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{{Infobox_gene}}
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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 [[adipose-derived hormones|adipose-derived]] [[peptide hormone]] that in humans is encoded by the ''RETN'' [[gene]].<ref name="pmid12050208">{{cite journal |vauthors=Wang H, Chu WS, Hemphill C, Elbein SC | title = Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians | journal = J. Clin. Endocrinol. Metab. | volume = 87 | issue = 6 | pages = 2520–4 |date=June 2002 | pmid = 12050208 | doi = 10.1210/jc.87.6.2520| url = }}</ref>
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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 [[peptide|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 ([[diabetes mellitus type 2|T2DM]]).<ref name="pmid17952831">{{cite journal | author = Lazar MA | title = Resistin- and Obesity-associated metabolic diseases | journal = Horm. Metab. Res. | volume = 39 | issue = 10 | pages = 710–6 |date=October 2007 | pmid = 17952831 | doi = 10.1055/s-2007-985897 | url =  }}</ref>
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Resistin
| HGNCid = 20389
| Symbol = RETN
| AltSymbols =; ADSF; FIZZ3; MGC126603; MGC126609; RETN1; RSTN; XCP1
| OMIM = 605565
| ECnumber = 
| Homologene = 10703
| MGIid = 1888506
| GeneAtlas_image1 = PBB_GE_RETN_220570_at_tn.png
  | Function = {{GNF_GO|id=GO:0005179 |text = hormone activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}}
| Process = {{GNF_GO|id=GO:0008150 |text = biological_process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 56729
    | Hs_Ensembl = ENSG00000104918
    | Hs_RefseqProtein = NP_065148
    | Hs_RefseqmRNA = NM_020415
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 19
    | Hs_GenLoc_start = 7639972
    | Hs_GenLoc_end = 7641340
    | Hs_Uniprot = Q9HD89
    | Mm_EntrezGene = 57264
    | Mm_Ensembl = ENSMUSG00000012705
    | Mm_RefseqmRNA = NM_022984
    | Mm_RefseqProtein = NP_075360
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 8
    | Mm_GenLoc_start = 3655771
    | Mm_GenLoc_end = 3659817
    | Mm_Uniprot = Q3V2F6
  }}
}}
{{SI}}
__NOTOC__
{{GS}}


Resistin has been shown to cause "high levels of 'bad' [[cholesterol]] ([[low-density lipoprotein]] or LDL), increasing the risk of heart disease  [...]  resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the [[liver]].  As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in [[arteries]], increasing the risk of heart disease.  [...] resistin adversely impacts the effects of [[statins]], the main cholesterol-reducing drug used in the treatment and prevention of [[cardiovascular]] disease."<ref name="Canadian scientists discover cause of high cholesterol">{{cite web|url=http://www.sciencecodex.com/canadian_scientists_discover_cause_of_high_cholesterol-101029 |title=Canadian scientists discover cause of high cholesterol}}</ref>


