Biology:Resistin

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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

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 derived from adipose tissue that in humans is encoded by the RETN gene.[1]

In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue. The length of the resistin pre-peptide in human is 108 amino acid residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa. Resistin is an adipose-derived hormone (similar to a cytokine) whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes mellitus (T2DM).[2]

Discovery

Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine.[3] It was called "resistin" because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance.

This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, rats, and mice).[3][4][5][6][7] Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.[8][9][10]

This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects, a subject reviewed by Vidal-Puig and O'Rahilly in 2001,[11] and by M.A. Lazar in 2007.[12]

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.[13][14][15][16]

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.[17][18] 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.[19] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[20] 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.[21]

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,[22][23] 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.[24] 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.[25] 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.)[26]

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][27][28] Conversely, serum resistin levels to decline with decreased adiposity following medical treatment.[29] Specifically, central obesity (waistline adipose tissue) is the region of adipose tissue that contributes most to rising levels of serum resistin.[30] This is significant, considering the link between central obesity and insulin resistance, two marked peculiarities of T2DM.[5][31]

Although resistin levels increase with obesity, it is questioned whether this increase is responsible for the insulin resistance associated with increased adiposity.[citation needed] Several reports have shown a positive correlation between resistin levels and insulin resistance.[32][33][34][35] This is supported by reports of correlation between resistin levels and subjects with T2DM.[3][27][36][37] 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.[38]

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.[39] 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.[citation needed] Nevertheless, this theory lacks support from the entire scientific community, as a number of studies present evidence against it.[40][41][42] Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,[43][44][45] 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.[17] 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].

Although nearly as many scientists oppose the theory as those who support it [citation needed], 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.

Structure

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

Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions that make up its structure. The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. Each protein subunit comprises a carboxy-terminal disulfide-rich beta sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. The globular domain from resistin contains five disulfide bonds (Cys35-Cys88, Cys47-Cys87, Cys56-Cys73, Cys58-Cys75, and Cys62-Cys77). This suggests that the disulfide pattern will be conserved.

The interchain disulfide bonds of resistin and resistin-like molecule β (RELMß) are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds is 9.9%, and 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin's disulfides in high-resolution.

A Cys6Ser resistin mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect a mandatory step toward activation. Other results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.

