Role of Resistin in Various Diseases with Special Emphasis on Periodontal and Periapical Inflammation – A Review

ABSTRACT

Resistin is a small adipocyte-specific secretory hormone molecule. It has been associated with a number of cellular and metabolic processes. It has also been essentially implicated to have a vital role in the interplay between insulin resistance, obesity, and type II diabetes. Numerous clinical studies have demonstrated an association between many pathological illnesses with elevated serum resistin levels. It has also been shown to affect and modulate various molecular processes such as atherosclerosis, cancer cell metabolism, and inflammation. Periodontitis is a widespread inflammatory disease affecting human beings. Periapical periodontitis is an inflammatory disease that manifests as a sequela of untreated dental caries. Therefore, in this article, we summarize the divergent physiological roles played by resistin and its association with the mechanism of various pathologies. Moreover, current scientific studies discussing its association and role in common dental pathologies, periodontitis, and apical periodontitis are reviewed.

INTRODUCTION

Resistin (Retn) is a newly discovered cysteine-rich peptide hormone released by adipocytes, astrocytes, intestinal epithelium, monocytes, and skeletal muscle cells.[1-4] It is a member of the cysteine-rich protein family. It has recently been discovered to be pertinent to diseases associated with inflammation. It plays a significant role in amplifying the inflammatory state associated with a number of disorders, including cardiovascular diseases, metabolic syndrome, and type 2 diabetes.[5] Moreover, it is connected with serum C-reactive protein (CRP).[6] It is an endogenous ligand of Toll-like receptor 4 that activates a number of inflammatory signals.[7] It also plays a variety of roles in the human body, one of which is bone remodeling.[8] It was named resistin for its capacity to inhibit (resist) the action of insulin.[1]

Retn belongs to the family of tissue-specific signaling molecules called resistin-like molecules. Retn is a 12.5 kDa (108 amino acids) c-terminal cysteine-rich protein peptide with its gene located on chromosome 19 in humans.[9] On the surface of adipose tissue progenitor cells, decorin, a molecule secreted in the extracellular matrix, was identified; decorin and its isoforms may function as functional resistin receptors in peripheral tissues.[10,11] Resistin has also been found to bind to the receptors such as cytoskeletal protein cyclase-associated protein 1 (CAP1), Receptor Tyrosine like Orphan Receptor 1 (ROR1), and Toll-like receptor 4 (TLR4) and activate these signaling cascades.[12]

PHYSIOLOGICAL ROLE OF RESISTIN

Adipokines modulate various physiological processes such as appetite, blood pressure, endothelial functions, energy expenditure, fat distribution, glucose metabolism, hemostasis, immunity, insulin sensitivity and secretion, lipid metabolism, and neuroendocrine functions [Table 1].[13] Resistin is an adipokine which appears to have multiple roles in the human physiology. In the embryonic stage, placenta produces resistin, which is then released into the maternal and fetal compartments, and it appears to have a favorable effect on the pregnancy.[14]

Table 1.

Functions of Resistin

Authors	Role of Serum Resistin
Badoer et al. 2015[16] and Badoer E 2021[17]	It has an influence on the sympathetic nerve activity within the central nervous system.
Acquarone et al. 2019[18]	It regulates glucose metabolism.
Jamaluddin et al. 2012[4] and Qiu et al. 2014[19]	It can directly trigger complement system activation.
Filková et al. 2009[20]	Its primary physiological function appears to regulate inflammatory, immunological, and auto-immune reactions.
Filková et al. 2009[20]	It plays a role in chemotaxis and leuckocyte recruitment at sites of inflammation.
Qi et al. 2008[21]	It enhances the Th1 immune response
Morash et al. 2002[3]	Possible role during prepubertal maturation of the hypothalamic-pituitary system.
Chen et al. 2020[22]	It leads to adhesion molecule expression (including TNF-a/IL-6).
Mesiano 2019[14]	It appears to favor pregnancy by upregulating the supply of nutrients to the fetus.

The various adipokines that have been identified include apelin, C1q/TNF-related proteins (CTRPs), chemerin, diponectin, the family with sequence similarity to 19 member A5 (FAM19A5), follistatin-like 1 (FSTL1), leptin, lipocalin-2 (LCN2), nesfatin-1 (nesfatin), omentin, plasminogen activator inhibitor-1 (PAI-1), progranulin (PGRN), resistin, retinol-binding protein 4 (RPB4), secreted frizzled-related protein 5 (SFRP5), secreted protein acidic and rich in cysteine (SPARC), vaspin, visfatin, and wingless-type inducible signaling pathway protein-1 (WISP1).[15]

RESISTIN AND ITS ROLE IN PATHOGENESIS OF VARIOUS DISEASES

Adipokines are crucial elements of the neuroendocrine-immune network and serve as molecular bridges between many diseases and obesity.[23] Resistin is a pro-inflammatory adipokine that shows increased serum levels in various immunological disorders such as cardiovascular diseases, rheumatoid arthritis, or sepsis. It is also elevated in cancer patients and is associated with the aggressiveness of cancer cells. Last, it plays a pivotal role in obesity, hypercholesterolemia, and type II diabetes mellitus.[12] The various studies that have shown an association between increased resistin levels and different pathologies are summarized in Table 2. However, caution must be exercised in interpolating the results as many of the studies as they are observational and hence are prone to bias and cannot demonstrate casualty.[24]

Table 2.