== Discovery ==
Resistin was discovered in 2001 by the group of Dr [[Mitchell Lazar|Mitchell A. Lazar]] from the [[University of Pennsylvania]] School of Medicine.<ref name="p30">{{cite journal |vauthors=Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA | title = The hormone resistin links obesity to diabetes | journal = Nature | volume = 409 | issue = 6818 | pages = 307–12 |date=January 2001 | pmid = 11201732 | doi = 10.1038/35053000 | url =  }}</ref>  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 [[Blood serum|serum]] resistin levels increase with obesity in several model systems (humans, [[rat]]s, and [[mice]]).<ref name="p30"/><ref name="p4">{{cite journal |vauthors=Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV | title = Serum resistin (FIZZ3) protein is increased in obese humans | journal = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 11 | pages = 5452–5 |date=November 2003 | pmid = 14602788 | doi = 10.1210/jc.2002-021808 | url =  }}</ref><ref name="p8">{{cite journal |vauthors=Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N | title = Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? | journal = Diabetes | volume = 51 | issue = 10 | pages = 2951–8 |date=October 2002 | pmid = 12351432 | doi = 10.2337/diabetes.51.10.2951 | url =  }}</ref><ref name="p16">{{cite journal |vauthors=Levy JR, Davenport B, Clore JN, Stevens W | title = Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats | journal = Am. J. Physiol. Endocrinol. Metab. | volume = 282 | issue = 3 | pages = E626–33 |date=March 2002 | pmid = 11832366 | doi = 10.1152/ajpendo.00346.2001 | url =  }}</ref><ref name="McTernanMcTernan2002">{{cite journal|last1=McTernan|first1=CL|last2=McTernan|first2=PG|last3=Harte|first3=AL|last4=Levick|first4=PL|last5=Barnett|first5=AH|last6=Kumar|first6=S|title=Resistin, central obesity, and type 2 diabetes|journal=The Lancet|volume=359|issue=9300|year=2002|pages=46–47|issn=0140-6736|doi=10.1016/S0140-6736(02)07281-1}}</ref> Since these observations, further research has linked resistin to other physiological systems such as [[inflammation]] and energy [[homeostasis]].<ref name="p1">{{cite journal | author = Adeghate E | title = An update on the biology and physiology of resistin | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 19–20 | pages = 2485–96 |date=October 2004 | pmid = 15526156 | doi = 10.1007/s00018-004-4083-2 | url =  }}</ref><ref name="p31">{{cite journal |vauthors=Stumvoll M, Häring H | title = Resistin and adiponectin--of mice and men | journal = Obes. Res. | volume = 10 | issue = 11 | pages = 1197–9 |date=November 2002 | pmid = 12429885 | doi = 10.1038/oby.2002.162 | url =  }}</ref><ref name="p34">{{cite journal |vauthors=Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, Simón I, Soler J, Richart C | title = Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity | journal = Obes. Res. | volume = 12 | issue = 6 | pages = 962–71 |date=June 2004 | pmid = 15229336 | doi = 10.1038/oby.2004.118 | url =  }}</ref>


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.


'''Resistin''' is a [[hormone]] secreted by [[adipose tissue]]. It is also known as "''[[serine]]/[[cysteine]]-rich [[adipocyte]]-Specific Secretory Factor''" (ADSF or FIZZ3). The length of the resistin [[peptide|pre-peptide]] in human is 108 [[aminoacid]]s (in the mouse and rat it's 114 aa); the [[molecular weight]] is ~12.5 kDa.  Among the hormones synthesized and released from [[adipose tissue]] ([[adiponectin]], [[angiotensin]], [[estradiol]], [[IL-6]], [[leptin]], [[PAI-1]], [[TNF-α]], and resistin (also known as ADSF or FIZZ3)), resistin is an [[adipocytokine]] whose physiologic role has been the subject of much controversy regarding its involvement with [[obesity]] and [[type II diabetes mellitus]] (T2DM).  Resistin was first discovered in 2001 (30) and was originally 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) (4, 8, 16, 19, and 30).  Since these observations, further research has linked resistin to other physiological systems such as [[inflammation]] and energy [[homeostasis]] (1, 31, and 34).  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.
== Inflammation ==


==Discovery==
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.<ref name="p11">{{cite journal |vauthors=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 FV Jr)), Shelton DL, Hébert CC | title = FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family | journal = EMBO J. | volume = 19 | issue = 15 | pages = 4046–55 |date=August 2000 | pmid = 10921885 | pmc = 306596 | doi = 10.1093/emboj/19.15.4046 | url =  }}</ref><ref name="p13">{{cite journal |vauthors=Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG | title = The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes | journal = J. Clin. Endocrinol. Metab. | volume = 92 | issue = 1 | pages = 270–6 |date=January 2007 | pmid = 17062773 | doi = 10.1210/jc.2006-1151 | url =  }}</ref><ref name="p18">{{cite journal |vauthors=Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M | title = Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients | journal = Transplant. Proc. | volume = 38 | issue = 10 | pages = 3434–6 |date=December 2006 | pmid = 17175295 | doi = 10.1016/j.transproceed.2006.10.140 | url =  }}</ref><ref name="pmid17183659">{{cite journal | vauthors = Nagaev I, Bokarewa M, Tarkowski A, Smith U | title = Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes | journal = PLoS ONE | volume = 1 | issue = 1| pages = e31 | year = 2006 | pmid = 17183659 | pmc = 1762367 | doi = 10.1371/journal.pone.0000031 | url = | editor1-last = Valcarcel | editor1-first = Juan  }}</ref>
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from University of Pennsylvania School of Medicine. It was called "resistin" because of the observed [[insulin]] resistance in mice injected with resistin (Steppan ''et al'').


