Biology:Resistin

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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.[1]

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).[2]

Discovery

Resistin was discovered in 2001 and identified as a hormone produced by adipose tissue, with a role in promoting insulin resistance.[3] Elevated resistin levels were linked to insulin resistance and were shown to increase with obesity, supporting its role in metabolic dysfunction.[3][4][5][6][7]

Subsequent studies highlighted resistin's involvement in inflammatory processes and energy homeostasis, indicating a broader physiological role beyond insulin resistance.[8][9][10]

Recent reviews have synthesized these findings, supporting resistin's proposed role in mediating the link between obesity and insulin resistance, as well as its potential contributions to inflammation and metabolic diseases.[11][12]

Structure

Resistin
Identifiers
SymbolResistin
PfamPF06954
InterProIPR009714
SCOP21rgx / SCOPe / SUPFAM
OPM superfamily384
OPM protein1rgx

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.[13][14] 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.[13][14] 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.[13][14] The C-terminal head domain is notable for its positive electrostatic surface and exposed hydrophobic residues, which may contribute to the protein's biological activity, including its antimicrobial properties.[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.[13] This structural organization is highly conserved within the resistin-like molecule (RELM) family and is thought to underpin resistin's diverse physiological roles.[13][14]

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.[13][15]

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).[13] 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.[13] This dual functionality positions resistin as an important regulator of host defense and inflammatory balance in both health and disease.[13]

Clinical significance

Obesity and insulin resistance

Arguments for

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.[4][10][16][17] Conversely, serum resistin levels to decline with decreased adiposity following medical treatment.[18] Specifically, central obesity (waistline adipose tissue) is the region of adipose tissue that contributes most to rising levels of serum resistin.[19] This is significant, considering the link between central obesity and insulin resistance, two marked peculiarities of T2DM.[5][20]

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.[3][16][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.

Arguments against

The amount of evidence supporting the resistin link theory between obesity and T2DM is vast. Nevertheless, this theory lacks support from the entire scientific community, as a number of studies present evidence against it.[29][30][31] Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,[32][33][34] suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between obesity and T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented; such studies instead report that weight loss is associated with marked increases in serum resistin.[35] The idea that resistin links obesity to T2DM is under scrutiny, reports have been made of ubiquitous resistin expression in many tissues, rather than only those characteristic of obesity, such as adipocytes {{Citation needed|date=August 2012} Although nearly as many scientists oppose the theory as those who support it , there is sufficient evidence to support the idea that resistin does have some incompletely defined role in energy homeostasis, while also demonstrating properties that help to incite inflammatory responses to sites of infection.

Inflammation

Inflammation is the first innate immune response to infection or irritation resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine, prostaglandin, and pro-inflammatory cytokines.

As cited, it has recently been discovered that resistin also participates in the inflammatory response.[36][37][38][39]

In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion.[35][40] It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection.[41] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[42] which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.[43]

In accordance, it is expected that, if resistin does serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then proportional increases in chronic inflammation in association with obesity and insulin resistance should be observed. Recent data has shown that this is possible by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation,[44][45] which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with lowered renal function and inflammation, but not with insulin resistance.[46] Notwithstanding, regarding resistin and the inflammatory response, it can be concluded that resistin does bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.

This adipokine is associated with markers of inflammation in seminal plasma and the concentrations of seminal resistin correlate positively with those of proinflammatory mediators such as interleukin-6 (IL-6), elastase and tumor necrosis factor-α (TNF-α). During inflammation, the concentrations of cytokines and ROS increase, and this may have a deleterious effect on the male reproductive function.[47] One study showed that there was a negative correlation between the concentrations of seminal resistin and spermatic motility and vitality. (The seminal concentrations of resistin were significantly higher in cases of leukocyte spermia or if the patients were smokers.)[48]

