Resistin
Resistinalso known asadipose tissue-specific secretory factor(ADSF) orC/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein(XCP1) is acysteine-richpeptide hormonederived fromadipose tissuethat in humans is encoded by theRETNgene.[5]
Inprimates,pigs, and dogs, resistin is secreted byimmuneandepithelialcells, while, in rodents, it is secreted by adipose tissue. The length of the resistinpre-peptidein human is 108amino acidresidues and in the mouse and rat it is 114 aa; themolecular weightis ~12.5kDa.Resistin is anadipose-derived hormone(similar to acytokine) whose physiologic role has been the subject of much controversy regarding its involvement withobesityand type II diabetes mellitus (T2DM).[6]
Discovery
[edit]Resistin was discovered in 2001 by the group of DrMitchell A. Lazarfrom theUniversity of PennsylvaniaSchool of Medicine.[7]It was called "resistin" because of the observedinsulinresistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serveendocrinefunctions likely involved ininsulin resistance.
This idea primarily stems from studies demonstrating thatserumresistin levels increase with obesity in several model systems (humans,rats,andmice).[7][8][9][10][11]Since these observations, further research has linked resistin to other physiological systems such asinflammationand energyhomeostasis.[12][13][14]
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 byVidal-PuigandO'Rahillyin 2001,[15]and by M.A. Lazar in 2007.[16]
Inflammation
[edit]Inflammation is the firstinnate immune responsetoinfectionorirritationresulting fromleukocyte(neutrophils,mast cells,etc.) accumulation and their secretion of inflammatory,biogenicchemicals such ashistamine,prostaglandin,and pro-inflammatorycytokines.As cited, it has recently been discovered that resistin also participates in the inflammatory response.[17][18][19][20]
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 anNF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion.[21][22]It has also been demonstrated that resistin upregulates intercellularadhesionmolecule-1 (ICAM1)vascularcell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied inchemotacticpathways involved inleukocyterecruitment to sites of infection.[23]Resistin itself can be upregulated by interleukins and also bymicrobialantigens such aslipopolysaccharide,[24]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.[25]
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 inchronic inflammationin 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,[26][27]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 chronickidney diseaseare associated with lowered renal function and inflammation, but not with insulin resistance.[28]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 inflammatorydiseaseswith 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.[29]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.)[30]
Obesity and insulin resistance
[edit]Arguments for
[edit]Much of what ishypothesizedabout a resistin role in energymetabolismand T2DM can be derived from studies showing strong correlations between resistin and obesity. The premise being thatserumresistin levels increase with increasedadiposity.[8][14][31][32]Conversely, serum resistin levels to decline with decreased adiposity followingmedicaltreatment.[33]Specifically,central obesity(waistline adipose tissue) is the region of adipose tissue that contributes most to rising levels of serum resistin.[34]This is significant, considering the link between central obesity and insulin resistance, two marked peculiarities of T2DM.[9][35]
Although resistin levels increase with obesity, it is questioned whether this increase is responsible for theinsulin resistanceassociated with increased adiposity.[citation needed]Several reports have shown a positive correlation between resistin levels andinsulin resistance.[36][37][38][39]This is supported by reports of correlation between resistin levels and subjects with T2DM.[7][31][40][41]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.[42]
Resistin can increase levels of circulatinglow-density lipoprotein(LDL) and accelerates LDL accumulation inarteries,increasing risk of heart disease has an adverse impact on the efficacy ofstatins,the primary drug used to reduce cholesterol in fighting ofcardiovascular disease.[43]In the liver, resistin increases LDL production and degrades LDL receptors, impairing the ability to process LDL.
Arguments against
[edit]The amount of evidence supporting the resistin link theory between obesity and T2DM is vast.[citation needed]Nevertheless, this theory lacks support from the entirescientific community,as a number of studies present evidence against it.[44][45][46]Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,[47][48][49]suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links betweenobesityand 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.[21]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 inenergy homeostasis,while also demonstrating properties that help to inciteinflammatory responsesto sites ofinfection.
Structure
[edit]Resistin | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | Resistin | ||||||||
Pfam | PF06954 | ||||||||
InterPro | IPR009714 | ||||||||
SCOP2 | 1rgx/SCOPe/SUPFAM | ||||||||
OPM superfamily | 384 | ||||||||
OPM protein | 1rgx | ||||||||
|
Crystal structures of resistin reveal an unusual composition of several subunits that are held together bynon-covalent interactionsthat 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-richbeta sandwich"head" domain and an amino-terminal alpha-helical "tail" segment. Thealpha-helicalsegments associate to form three-stranded coils, and surface-exposed interchaindisulfide linkagesmediate 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
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000104918–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000012705–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^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".J. Clin. Endocrinol. Metab.87(6): 2520–4.doi:10.1210/jcem.87.6.8528.PMID12050208.
- ^Lazar MA (October 2007)."Resistin- and Obesity-associated metabolic diseases".Horm. Metab. Res.39(10): 710–6.doi:10.1055/s-2007-985897.PMID17952831.
- ^abcSteppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA (January 2001). "The hormone resistin links obesity to diabetes".Nature.409(6818): 307–12.doi:10.1038/35053000.PMID11201732.S2CID4358808.
- ^abDegawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV (November 2003)."Serum resistin (FIZZ3) protein is increased in obese humans".J. Clin. Endocrinol. Metab.88(11): 5452–5.doi:10.1210/jc.2002-021808.PMID14602788.
- ^abGabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (October 2002)."Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?".Diabetes.51(10): 2951–8.doi:10.2337/diabetes.51.10.2951.PMID12351432.