== Resistin and inflammation ==
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.<ref name="p22">{{cite journal |vauthors=Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R | title = Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss | journal = Obes. Res. | volume = 10 | issue = 11 | pages = 1095–103 |date=November 2002 | pmid = 12429872 | doi = 10.1038/oby.2002.149 | url =  }}</ref><ref name="p28">{{cite journal |vauthors=Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ | title = Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway | journal = Biochem. Biophys. Res. Commun. | volume = 334 | issue = 4 | pages = 1092–101 |date=September 2005 | pmid = 16039994 | doi = 10.1016/j.bbrc.2005.06.202 | url =  }}</ref> It has also been demonstrated that resistin upregulates intercellular [[adhesion]] molecule-1 ([[ICAM1]]) [[Blood vessel|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.<ref name="p35">{{cite journal |vauthors=Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA | title = Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction | journal = Circulation | volume = 108 | issue = 6 | pages = 736–40 |date=August 2003 | pmid = 12874180 | doi = 10.1161/01.CIR.0000084503.91330.49 | url = }}</ref> Resistin itself can be upregulated by interleukins and also by [[microbial]] antigens such as [[lipopolysaccharide]],<ref name="p17">{{cite journal |vauthors=Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL | title = Lipopolysaccharide increases resistin gene expression in vivo and in vitro | journal = FEBS Lett. | volume = 530 | issue = 1–3 | pages = 158–62 |date=October 2002 | pmid = 12387885 | doi = 10.1016/S0014-5793(02)03450-6| url = http://linkinghub.elsevier.com/retrieve/pii/S0014579302034506 }}</ref> 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.<ref name="pmid15864338">{{cite journal |vauthors=Wellen KE, Hotamisligil GS | title = Inflammation, stress, and diabetes | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1111–9 |date=May 2005 | pmid = 15864338 | pmc = 1087185 | doi = 10.1172/JCI25102 | url =  }}</ref>
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in [[chronic inflammation]] in association with obesity and insulin resistance.  In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation,<ref name="p38">{{cite journal |vauthors=Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME | title = Adiponectin differentially regulates cytokines in porcine macrophages | journal = Biochem. Biophys. Res. Commun. | volume = 316 | issue = 3 | pages = 924–9 |date=April 2004 | pmid = 15033490 | doi = 10.1016/j.bbrc.2004.02.130 | url =  }}</ref><ref name="p39">{{cite journal |vauthors=Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y | title = Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages | journal = Blood | volume = 96 | issue = 5 | pages = 1723–32 |date=September 2000 | pmid = 10961870 | doi = | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10961870 }}</ref> 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.<ref name="p3">{{cite journal |vauthors=Axelsson J, Bergsten A, Qureshi AR, Heimbürger O, Bárány P, Lönnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P | title = Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance | journal = Kidney Int. | volume = 69 | issue = 3 | pages = 596–604 |date=February 2006 | pmid = 16395259 | doi = 10.1038/sj.ki.5000089 | url =  }}</ref> Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory [[diseases]] with or without associated insulin resistance.


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 found that resistin also participates in the inflammatory response (11, 13, 18, and 23).  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 NFқB-mediated fashion (22, 28).  It has also been demonstrated that resistin upregulates intracellular [[adhesion]] molecule-1 ([[ICAM1]]) [[Blood vessel|vascular]] cell-adhesion molecule-1 ([[VCAM1]]) and [[CCL2]], all of which are occupied in [[chemotactic]] pathways involved in [[leukocyte]] recruitment to sites of infection (35).  Resistin itself can be upregulated by interleukins and also by [[microbial]] antigens such as [[lipopolysaccharide]] (17), 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 (37).
== Obesity and insulin resistance ==
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in [[chronic inflammation]] in association with obesity and insulin resistance.  In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation (38, 39) 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 declined renal function and inflammation, but not with insulin resistance (3).  Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory [[diseases]] with or without associated insulin resistance.