Role of resistin in the pathogenesis of various diseases

Authors	Pathogenesis	Disease
Al Mutairi et al. 2011,[25] Ballantyne et al. 2016,[26] and Al-Asy and Mabrouk 2017[27]	It is a disease marker and predictor of asthma risk. It may play a contributory role in obese asthma phenotype.	Asthma
Baker et al. 2011[28]	Resistin levels are elevated in subjects with SLE.	Autoimmune diseases (lupus erythematosus)
Deb et al. 2021[12]	It plays a role in increasing the aggressiveness of cancer cells.	Cancer
Konrad et al. 2007[29] and Ortega Moreno et al. 2020[30]	Higher serum resistin levels were observed.	Crohn’s disease
Zhou et al. 2021,[31] Rashid 2013,[32] and Reilly et al.[33]	Possible role in the aggravation of inflammation and dyslipidemia. The presence of resistin in atherosclerotic plaques is suggestive of being a key molecule in the pathological process of atherosclerosis formation.	Atherosclerosis
Malo et al. 2011[34] and Singh et al. 2015[35]	Increased resistin levels are associated with metabolic disturbances. Increased resistin levels are associated with metabolic risk factors.	Metabolic diseases
Reddy et al. 2015[36] Colica and Abenavoli et al. 2018[37]	Elevated levels of resistin are observed. These levels seem to correlate with liver damage.	Non-alcoholic fatty liver disease
Tariq et al. 2022,[8] Mohiti-Ardekani et al. 2022,[38] and Kawai et al. 2012[39]	Conflicting observational studies with a growing body of scientific literature showing higher resistin levels to be associated with a lower bone mineral density and greater risk of fractures.	Osteoporosis
Al-Hamshary et al. 2016,[40] Menzaghii et al. 2012,[41] Baker et al. 2011,[28] Tabara et al. 2008,[42] Ellington et al. 2007,[43] and Nüsken et al. 2006[44]	Resistin levels have been variably associated with renal dysfunction	Renal failure
Pellicano et al. 2022[45]	It has been implied in microvascular dysfunction. It is indicated as a marker for digital ulcers in systemic sclerosis.	Systemic sclerosis
Rashid 2013[32]	In obesity-induced dyslipidemia, detrimental adipose tissue resistin secretion occurs.	Dyslipidemia
Del Cristo Rodríguez Pérez M et al. 2022[46]	It raises the risk of death from all causes in the general population.	Mortality
Devanoorkar et al. 2014,[5] Gharibeh et al. 2010,[47] and Qatanani et al. 2009[48]	It is linked to insulin resistance	Diabetes mellitus (type 2)
Gharibeh et al. 2010[47]	Suggestive of role in obesity. Positively associated with weight circumference.	Obesity
Kougias et al. 2005[49] and Ramirez et al. 2019[9]	It can trigger endothelial dysfunction.	Adverse cardiac events.
Moretti et al. 2019[50]	Resistin levels are seen elevated in cases of leukocytospermia and may have a detrimental effect on spermatogenesis.	Male infertility

RESISTIN IN PERIODONTAL INFLAMMATION

Periodontitis is a multi-factorial disease characterized by multi-bacterial low-grade infection along with dysbiotic biofilm and an exaggerated host-immune inflammatory system. A variety of inflammatory mediators are released from inflamed periodontium, and they could be detected in periodontal tissue, gingival crevicular fluid (GCF), and saliva.[5,51] Nogueira et al.[52] showed in a recent study that periodontal tissues and cells produce resistin. Additionally, microbial and inflammatory stimuli increase the periodontium’s expression and synthesis of resistin. Furthermore, resistin appears to disrupt the metabolism of soft and hard tissues during periodontitis by lowering alkaline phosphatase (ALP) activity and markers of bone and matrix formation. Several observational studies have shown that resistin elevated significantly in GCF, saliva, and serum among periodontitis patients.[53–57] In a study among elderly individuals in Japan, Furugen et al.[54] found that subjects with periodontitis with at least one tooth with a probing pocket depth of more than 6 mm had serum resistin levels that were twice as high in participants without periodontitis. In a study by Devanoorkar et al.,[58] they found that serum resistin levels were elevated in periodontitis patients. They also found that the serum resistin levels decrease post non-surgical periodontal therapy (NSPT). However, their study did not show the changes to have statistical significance. However, a study among diabetic patients by Joshi et al.[59] found that NSPT led to a statistically significant reduction of GCF resistin levels. Hence, they observed that resistin levels could be used as an inflammatory biomarker for diabetes-related periodontal disease. Further similar results were found among obese patients with periodontitis.[60] However, in another study by Md Tahir et al.,[61] the authors observed no significant correlation between the impact of NSPT and resistin levels.

RESISTIN IN PERIAPICAL INFLAMMATION

Apical periodontitis is an inflammatory condition of periapical tissues caused by the host’s immune response to pulpal infection and irritants of endodontic microbial origin.[62,63] Resistin is ‘‘found in inflammatory zone” (FIZZ) protein that is present in connective tissue inflammation. However, its presence in inflamed pulp and if it plays any role in pulpal pathology and inflammation are yet to be studied.

CONCLUSION

Resistin is an adipokine, peptide hormone with a pro-inflammatory effect on different tissues. Its role in various physiological and pathological states is still unraveling. As we understand the mechanisms by which it interacts and modulates physiological processes along with its pathologic secretion, we would be able to appropriately use it as a biomarker and a protein of therapeutic interest. Hence, this review sums up the current scientific knowledge about resistin with an emphasis on periodontal and periapical inflammation.

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Conflicts of interest

There are no conflicts of interest.