (adiponectin) in chicken". Cytogenetic and Genome Research 112 (1–2): 148–151. 2006. doi:10.1159/000087527. PMID 16276104. 
  38. ↑ "Adiponectin and adiponectin receptor genes are coexpressed during zebrafish embryogenesis and regulated by food deprivation". Developmental Dynamics 237 (6): 1682–1690. June 2008. doi:10.1002/dvdy.21559. PMID 18489000. 
  39. ↑ "The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism". Metabolism 100: 153953. November 2019. doi:10.1016/j.metabol.2019.153953. PMID 31377319. 
  40. ↑ "Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication". Biochimie 94 (10): 2126–2130. October 2012. doi:10.1016/j.biochi.2012.01.008. PMID 22342903. 
  41. ↑ Iwashima, Yoshio; Katsuya, Tomohiro; Ishikawa, Kazuhiko; Ouchi, Noriyuki; Ohishi, Mitsuru; Sugimoto, Ken; Fu, Yuxiao; Motone, Masaharu et al. (June 2004). "Hypoadiponectinemia Is an Independent Risk Factor for Hypertension" (in en). Hypertension 43 (6): 1318–1323. doi:10.1161/01.HYP.0000129281.03801.4b. ISSN 0194-911X. PMID 15123570. 
  42. ↑ "Decreased serum levels of adiponectin in adult attention deficit hyperactivity disorder". Psychiatry Research 216 (1): 123–130. April 2014. doi:10.1016/j.psychres.2014.01.025. PMID 24559850. 
  43. ↑ "Serum adipokine levels in rheumatoid arthritis patients and their contributions to the resistance to treatment". Molecular Medicine Reports 9 (1): 255–260. January 2014. doi:10.3892/mmr.2013.1764. PMID 24173909. 
  44. ↑ "Discriminatory Value of Adiponectin to Leptin Ratio for COVID-19 Pneumonia" (in en). International Journal of Endocrinology 2022: 1–9. 2022-04-26. doi:10.1155/2022/9908450. ISSN 1687-8345. PMID 35529082. 
  45. ↑ 45.0 45.1 "Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin". Proceedings of the National Academy of Sciences of the United States of America 111 (44): 15810–15815. November 2014. doi:10.1073/pnas.1415219111. PMID 25331877. Bibcode: 2014PNAS..11115810Y. 
  46. ↑ "Coffee and metabolic impairment: An updated review of epidemiological studies" (in en). NFS Journal 3: 1–7. 2016-08-01. doi:10.1016/j.nfs.2016.02.001. ISSN 2352-3646. 
  47. ↑ "Modulation of adiponectin as a potential therapeutic strategy". Atherosclerosis 233 (2): 721–728. April 2014. doi:10.1016/j.atherosclerosis.2014.01.051. PMID 24603219. 
  48. ↑ "A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity". Nature 503 (7477): 493–499. November 2013. doi:10.1038/nature12656. PMID 24172895. Bibcode: 2013Natur.503..493O. 
  49. ↑ "Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects". Diabetes, Obesity & Metabolism 10 (7): 586–592. July 2008. doi:10.1111/j.1463-1326.2007.00752.x. PMID 17645559. 
  50. ↑ "Sweet potato for type 2 diabetes mellitus". The Cochrane Database of Systematic Reviews 9 (9): CD009128. September 2013. doi:10.1002/14651858.CD009128.pub3. PMID 24000051. 
  51. ↑ "Adiponectin does not cross the blood-brain barrier but modifies cytokine expression of brain endothelial cells". Diabetes 55 (1): 141–147. January 2006. doi:10.2337/diabetes.55.1.141. PMID 16380487. 
  52. ↑ "Adipose tissue adiponectin production and adiponectin serum concentration in human obesity and insulin resistance". The Journal of Clinical Endocrinology and Metabolism 89 (3): 1391–1396. March 2004. doi:10.1210/jc.2003-031458. PMID 15001639. 

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