== Resistin, 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 hefty correlations between resistin and obesity.  The underlying belief among those in support of this theory is that [[serum]] resistin levels will increase with increased [[adiposity]] (2, 4, 14, and 34).  Conversely, serum resistin levels have been found to decline with decreased adiposity following [[medical]] treatment (33). Specifically, [[central obesity]] (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin (19, 21). This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM (5, 8).
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 underlying belief among those in support of this theory is that [[Blood serum|serum]] resistin levels will increase with increased [[adiposity]].<ref name="p4"/><ref name="p34"/><ref name="p2">{{cite journal |vauthors=Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P | title = 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 | journal = Endocrinology | volume = 145 | issue = 5 | pages = 2206–13 |date=May 2004 | pmid = 14962997 | doi = 10.1210/en.2003-1679 | url =  }}</ref><ref name="p14">{{cite journal |vauthors=Lee JH, Bullen JW, Stoyneva VL, Mantzoros CS | title = Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia | journal = Am. J. Physiol. Endocrinol. Metab. | volume = 288 | issue = 3 | pages = E625–32 |date=March 2005 | pmid = 15522996 | doi = 10.1152/ajpendo.00184.2004 | url = }}</ref> Conversely, serum resistin levels have been found to decline with decreased adiposity following [[medical]] treatment.<ref name="p33">{{cite journal |vauthors=Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S | title = Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines | journal = Metab. Clin. Exp. | volume = 53 | issue = 4 | pages = 430–4 |date=April 2004 | pmid = 15045687 | doi = 10.1016/j.metabol.2003.11.022 | url =  }}</ref> Specifically, [[central obesity]] (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.<ref name="McTernan2002">{{cite journal|last1=McTernan|first1=P. G.|title=Increased Resistin Gene and Protein Expression in Human Abdominal Adipose Tissue|journal=Journal of Clinical Endocrinology & Metabolism|volume=87|issue=5|year=2002|pages=2407–2407|issn=0021-972X|doi=10.1210/jcem.87.5.8627}}</ref> This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.<ref name="p8"/><ref name="pmid14768774">{{cite journal |vauthors=Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS | title = The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity | journal = Diabetes Nutr. Metab. | volume = 16 | issue = 4 | pages = 243–50 |date=August 2003 | pmid = 14768774 | doi = | url =  }}</ref>
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the [[insulin resistance]] apparently associated with increased adiposity?  Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and [[insulin resistance]] (10, 25, 27, and 29).  This discovery is further authenticated by studies which confirmed a direct correlation between resistin levels and subjects with T2DM (2, 7, 20, and 30).  Provided that resistin is at least in part due to the insulin resistance coupled to T2DM, fabricating drugs which specifically target cascades leading to decreased serum resistin in T2DM subjects will surely deliver immense therapeutic benefits (32).
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the [[insulin resistance]] that appears to be associated with increased adiposity?  Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and [[insulin resistance]].<ref name="pmid12447443">{{cite journal |vauthors=Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS | title = A central role for JNK in obesity and insulin resistance | journal = Nature | volume = 420 | issue = 6913 | pages = 333–6 |date=November 2002 | pmid = 12447443 | doi = 10.1038/nature01137 | url = http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html }}</ref><ref name="p25">{{cite journal |vauthors=Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS | title = Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting | journal = Diabetes | volume = 53 | issue = 7 | pages = 1671–9 |date=July 2004 | pmid = 15220189 | doi = 10.2337/diabetes.53.7.1671 | url =  }}</ref><ref name="p27">{{cite journal |vauthors=Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ | title = Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance | journal = Eur. J. Endocrinol. | volume = 149 | issue = 4 | pages = 331–5 |date=October 2003 | pmid = 14514348 | doi = 10.1530/eje.0.1490331 | url =  }}</ref><ref name="p29">{{cite journal |vauthors=Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G | title = A promoter genotype and oxidative stress potentially link resistin to human insulin resistance | journal = Diabetes | volume = 52 | issue = 7 | pages = 1611–8 |date=July 2003 | pmid = 12829623 | doi =  10.2337/diabetes.52.7.1611 | url = }}</ref> This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM.<ref name="p30"/><ref name="p2"/><ref name="p7">{{cite journal |vauthors=Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M | title = Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes | journal = Clin. Chim. Acta | volume = 339 | issue = 1–2 | pages = 57–63 |date=January 2004 | pmid = 14687894 | doi = 10.1016/j.cccn.2003.09.009 | url =  }}</ref><ref name="p20">{{cite journal | author = McTernan PG | title = 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 | journal = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 12 | pages = 6098–106 |date=December 2003 | pmid = 14671216 | doi = 10.1210/jc.2003-030898 | url = |name-list-format=vanc| author2 = Fisher FM | author3 = Valsamakis G | display-authors = 3 | last4 = Chetty | first4 = R | last5 = Harte | first5 = A | last6 = McTernan | first6 = CL | last7 = Clark | first7 = PM | last8 = Smith | first8 = SA | last9 = Barnett | first9 = AH  }}</ref> If resistin does contribute to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects might deliver immense therapeutic benefits.<ref name="pmid17119268">{{cite journal | author = Tjokroprawiro A | title = New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer) | journal = Acta Med Indones | volume = 38 | issue = 3 | pages = 160–6 | year = 2006 | pmid = 17119268  }}</ref>