References

  1. ↑ "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. June 2002. doi:10.1210/jcem.87.6.8528. PMID 12050208. 
  2. ↑ "Resistin- and Obesity-associated metabolic diseases". Hormone and Metabolic Research 39 (10): 710–716. October 2007. doi:10.1055/s-2007-985897. PMID 17952831. 
  3. ↑ 3.0 3.1 3.2 "The hormone resistin links obesity to diabetes". Nature 409 (6818): 307–312. January 2001. doi:10.1038/35053000. PMID 11201732. Bibcode: 2001Natur.409..307S. 
  4. ↑ 4.0 4.1 "Serum resistin (FIZZ3) protein is increased in obese humans". The Journal of Clinical Endocrinology and Metabolism 88 (11): 5452–5455. November 2003. doi:10.1210/jc.2002-021808. PMID 14602788. 
  5. ↑ 5.0 5.1 "Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?". Diabetes 51 (10): 2951–2958. October 2002. doi:10.2337/diabetes.51.10.2951. PMID 12351432. 
  6. ↑ "Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats". American Journal of Physiology. Endocrinology and Metabolism 282 (3): E626–E633. March 2002. doi:10.1152/ajpendo.00346.2001. PMID 11832366. 
  7. ↑ "Resistin, central obesity, and type 2 diabetes". Lancet (London, England) 359 (9300): 46–47. January 2002. doi:10.1016/S0140-6736(02)07281-1. PMID 11809189. 
  8. ↑ "An update on the biology and physiology of resistin". Cellular and Molecular Life Sciences 61 (19–20): 2485–2496. October 2004. doi:10.1007/s00018-004-4083-2. PMID 15526156. 
  9. ↑ "Resistin and adiponectin--of mice and men". Obesity Research 10 (11): 1197–1199. November 2002. doi:10.1038/oby.2002.162. PMID 12429885. 
  10. ↑ 10.0 10.1 "Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity". Obesity Research 12 (6): 962–971. June 2004. doi:10.1038/oby.2004.118. PMID 15229336. 
  11. ↑ "Resistin: a new link between obesity and insulin resistance?". Clinical Endocrinology 55 (4): 437–438. 2001. doi:10.1046/j.1365-2265.2001.01377.x. ISSN 0300-0664. PMID 11678824. 
  12. ↑ "Resistin- and Obesity-associated metabolic diseases". Hormone and Metabolic Research 39 (10): 710–716. 2007. doi:10.1055/s-2007-985897. ISSN 0018-5043. PMID 17952831. 
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 "Resistin, a Novel Host Defense Peptide of Innate Immunity". Frontiers in Immunology 12. 2021. doi:10.3389/fimmu.2021.699807. PMID 34220862. 
  14. ↑ 14.0 14.1 14.2 14.3 "Disulfide-dependent multimeric assembly of resistin family hormones". Science (New York, N.Y.) 304 (5674): 1154–1158. May 2004. doi:10.1126/science.1093466. PMID 15155948. Bibcode: 2004Sci...304.1154P. 
  15. ↑ "Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes". Cell Metabolism 19 (3): 484–97. March 2014. doi:10.1016/j.cmet.2014.01.013. PMID 24606903. 
  16. ↑ 16.0 16.1 "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. May 2004. doi:10.1210/en.2003-1679. PMID 14962997. 
  17. ↑ "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. March 2005. doi:10.1152/ajpendo.00184.2004. PMID 15522996. 
  18. ↑ "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. April 2004. doi:10.1016/j.metabol.2003.11.022. PMID 15045687. 
  19. ↑ "Increased resistin gene and protein expression in human abdominal adipose tissue". The Journal of Clinical Endocrinology and Metabolism 87 (5): 2407. May 2002. doi:10.1210/jcem.87.5.8627. PMID 11994397. 
  20. ↑ "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. August 2003. PMID 14768774. 
  21. ↑ "A central role for JNK in obesity and insulin resistance". Nature 420 (6913): 333–336. November 2002. doi:10.1038/nature01137. PMID 12447443. Bibcode: 2002Natur.420..333H. http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html. 
  22. ↑ "Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting". Diabetes 53 (7): 1671–1679. July 2004. doi:10.2337/diabetes.53.7.1671. PMID 15220189. 
  23. ↑ "Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance". European Journal of Endocrinology 149 (4): 331–335. October 2003. doi:10.1530/eje.0.1490331. PMID 14514348. 
  24. ↑ "A promoter genotype and oxidative stress potentially link resistin to human insulin resistance". Diabetes 52 (7): 1611–1618. July 2003. doi:10.2337/diabetes.52.7.1611. PMID 12829623. 
  25. ↑ "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. January 2004. doi:10.1016/j.cccn.2003.09.009. PMID 14687894. 