- ^Levy JR, Davenport B, Clore JN, Stevens W (March 2002). "Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats".Am. J. Physiol. Endocrinol. Metab.282(3): E626–33.doi:10.1152/ajpendo.00346.2001.PMID11832366.S2CID25303054.
- ^McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S (January 2002). "Resistin, central obesity, and type 2 diabetes".Lancet.359(9300): 46–7.doi:10.1016/S0140-6736(02)07281-1.PMID11809189.S2CID21927880.
- ^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.PMID15526156.S2CID22832421.
- ^Stumvoll M, Häring H (November 2002). "Resistin and adiponectin--of mice and men".Obes. Res.10(11): 1197–9.doi:10.1038/oby.2002.162.PMID12429885.
- ^abVendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, Simón I, Soler J, Richart C (June 2004)."Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity".Obes. Res.12(6): 962–71.doi:10.1038/oby.2004.118.PMID15229336.
- ^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.ISSN0300-0664.PMID11678824.S2CID6087337.
- ^Lazar, M. A. (2007)."Resistin- and Obesity-associated metabolic diseases".Hormone and Metabolic Research.39(10): 710–716.doi:10.1055/s-2007-985897.ISSN0018-5043.PMID17952831.
- ^Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale Jr FV, Shelton DL, Hébert CC (August 2000)."FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family".EMBO J.19(15): 4046–55.doi:10.1093/emboj/19.15.4046.PMC306596.PMID10921885.
- ^Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG (January 2007)."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.doi:10.1210/jc.2006-1151.PMID17062773.
- ^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".Transplant. Proc.38(10): 3434–6.doi:10.1016/j.transproceed.2006.10.140.PMID17175295.
- ^Nagaev I, Bokarewa M, Tarkowski A, Smith U (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.PMC1762367.PMID17183659.
- ^abMilan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R (November 2002)."Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss".Obes. Res.10(11): 1095–103.doi:10.1038/oby.2002.149.PMID12429872.
- ^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".Biochem. Biophys. Res. Commun.334(4): 1092–101.doi:10.1016/j.bbrc.2005.06.202.PMID16039994.S2CID29273978.
- ^Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA (August 2003)."Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction".Circulation.108(6): 736–40.doi:10.1161/01.CIR.0000084503.91330.49.PMID12874180.
- ^Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL (October 2002). "Lipopolysaccharide increases resistin gene expression in vivo and in vitro".FEBS Lett.530(1–3): 158–62.doi:10.1016/S0014-5793(02)03450-6.PMID12387885.S2CID45491974.
- ^Wellen KE, Hotamisligil GS (May 2005)."Inflammation, stress, and diabetes".J. Clin. Invest.115(5): 1111–9.doi:10.1172/JCI25102.PMC1087185.PMID15864338.
- ^Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME (April 2004). "Adiponectin differentially regulates cytokines in porcine macrophages".Biochem. Biophys. Res. Commun.316(3): 924–9.doi:10.1016/j.bbrc.2004.02.130.PMID15033490.
- ^Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y (September 2000)."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.doi:10.1182/blood.V96.5.1723.PMID10961870.
- ^Axelsson J, Bergsten A, Qureshi AR, Heimbürger O, Bárány P, Lönnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P (February 2006)."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.doi:10.1038/sj.ki.5000089.PMID16395259.
- ^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.PMC6008818.PMID29971101.
- ^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.PMC6854241.PMID31772701.
- ^abAsensio 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): 2206–13.doi:10.1210/en.2003-1679.PMID14962997.
- ^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): E625-32.doi:10.1152/ajpendo.00184.2004.PMID15522996.S2CID20609673.
- ^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.53(4): 430–4.doi:10.1016/j.metabol.2003.11.022.PMID15045687.
- ^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): 2407–2410.doi:10.1210/jcem.87.5.8627.PMID11994397.
- ^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): 243–50.PMID14768774.
- ^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): 333–6.Bibcode:2002Natur.420..333H.doi:10.1038/nature01137.PMID12447443.S2CID1659156.
- ^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): 1671–9.doi:10.2337/diabetes.53.7.1671.PMID15220189.
- ^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): 331–5.doi:10.1530/eje.0.1490331.PMID14514348.
- ^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): 1611–8.doi:10.2337/diabetes.52.7.1611.PMID12829623.
- ^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.PMID14687894.
- ^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): 6098–106.doi:10.1210/jc.2003-030898.PMID14671216.
- ^Tjokroprawiro A (2006). "New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer)".Acta Medica Indonesiana.38(3): 160–6.PMID17119268.
- ^"Canadian scientists discover cause of high cholesterol".Science Codex.October 28, 2012.
- ^Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M (January 2003). "Resistin release by human adipose tissue explants in primary culture".Biochem. Biophys. Res. Commun.300(3): 674–8.doi:10.1016/S0006-291X(02)02864-4.PMID12507502.
- ^Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS (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".J. Clin. Endocrinol. Metab.88(10): 4848–56.doi:10.1210/jc.2003-030519.PMID14557464.
- ^Nagaev I, Smith U (July 2001). "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.doi:10.1006/bbrc.2001.5173.PMID11444881.
- ^Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR (April 2004)."Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects".J. Clin. Endocrinol. Metab.89(4): 1844–8.doi:10.1210/jc.2003-031410.PMID15070954.
- ^Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S (October 2001)."Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans".Diabetes.50(10): 2199–202.doi:10.2337/diabetes.50.10.2199.PMID11574398.
- ^Way JM, Görgün CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Willson TM, Kliewer SA, Hotamisligil GS (July 2001)."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.doi:10.1074/jbc.C100189200.PMID11373275.
External links
[edit]- Resistinat the U.S. National Library of MedicineMedical Subject Headings(MeSH)