== Controversy ==
=== Arguments against ===
The amount of [[evidence]] supporting the resistin link theory between obesity and T2DM is vast.{{Citation needed|date=August 2012}}  Nevertheless, this [[theory]] lacks support from the entire [[scientific community]], as the number of studies presenting evidence against it continues to expand.<ref name="p6">{{cite journal |vauthors=Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M | title = Resistin release by human adipose tissue explants in primary culture | journal = Biochem. Biophys. Res. Commun. | volume = 300 | issue = 3 | pages = 674–8 |date=January 2003 | pmid = 12507502 | doi = 10.1016/S0006-291X(02)02864-4 | url =  }}</ref><ref name="p15">{{cite journal |vauthors=Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS | title = 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 | journal = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 10 | pages = 4848–56 |date=October 2003 | pmid = 14557464 | doi = 10.1210/jc.2003-030519 | url =  }}</ref><ref name="p24">{{cite journal |vauthors=Nagaev I, Smith U | title = Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle | journal = Biochem. Biophys. Res. Commun. | volume = 285 | issue = 2 | pages = 561–4 |date=July 2001 | pmid = 11444881 | doi = 10.1006/bbrc.2001.5173 | url =  }}</ref> Such studies have found significantly decreased serum concentrations of resistin with increased [[adiposity]],<ref name="p9">{{cite journal |vauthors=Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR | title = Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects | journal = J. Clin. Endocrinol. Metab. | volume = 89 | issue = 4 | pages = 1844–8 |date=April 2004 | pmid = 15070954 | doi = 10.1210/jc.2003-031410 | url =  }}</ref><ref name="p26">{{cite journal |vauthors=Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S | title = Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans | journal = Diabetes | volume = 50 | issue = 10 | pages = 2199–202 |date=October 2001 | pmid = 11574398 | doi = 10.2337/diabetes.50.10.2199 | url =  }}</ref><ref name="p36">{{cite journal |vauthors=Way JM, Görgün CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, ((Oliver WR Jr)), Willson TM, Kliewer SA, Hotamisligil GS | title = Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists | journal = J. Biol. Chem. | volume = 276 | issue = 28 | pages = 25651–3 |date=July 2001 | pmid = 11373275 | doi = 10.1074/jbc.C100189200 | url =  }}</ref> 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.<ref name="p22"/> The idea that resistin links obesity to T2DM is now under even more scrutiny, as recent investigations have confirmed ubiquitous expression of resistin in many tissues, rather than those only characteristic of obesity, such as adipocytes.