References

  1. ↑ "Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians". J. Clin. Endocrinol. Metab. 87 (6): 2520–4. June 2002. doi:10.1210/jcem.87.6.8528. PMID 12050208. 
  2. ↑ Lazar MA (October 2007). "Resistin- and Obesity-associated metabolic diseases". Horm. Metab. Res. 39 (10): 710–6. 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): 307–12. January 2001. doi:10.1038/35053000. PMID 11201732. 
  4. ↑ 4.0 4.1 "Serum resistin (FIZZ3) protein is increased in obese humans". J. Clin. Endocrinol. Metab. 88 (11): 5452–5. 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): 2951–8. October 2002. doi:10.2337/diabetes.51.10.2951. PMID 12351432. 
  6. ↑ "Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats". Am. J. Physiol. Endocrinol. Metab. 282 (3): E626–33. March 2002. doi:10.1152/ajpendo.00346.2001. PMID 11832366. 
  7. ↑ "Resistin, central obesity, and type 2 diabetes". Lancet 359 (9300): 46–7. January 2002. doi:10.1016/S0140-6736(02)07281-1. PMID 11809189. 
  8. ↑ Adeghate E (October 2004). "An update on the biology and physiology of resistin". Cell. Mol. Life Sci. 61 (19–20): 2485–96. doi:10.1007/s00018-004-4083-2. PMID 15526156. 
  9. ↑ "Resistin and adiponectin--of mice and men". Obes. Res. 10 (11): 1197–9. 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". Obes. Res. 12 (6): 962–71. June 2004. doi:10.1038/oby.2004.118. PMID 15229336. 
  11. ↑ Vidal-Puig, A.; O'Rahilly, S. (2001). "Resistin: a new link between obesity and insulin resistance?". Clinical Endocrinology 55 (4): 437–438. doi:10.1046/j.1365-2265.2001.01377.x. ISSN 0300-0664. PMID 11678824. https://pubmed.ncbi.nlm.nih.gov/11678824/. 
  12. ↑ Lazar, M. A. (2007). "Resistin- and Obesity-associated metabolic diseases". Hormone and Metabolic Research 39 (10): 710–716. doi:10.1055/s-2007-985897. ISSN 0018-5043. PMID 17952831. 
  13. ↑ "FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family". EMBO J. 19 (15): 4046–55. August 2000. doi:10.1093/emboj/19.15.4046. PMID 10921885. 
  14. ↑ "The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes". J. Clin. Endocrinol. Metab. 92 (1): 270–6. January 2007. doi:10.1210/jc.2006-1151. PMID 17062773. 
  15. ↑ "Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients". Transplant. Proc. 38 (10): 3434–6. December 2006. doi:10.1016/j.transproceed.2006.10.140. PMID 17175295. 
  16. ↑ "Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes". PLOS ONE 1 (1): e31. 2006. doi:10.1371/journal.pone.0000031. PMID 17183659. Bibcode: 2006PLoSO...1...31N. 
  17. ↑ 17.0 17.1 "Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss". Obes. Res. 10 (11): 1095–103. November 2002. doi:10.1038/oby.2002.149. PMID 12429872. 
  18. ↑ "Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway". Biochem. Biophys. Res. Commun. 334 (4): 1092–101. September 2005. doi:10.1016/j.bbrc.2005.06.202. PMID 16039994. 
  19. ↑ "Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction". Circulation 108 (6): 736–40. August 2003. doi:10.1161/01.CIR.0000084503.91330.49. PMID 12874180. 
  20. ↑ "Lipopolysaccharide increases resistin gene expression in vivo and in vitro". FEBS Lett. 530 (1–3): 158–62. October 2002. doi:10.1016/S0014-5793(02)03450-6. PMID 12387885. 
  21. ↑ "Inflammation, stress, and diabetes". J. Clin. Invest. 115 (5): 1111–9. May 2005. doi:10.1172/JCI25102. PMID 15864338. 
  22. ↑ "Adiponectin differentially regulates cytokines in porcine macrophages". Biochem. Biophys. Res. Commun. 316 (3): 924–9. April 2004. doi:10.1016/j.bbrc.2004.02.130. PMID 15033490. 
  23. ↑ "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): 1723–32. September 2000. doi:10.1182/blood.V96.5.1723. PMID 10961870. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10961870. 
  24. ↑ "Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance". Kidney Int. 69 (3): 596–604. February 2006. doi:10.1038/sj.ki.5000089. PMID 16395259. 
  25. ↑ "Adipokines in Semen: Physiopathology and Effects on Spermatozoas". International Journal of Endocrinology 2018: 3906490. 2018. doi:10.1155/2018/3906490. PMID 29971101. 
  26. ↑ "Resistin in Human Seminal Plasma: Relationship with Lipid Peroxidation, CAT Activity, GSH/GSSG Ratio, and Semen Parameters". Oxidative Medicine and Cellular Longevity 2019: 2192093. 2019. doi:10.1155/2019/2192093. PMID 31772701. 
  27. ↑ 27.0 27.1 "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): 2206–13. May 2004. doi:10.1210/en.2003-1679. PMID 14962997. 
  28. ↑ "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): E625-32. March 2005. doi:10.1152/ajpendo.00184.2004. PMID 15522996. 
  29. ↑ "Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines". Metabolism 53 (4): 430–4. April 2004. doi:10.1016/j.metabol.2003.11.022. PMID 15045687. 
  30. ↑ "Increased resistin gene and protein expression in human abdominal adipose tissue". The Journal of Clinical Endocrinology and Metabolism 87 (5): 2407–2410. May 2002. doi:10.1210/jcem.87.5.8627. PMID 11994397. 
  31. ↑ "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): 243–50. August 2003. PMID 14768774. 
  32. ↑ "A central role for JNK in obesity and insulin resistance". Nature 420 (6913): 333–6. November 2002. doi:10.1038/nature01137. PMID 12447443. Bibcode: 2002Natur.420..333H. http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html. 
  33. ↑ "Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting". Diabetes 53 (7): 1671–9. July 2004. doi:10.2337/diabetes.53.7.1671. PMID 15220189. 
  34. ↑ "Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance". European Journal of Endocrinology 149 (4): 331–5. October 2003. doi:10.1530/eje.0.1490331. PMID 14514348. 
  35. ↑ "A promoter genotype and oxidative stress potentially link resistin to human insulin resistance". Diabetes 52 (7): 1611–8. July 2003. doi:10.2337/diabetes.52.7.1611. PMID 12829623. 
  36. ↑ "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. 
  37. ↑ "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): 6098–106. December 2003. doi:10.1210/jc.2003-030898. PMID 14671216. 
  38. ↑ "New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer)". Acta Medica Indonesiana 38 (3): 160–6. 2006. PMID 17119268. 
  39. ↑ "Canadian scientists discover cause of high cholesterol". October 28, 2012. https://www.sciencecodex.com/canadian_scientists_discover_cause_of_high_cholesterol-101029. 
  40. ↑ "Resistin release by human adipose tissue explants in primary culture". Biochem. Biophys. Res. Commun. 300 (3): 674–8. January 2003. doi:10.1016/S0006-291X(02)02864-4. PMID 12507502. 
  41. ↑ "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". J. Clin. Endocrinol. Metab. 88 (10): 4848–56. October 2003. doi:10.1210/jc.2003-030519. PMID 14557464. 
  42. ↑ "Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle". Biochem. Biophys. Res. Commun. 285 (2): 561–4. July 2001. doi:10.1006/bbrc.2001.5173. PMID 11444881. 
  43. ↑ "Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects". J. Clin. Endocrinol. Metab. 89 (4): 1844–8. April 2004. doi:10.1210/jc.2003-031410. PMID 15070954. 
  44. ↑ "Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans". Diabetes 50 (10): 2199–202. October 2001. doi:10.2337/diabetes.50.10.2199. PMID 11574398. 
  45. ↑ "Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists". J. Biol. Chem. 276 (28): 25651–3. July 2001. doi:10.1074/jbc.C100189200. PMID 11373275. 

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