Resistin

RETN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesRETN, ADSF, FIZZ3, RETN1, RSTN, XCP1, resistin
External IDsOMIM: 605565; MGI: 1888506; HomoloGene: 10703; GeneCards: RETN; OMA:RETN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

56729

57264

Ensembl

ENSG00000104918

ENSMUSG00000012705

UniProt

Q9HD89

Q99P87

RefSeq (mRNA)

NM_020415
NM_001193374
NM_001385725
NM_001385726
NM_001385727

NM_001204959
NM_022984

RefSeq (protein)

NP_001180303
NP_065148

NP_001191888
NP_075360

Location (UCSC)Chr 19: 7.67 – 7.67 MbChr 8: 3.71 – 3.71 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Resistin, also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1), is a cysteine-rich peptide hormone that is derived from adipose tissue and, in humans, is encoded by the RETN gene.[5]

In primates, pigs, and dogs, resistin is secreted primarily by immune and epithelial cells, whereas in rodents, it is mainly secreted by adipose tissue. The human resistin pre-peptide consists of 108 amino acid residues, while in mice and rats it is 114 amino acids in length; the molecular weight is approximately 12.5 kDa. Resistin is classified as an adipose-derived hormone (similar to a cytokine), and its physiological role has been widely debated, particularly regarding its involvement in obesity and type II diabetes mellitus (T2DM).[6]

Discovery and structure

Resistin was discovered in 2001 and identified as a hormone produced by adipose tissue, with a role in promoting insulin resistance.[7] Specifically, elevated resistin levels appear to interfere with the action of insulin on adipose cells.[7][8][9] Subsequent studies noted a link between resistin and activation of pro-inflammatory cytokines.[10][11]

Resistin
Identifiers
SymbolResistin
PfamPF06954
InterProIPR009714
SCOP21rgx / SCOPe / SUPFAM
OPM superfamily384
OPM protein1rgx
Available protein structures:
PDB  IPR009714 PF06954 (ECOD; PDBsum)  
AlphaFold

Resistin is a cysteine-rich, secreted peptide hormone characterized by a unique multimeric structure. Each resistin monomer consists of a C-terminal, disulfide-rich beta-sandwich "head" domain and an N-terminal alpha-helical "tail" segment.[12][13] The head domain adopts a six-stranded jelly-roll topology, forming two three-stranded antiparallel beta-sheets, while the tail segments associate to create three-stranded coiled coils.[12][13] These monomers assemble into trimers, and further interchain disulfide linkages mediate the formation of tail-to-tail hexamers, resulting in a multimeric assembly stabilized by disulfide bonds.[12][13] In circulation, resistin exists in multiple assembly states, including high-molecular-mass hexamers and lower-molecular-mass trimers, with the oligomeric form in humans showing greater proinflammatory activity.[12] This structural organization is highly conserved within the resistin-like molecule family of peptide hormones.[12][13]

Function

Resistin is a multifunctional hormone that plays critical roles in metabolic regulation, inflammation, and innate immunity. In humans, resistin is primarily expressed by immune cells such as monocytes and macrophages, where it acts as a pro-inflammatory cytokine by stimulating the production of cytokines including IL-6, IL-1β, and TNF-α through activation of signaling pathways involving the TLR4 and CAP1 receptors.[12][14]

Beyond its pro-inflammatory effects, resistin also demonstrates direct antimicrobial activity by damaging bacterial membranes, and it modulates immune responses by recruiting and activating immune cells, promoting chemokine production, and enhancing the formation of neutrophil extracellular traps (NETs).[12] Notably, resistin exhibits bidirectional immunomodulatory properties: while it can amplify inflammation in response to certain stimuli, it can also attenuate excessive inflammatory responses triggered by bacterial products such as lipopolysaccharide (LPS), potentially by competing for TLR4 binding or directly neutralizing LPS.[12] This dual functionality positions resistin as an important regulator of host defense and inflammatory balance in both health and disease.[12]

Clinical significance

Obesity and insulin resistance

Much of what is hypothesized about a resistin role in energy metabolism and T2DM can be derived from studies showing strong correlations between resistin and obesity, the premise being that serum resistin levels increase with increased adiposity.[11][15][16] Conversely, serum resistin levels to decline with decreased adiposity following medical treatment.[17] Specifically, central obesity (waistline adipose tissue) is the region of adipose tissue that contributes most to rising levels of serum resistin.[18] This is significant, considering the link between central obesity and insulin resistance, two marked peculiarities of T2DM.[19] On the other hand, at least one study has found no correlation between resistin levels and obesity or insulin resistance in humans,[20] so the resistin–insulin resistance connection may be regarded as somewhat unsettled.