The amount of evidence supporting the resistin link theory between obesity and T2DM is vast and will most likely continue to grow.  Nevertheless, this theory lacks support from the entire scientific community at large as an increasingly greater number of studies presenting contradictory evidences continue to emerge (6, 15 and 24).  Such studies found significantly decreased serum concentrations of resistin with increased [[adiposity]] (9, 26, and 36) suggesting that not only is resistin downregulated in obese subjects but that it also presents itself as an unlikely candidate for linking [[obesity]] to T2DM.  Data has also been presented contradicting the idea that weight loss coincided with decreased serum resistin concentrations finding that it instead matched up with marked increases in serum resistin (22).  In reality, most all findings (many times elucidated under the same experimental conditions) reported by groups opposing the resistin link theory are the exact opposite from what those groups who support the theory have observed.  The idea that resistin links [[obesity]] to T2DM is now under even more scrutiny as recent investigations have confirmed a rather vast expression of resistin in many tissues rather than those only characteristic of obesity such as adipocytes.  
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 balance (biology)|energy homeostasis]], while also demonstrating properties that help to incite [[Inflammation|inflammatory responses]] to sites of [[infection]].


With nearly as many [[scientists]] against this theory as those scientists who seem to support it, the likelihood that resistin will ever be viewed as the key node linking [[obesity]] to T2DM in the near future is very low.  The very extent to which these two views oppose each other raises questions about the synchrony of methodology used in these respective groups which resulted in polar opposite results.  It is unsurprising, however, that a “discovery” linking T2DM to [[obesity]] via resistin-mediated pathways would not go unchallenged in a highly competitive scientific world.  Nevertheless, we can certainly conclude that among this giant debate lies sufficient evidence to support the idea that resistin does have some incompletely-defined role in energy homeostasis while also demonstrating properties which help to incite [[inflammatory responses]] to sites of [[infection]].
== Structure ==
 
{{Unreferenced section|date=October 2017}}{{Pfam_box
==References==
| Symbol = Resistin
{{refbegin|2}}
| Name = Resistin  
1.) Adeghate E. An update on the biology and physiology of resistin.  Cellular and Molecular Life Sciences.  61: 2485–2496, 2004.
| image =
 
| width =
2.) Asensio, C., Cettour-Rose, P., Theander-Carrillo, C., Rohner-Jeanrenaud, F. and Muzzin, P. 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: 2206–2213, 2004.
| caption =
 
| Pfam= PF06954
3.) Axelsson J, Bergsten A, Qureshi AR, Heimburger O, Barany P, Lonnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P.  Elevate 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, 2006.
| InterPro= IPR009714
 
| SMART=
4.) Degawa-Yamauchi MBJE, Juliar BE, Watson W, Kerr K, Jones RM, Zhu Q & Considine RV.  Serum resistin (FIZZ3) protein is increased in obese humans.  Journal of Clinical Endocrinology and Metabolism.  88: 5452–5455, 2003.
| Prosite =         
 
| SCOP = 1rgx 
5.) Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS.  The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity.  Diabetes Butr Metab.  16(4): 243-250, 2003.
| TCDB =
 
| OPM family= 384
6.) Fain JN, Cheema PS, Bahouth SW & Lloyd Hiler M.  Resistin release by human adipose tissue explants in primary culture.  Biochemical and Biophysical Research Communications.  300: 674–678, 2003.
| OPM protein= 1rgx
 
| PDB=   
7.) Fujinami, A., Obayashi, H., Ohta, K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M.  Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes.  Clin. Chim. Acta.  339: 57–63, 2004.
}}
 
8.) Gabriely, I., Ma, X. H., Yang, X. M., Atzmon G, Rajala MW, berg AH, Sherer P, Rossetti L, Barzilai N.  Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes.  51: 2951–2958, 2002.
 
9.) Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR.  Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects.  J Clin Endocrinol Metab.  89(4):1844-1848, 2004.
 
10.) Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS.  A central role for JNK in obesity and insulin resistance.  Nature.  420: 333-336, 2002. [http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html]
 
11.) Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W. Nelson C. Lowman HB, Wright BD, Skelton NJ, Franta GD, Tumas DB, Peale FV Jr, Shelton DL, Hebert CC.  FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family.  EMBO J.  19(15): 4046-4055, 2000.
 
12.) Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR.  Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro.  Biochem Biophys Res Commun.  309(2): 286-290, 2003.
 
13.) Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG.  The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes.  J Clin endocrinol Metab.  92(1): 270-276, 2007.
 
