Resistin: Difference between revisions
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=== Arguments against === |
=== Arguments against === |
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The amount of |
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 }}</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 | doi-access = free }}</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 }}</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 | doi-access = free }}</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 | doi-access = free }}</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 | doi-access = free }}</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. |
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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]]. |
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]]. |
Revision as of 20:07, 17 February 2021
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.[5]
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).[6]
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."[7]
Discovery
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine.[8] 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).[8][9][10][11][12] Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.[13][14][15]
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.[16][17][18][19]
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.[20][21] 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.[22] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[23] 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.[24]
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,[25][26] 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.[27] 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.
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.[28] one study reperesented 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)[29]
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.[9][15][30][31] Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment.[32] Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.[33] This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.[10][34]
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.[35][36][37][38] This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM.[8][30][39][40] 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.[41]
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.[42][43][44] Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,[45][46][47] 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.[20] 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 | |||||||||
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 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
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000012705 – Ensembl, May 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ a b Milan 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. PMID 12429872.
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- ^ 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. S2CID 45491974.
- ^ 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.
- ^ 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. PMID 15033490.
- ^ 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. PMID 10961870.
- ^ 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. PMID 16395259.
- ^ Elfassy Y, Bastard JP, McAvoy C, Fellahi S, Dupont J, Levy R (2018). "Adipokines in Semen: Physiopathology and Effects on Spermatozoas". International Journal of Endocrinology. 2018: 3906490. doi:10.1155/2018/3906490. PMC 6008818. PMID 29971101.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ Moretti E, Micheli L, Noto D, Fiaschi AI, Menchiari A, Cerretani D (2019). "Resistin in Human Seminal Plasma: Relationship with Lipid Peroxidation, CAT Activity, GSH/GSSG Ratio, and Semen Parameters". Oxidative Medicine and Cellular Longevity. 2019: 2192093. doi:10.1155/2019/2192093. PMC 6854241. PMID 31772701.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ a b Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P (May 2004). "Changes in glycemia by leptin administration or high- fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis". Endocrinology. 145 (5): 2206–13. doi:10.1210/en.2003-1679. PMID 14962997.
- ^ 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. PMID 15522996. S2CID 20609673.
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- ^ 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. PMID 14514348.
- ^ 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. PMID 12829623.
- ^ Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, et al. (January 2004). "Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes". Clinica Chimica Acta; International Journal of Clinical Chemistry. 339 (1–2): 57–63. doi:10.1016/j.cccn.2003.09.009. PMID 14687894.
- ^ 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. PMID 14671216.
- ^ 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. PMID 17119268.
- ^ 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. PMID 12507502.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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. PMID 11373275.
External links
- Resistin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)