Although resistin levels increase with obesity, it is questioned whether this increase is responsible for the insulin resistance associated with increased adiposity. Several reports have shown a positive correlation between resistin levels and insulin resistance.[21][22][23][24] This is supported by reports of correlation between resistin levels and subjects with T2DM.[7][15][25][26] If resistin contributes to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects may deliver therapeutic benefits.[27]

Resistin can increase levels of circulating low-density lipoprotein (LDL) and accelerates LDL accumulation in arteries, increasing risk of heart disease has an adverse impact on the efficacy of statins, the primary drug used to reduce cholesterol in fighting of cardiovascular disease.[28] In the liver, resistin increases LDL production and degrades LDL receptors, impairing the ability to process LDL.

Inflammation

Beyond its role as a hormone, resistin also contributes to inflammation.[29][30][31] Interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) are up-regulated by resistin in an NF-κB-mediated fashion.[32] Likewise, in vitro studies show Toll-like receptor 2 expression is increased by resistin.[29] It has also been demonstrated that resistin upregulates vascular cell-adhesion molecule-1 (VCAM1), involved in chemotactic movement of leukocytes to sites of infection.[33] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[34] which are recognized by leukocytes. Together, these findings suggest resistin may be a link in the well-known association between inflammation and insulin resistance.[35]