14.) Lee, J. H., Bullen, Jr, J. W., Stoyneva, V. L. and Mantzoros, C. S. Circulating resistin in lean, obese and insulin-resistant mouse models: lack of association with insulinemia and glycemia. Am. J. Physiol. Endocrinol. Metab.  288: E625–E632, 2005.
 
15.) Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS.  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):4848-4856, 2003.
 
16.) Levy, J. R., Davenport, B., Clore, J. N. and Stevens, W.  Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats.  Am. J. Physiol. Endocrinol. Metab.  282: E626–E633, 2002.
 
17.) Lu SC, Shieh WY, Chen CY, HSU SC, Chen HL.  Lipopolysaccharide increases resistin gene expression in vivo and in vitro.  FEBS Lett.  530(1-3): 158-162, 2002.
 
18.) Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M.  Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients.  Transpant Proc.  38(10): 3434-3436, 2006.
 
19.) McTernan, C. L., McTernan, P. G., Harte, A. L., Levick, P. L., Barnett, A. H. and Kumar, S. Resistin, central obesity, and type 2 diabetes. Lancet.  359: 46–47, 2002.
 
20.) McTernan, P. G., Fisher, F. M., Valsamakis, G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S.  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.  J. Clin. Endocrinol. Metab. 88: 6098–6106, 2003.
 
21.) McTernan, P. G., McTernan, C. L., Chetty, R, Jenner K, Fisher FM, Lauer MN, Crocker J, Barnett AH, Kumar S.  Increased resistin gene and protein expression in human abdominal adipose tissue. J. Clin. Endocrinol. Metab.  87: 2407, 2002.
 
22.) Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G & Vettor R.  Regional adipose tissue differences of resistin and adiponectin expression in genetically obese rats: effect of weight loss.  Obesity Research.  10:  1095–1103, 2002.
 
23.) Nagaev I, Bokarewa M, Tarkowski A, Smith U.  Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting Both Leukocytes and Adipocytes.  PLoS ONE.  1: e31, 2006.
 
24.) Nagaev I, Smith U.  Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem. Biophys. Res. Commun. 285: 561–564, 2001.
 
25.) Rajala, M. W., Qi, Y., Patel, H. R., Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes.  53: 1671–1679, 2004.
 
26.) Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV & O’Rahilly S.  Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator activated receptor-gamma action in humans.  Diabetes.  50: 2199–2202, 2001.
 
27.) Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL and Murphy LJ.  Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance.  Eur. J. Endocrinol.  149: 331-335, 2003.
 
28.) Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ.  Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependant pathway.  Biochem Biochys Res Commun.  334(4): 1092-1101, 2005.


29.) Smith, S. R., Bai, F., Charbonneau, C., Janderova, L. and Argyropoulos, G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 52, 1611–1618, 2003.
Crystal structures of resistin reveal an unusual composition of several subunits that are held together by [[non-covalent interaction]]s 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 sheet|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 bridge|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.


30.) Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes.  Nature.  409:307-312, 2001.
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.


31.) Stumvoll M & Haring H.  Resistin and adiponectin – of mice and men.  Obesity Research.  11: 1197–1199, 2002.
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.
 
32.) Tjokroprawiro A.  New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer).  Acta Med Indones.  38(3): 160-166, 2006.
 
33.) Valsamakis, G., McTernan, P. G., Chetty, R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S.  Modest weight loss and reduction in waist circumference after medical treatment are associated with favourable changes in serum adipocytokines. Metab. Clin. Exp.  53:430–434, 2004.
 
34.) Vendrell J, Broch M, Vilarrasa N, Molina A, Gomez JM, Gutierrez C, Simon I, Soler J & Richart C.  Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity.  Obesity Research.  12: 962–971, 2004.
 
35.) Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA.  Resistin promotes endothelial cell activation: further evidnce of adipokine-endothelial interaction.  Circulation.  108(6): 736-740, 2003.
 
36.) Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Wilson TM, Kliewer SA & Hotamisligil GS. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.  Journal of Biological Chemistry. 276: 25651–25653, 2001. [http://www.hsph.harvard.edu/GSH-LAB/labrefs.html]
 
37.) Wellen KE, Hotamisligil GS.  Inflammation, stress, and diabetes.  J Clin Invest.  115(5): 1111-1119, 2005. [http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html]
 
38.) Wulster-Radcliffe, M. C., Ajuwon, K. M., Wang, J., Christian, J. A. and Spurlock, M. E.  Adiponectin differentially regulates cytokines in porcine macrophages. Biochem. Biophys. Res. Commun.  316: 924–929, 2004.
 