  26. ↑ "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. December 2003. doi:10.1210/jc.2003-030898. PMID 14671216. 
  27. ↑ "New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer)". Acta Medica Indonesiana 38 (3): 160–166. 2006. PMID 17119268. 
  28. ↑ "Canadian scientists discover cause of high cholesterol". October 28, 2012. https://www.sciencecodex.com/canadian_scientists_discover_cause_of_high_cholesterol-101029. 
  29. ↑ "Resistin release by human adipose tissue explants in primary culture". Biochemical and Biophysical Research Communications 300 (3): 674–678. January 2003. doi:10.1016/S0006-291X(02)02864-4. PMID 12507502. Bibcode: 2003BBRC..300..674F. 
  30. ↑ "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. October 2003. doi:10.1210/jc.2003-030519. PMID 14557464. 
  31. ↑ "Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle". Biochemical and Biophysical Research Communications 285 (2): 561–564. July 2001. doi:10.1006/bbrc.2001.5173. PMID 11444881. Bibcode: 2001BBRC..285..561N. 
  32. ↑ "Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects". The Journal of Clinical Endocrinology and Metabolism 89 (4): 1844–1848. April 2004. doi:10.1210/jc.2003-031410. PMID 15070954. 
  33. ↑ "Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans". Diabetes 50 (10): 2199–2202. October 2001. doi:10.2337/diabetes.50.10.2199. PMID 11574398. 
  34. ↑ "Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists". Journal of Biological Chemistry 276 (28): 25651–25653. July 2001. doi:10.1074/jbc.C100189200. PMID 11373275. 
  35. ↑ 35.0 35.1 "Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss". Obesity Research 10 (11): 1095–1103. November 2002. doi:10.1038/oby.2002.149. PMID 12429872. 
  36. ↑ "FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family". The EMBO Journal 19 (15): 4046–4055. August 2000. doi:10.1093/emboj/19.15.4046. PMID 10921885. 
  37. ↑ "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. January 2007. doi:10.1210/jc.2006-1151. PMID 17062773. 
  38. ↑ "Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients". Transplantation Proceedings 38 (10): 3434–3436. December 2006. doi:10.1016/j.transproceed.2006.10.140. PMID 17175295. 
  39. ↑ "Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes". PLOS ONE 1 (1). Dec 2006. doi:10.1371/journal.pone.0000031. PMID 17183659. Bibcode: 2006PLoSO...1...31N. 
  40. ↑ "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. September 2005. doi:10.1016/j.bbrc.2005.06.202. PMID 16039994. Bibcode: 2005BBRC..334.1092S. 
  41. ↑ "Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction". Circulation 108 (6): 736–740. August 2003. doi:10.1161/01.CIR.0000084503.91330.49. PMID 12874180. 
  42. ↑ "Lipopolysaccharide increases resistin gene expression in vivo and in vitro". FEBS Letters 530 (1–3): 158–162. October 2002. doi:10.1016/S0014-5793(02)03450-6. PMID 12387885. Bibcode: 2002FEBSL.530..158L. 
  43. ↑ "Inflammation, stress, and diabetes". The Journal of Clinical Investigation 115 (5): 1111–1119. May 2005. doi:10.1172/JCI25102. PMID 15864338. 
  44. ↑ "Adiponectin differentially regulates cytokines in porcine macrophages". Biochemical and Biophysical Research Communications 316 (3): 924–929. April 2004. doi:10.1016/j.bbrc.2004.02.130. PMID 15033490. Bibcode: 2004BBRC..316..924W. 
  45. ↑ "Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages". Blood 96 (5): 1723–1732. September 2000. doi:10.1182/blood.V96.5.1723. PMID 10961870. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10961870. 
  46. ↑ "Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance". Kidney International 69 (3): 596–604. February 2006. doi:10.1038/sj.ki.5000089. PMID 16395259. 
  47. ↑ "Adipokines in Semen: Physiopathology and Effects on Spermatozoas". International Journal of Endocrinology 2018. 2018. doi:10.1155/2018/3906490. PMID 29971101. 
  48. ↑ "Resistin in Human Seminal Plasma: Relationship with Lipid Peroxidation, CAT Activity, GSH/GSSG Ratio, and Semen Parameters". Oxidative Medicine and Cellular Longevity 2019. 2019. doi:10.1155/2019/2192093. PMID 31772701. 



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