Resistin also seems to be a marker of inflammation in semen. Resistin levels correlate positively with those of proinflammatory mediators such as interleukin-6 (IL-6), elastase and tumor necrosis factor-α (TNF-α) in seminal plasma. During inflammation, the concentrations of cytokines and ROS increase, and this may have a deleterious effect on the male reproductive function.[36] One study showed that there was a negative correlation between the concentrations of seminal resistin and spermatic motility and vitality.[37]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000104918 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000012705 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Wang H, Chu WS, Hemphill C, Elbein SC (June 2002). "Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians". The Journal of Clinical Endocrinology and Metabolism. 87 (6): 2520–2524. doi:10.1210/jcem.87.6.8528. PMID 12050208.
  6. ^ Lazar MA (October 2007). "Resistin- and Obesity-associated metabolic diseases". Hormone and Metabolic Research. 39 (10): 710–716. doi:10.1055/s-2007-985897. PMID 17952831.
  7. ^ a b c Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. (January 2001). "The hormone resistin links obesity to diabetes". Nature. 409 (6818): 307–312. Bibcode:2001Natur.409..307S. doi:10.1038/35053000. PMID 11201732. S2CID 4358808.
  8. ^ Levy JR, Davenport B, Clore JN, Stevens W (March 2002). "Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats". American Journal of Physiology. Endocrinology and Metabolism. 282 (3): E626–E633. doi:10.1152/ajpendo.00346.2001. PMID 11832366. S2CID 25303054.
  9. ^ McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S (January 2002). "Resistin, central obesity, and type 2 diabetes". Lancet. 359 (9300). London, England: 46–47. doi:10.1016/S0140-6736(02)07281-1. PMID 11809189. S2CID 21927880.
  10. ^ Adeghate E (October 2004). "An update on the biology and physiology of resistin". Cellular and Molecular Life Sciences. 61 (19–20): 2485–2496. doi:10.1007/s00018-004-4083-2. PMC 11924563. PMID 15526156. S2CID 22832421.
  11. ^ a b Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, et al. (June 2004). "Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity". Obesity Research. 12 (6): 962–971. doi:10.1038/oby.2004.118. PMID 15229336.
  12. ^ a b c d e f g h i Li Y, Yang Q, Cai D, Guo H, Fang J, Cui H, et al. (2021). "Resistin, a Novel Host Defense Peptide of Innate Immunity". Frontiers in Immunology. 12 699807. doi:10.3389/fimmu.2021.699807. PMC 8253364. PMID 34220862.
  13. ^ a b c d Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L (May 2004). "Disulfide-dependent multimeric assembly of resistin family hormones". Science. 304 (5674). New York, N.Y.: 1154–1158. Bibcode:2004Sci...304.1154P. doi:10.1126/science.1093466. PMID 15155948.
  14. ^ Lee S, Lee HC, Kwon YW, Lee SE, Cho Y, Kim J, et al. (March 2014). "Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes". Cell Metabolism. 19 (3): 484–97. doi:10.1016/j.cmet.2014.01.013. PMC 3969988. PMID 24606903.
  15. ^ a b Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P (May 2004). "Changes in glycemia by leptin administration or high- fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis". Endocrinology. 145 (5): 2206–2213. doi:10.1210/en.2003-1679. PMID 14962997.
  16. ^ Lee JH, Bullen JW, Stoyneva VL, Mantzoros CS (March 2005). "Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia". American Journal of Physiology. Endocrinology and Metabolism. 288 (3): E625–E632. doi:10.1152/ajpendo.00184.2004. PMID 15522996. S2CID 20609673.
  17. ^ Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, et al. (April 2004). "Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines". Metabolism: Clinical and Experimental. 53 (4): 430–434. doi:10.1016/j.metabol.2003.11.022. PMID 15045687.
  18. ^ McTernan PG, McTernan CL, Chetty R, Jenner K, Fisher FM, Lauer MN, et al. (May 2002). "Increased resistin gene and protein expression in human abdominal adipose tissue". The Journal of Clinical Endocrinology and Metabolism. 87 (5): 2407. doi:10.1210/jcem.87.5.8627. PMID 11994397.
  19. ^ Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS (August 2003). "The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity". Diabetes, Nutrition & Metabolism. 16 (4): 243–250. PMID 14768774.
  20. ^ Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, et al. (October 2003). "Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects". The Journal of Clinical Endocrinology and Metabolism. 88 (10): 4848–4856. doi:10.1210/jc.2003-030519. PMID 14557464.
  21. ^ Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, et al. (November 2002). "A central role for JNK in obesity and insulin resistance". Nature. 420 (6913): 333–336. Bibcode:2002Natur.420..333H. doi:10.1038/nature01137. PMID 12447443. S2CID 1659156.
  22. ^ Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, et al. (July 2004). "Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting". Diabetes. 53 (7): 1671–1679. doi:10.2337/diabetes.53.7.1671. PMID 15220189.
  23. ^ Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ (October 2003). "Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance". European Journal of Endocrinology. 149 (4): 331–335. doi:10.1530/eje.0.1490331. PMID 14514348.
  24. ^ Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G (July 2003). "A promoter genotype and oxidative stress potentially link resistin to human insulin resistance". Diabetes. 52 (7): 1611–1618. doi:10.2337/diabetes.52.7.1611. PMID 12829623.
  25. ^ Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, et al. (January 2004). "Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes". Clinica Chimica Acta; International Journal of Clinical Chemistry. 339 (1–2): 57–63. doi:10.1016/j.cccn.2003.09.009. PMID 14687894.
  26. ^ McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, et al. (December 2003). "Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes". The Journal of Clinical Endocrinology and Metabolism. 88 (12): 6098–6106. doi:10.1210/jc.2003-030898. PMID 14671216.
  27. ^ Tjokroprawiro A (2006). "New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer)". Acta Medica Indonesiana. 38 (3): 160–166. PMID 17119268.
  28. ^ "Canadian scientists discover cause of high cholesterol". Science Codex. October 28, 2012.
  29. ^ a b Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, et al. (January 2007). "The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes". The Journal of Clinical Endocrinology and Metabolism. 92 (1): 270–276. doi:10.1210/jc.2006-1151. PMID 17062773.
  30. ^ Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M (December 2006). "Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients". Transplantation Proceedings. 38 (10): 3434–3436. doi:10.1016/j.transproceed.2006.10.140. PMID 17175295.
  31. ^ Nagaev I, Bokarewa M, Tarkowski A, Smith U (Dec 2006). Valcarcel J (ed.). "Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes". PLOS ONE. 1 (1) e31. Bibcode:2006PLoSO...1...31N. doi:10.1371/journal.pone.0000031. PMC 1762367. PMID 17183659.
  32. ^ Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ (September 2005). "Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway". Biochemical and Biophysical Research Communications. 334 (4): 1092–1101. Bibcode:2005BBRC..334.1092S. doi:10.1016/j.bbrc.2005.06.202. PMID 16039994. S2CID 29273978.
  33. ^ Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, et al. (August 2003). "Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction". Circulation. 108 (6): 736–740. doi:10.1161/01.CIR.0000084503.91330.49. PMID 12874180.
  34. ^ Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL (October 2002). "Lipopolysaccharide increases resistin gene expression in vivo and in vitro". FEBS Letters. 530 (1–3): 158–162. Bibcode:2002FEBSL.530..158L. doi:10.1016/S0014-5793(02)03450-6. PMID 12387885. S2CID 45491974.
  35. ^ Wellen KE, Hotamisligil GS (May 2005). "Inflammation, stress, and diabetes". The Journal of Clinical Investigation. 115 (5): 1111–1119. doi:10.1172/JCI25102. PMC 1087185. PMID 15864338.
  36. ^ Elfassy Y, Bastard JP, McAvoy C, Fellahi S, Dupont J, Levy R (2018). "Adipokines in Semen: Physiopathology and Effects on Spermatozoas". International Journal of Endocrinology. 2018 3906490. doi:10.1155/2018/3906490. PMC 6008818. PMID 29971101.
  37. ^ Moretti E, Micheli L, Noto D, Fiaschi AI, Menchiari A, Cerretani D (2019). "Resistin in Human Seminal Plasma: Relationship with Lipid Peroxidation, CAT Activity, GSH/GSSG Ratio, and Semen Parameters". Oxidative Medicine and Cellular Longevity. 2019 2192093. doi:10.1155/2019/2192093. PMC 6854241. PMID 31772701.
This article is issued from Wikipedia. The text is available under Creative Commons Attribution-Share Alike 4.0 unless otherwise noted. Additional terms may apply for the media files.