39.) Yokota, T., Oritani, K., Takahashi, I., Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y.  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: 1723–1732, 2000.
 
40.) Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR, ''Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects.'' J Clin Endocrinol Metab 2004;89(4):1844-8. PMID 15070954.
 
41.) Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. ''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 2003;88(10):4848-56. PMID 14557464.
 
42.) Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. ''The hormone resistin links obesity to diabetes.'' Nature 2001;409:307-312. PMID 11201732.  
{{refend}}


== References ==
{{Reflist|2}}
<!--
This was reference 12, couldn't find any reference to it, although there were two references to ref. 22 so perhaps one of them should be to this one


{{Cite journal|pmid=12951047|year=2003|last1=Kaser|first1=S|last2=Kaser|first2=A|last3=Sandhofer|first3=A|last4=Ebenbichler|first4=CF|last5=Tilg|first5=H|last6=Patsch|first6=JR|title=Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro|volume=309|issue=2|pages=286–90|journal=Biochemical and Biophysical Research Communications|doi=10.1016/j.bbrc.2003.07.003}}
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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 adipose-derived peptide hormone 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]

Resistin has been shown to cause "high levels of 'bad' cholesterol (low-density lipoprotein or LDL), increasing the risk of heart disease [...] resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in arteries, increasing the risk of heart disease. [...] resistin adversely impacts the effects of statins, the main cholesterol-reducing drug used in the treatment and prevention of cardiovascular disease."[3]

Discovery

Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine.[4] 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).[4][5][6][7][8] Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.[9][10][11]

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.

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.[12][13][14][15]

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.[16][17] 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.[18] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[19] 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.[20]

In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation,[21][22] 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.[23] Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.

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 underlying belief among those in support of this theory is that serum resistin levels will increase with increased adiposity.[5][11][24][25] Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment.[26] Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.[27] This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.[6][28]

Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance that appears to be associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance.[29][30][31][32] This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM.[4][24][33][34] If resistin does contribute to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects might deliver immense therapeutic benefits.[35]

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 the number of studies presenting evidence against it continues to expand.[36][37][38] Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,[39][40][41] 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.[16] The idea that resistin links obesity to T2DM is now under even more scrutiny, as recent investigations have confirmed ubiquitous expression of resistin in many tissues, rather than those only characteristic of obesity, such as adipocytes.

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.

Structure

Resistin
Identifiers
SymbolResistin
PfamPF06954
InterProIPR009714
SCOP1rgx
SUPERFAMILY1rgx
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. ↑ 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/jc.87.6.2520. 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. ↑ "Canadian scientists discover cause of high cholesterol".
  4. ↑ 4.0 4.1 4.2 Steppan 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. PMID 11201732.
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  6. ↑ 6.0 6.1 Gabriely 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. PMID 12351432.
  7. ↑ 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. PMID 11832366.
  8. ↑ McTernan, CL; McTernan, PG; Harte, AL; Levick, PL; Barnett, AH; Kumar, S (2002). "Resistin, central obesity, and type 2 diabetes". The Lancet. 359 (9300): 46–47. doi:10.1016/S0140-6736(02)07281-1. ISSN 0140-6736.
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  13. ↑ 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. PMID 17062773.
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  17. ↑ 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. PMID 16039994.
  18. ↑ 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. PMID 12874180.
  19. ↑ 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. PMID 12387885.
  20. ↑ Wellen KE, Hotamisligil GS (May 2005). "Inflammation, stress, and diabetes". J. Clin. Invest. 115 (5): 1111–9. doi:10.1172/JCI25102. PMC 1087185. PMID 15864338.
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  24. ↑ 24.0 24.1 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): 2206–13. doi:10.1210/en.2003-1679. PMID 14962997.
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  37. ↑ 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. PMID 14557464.
  38. ↑ 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. PMID 11444881.
  39. ↑ 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. PMID 15070954.
  40. ↑ 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. PMID 11574398.
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