Adipokines in Periodontal disease – Culprits or Accomplice?

Sanjeela R. Guru¹, Suchetha Aghanashini², Nitin Saroch³

¹Professor, Department of Periodontics, Vydehi Institute of Dental Sciences and Research Centre,

Whitefield, Bangalore - 560066, Karnataka, India.

²Professor and Head, Department of Periodontics, DA Pandu Memorial R V Dental College and Hospital,

J.P. Nagar, Bangalore - 560078, Karnataka, India.

³Professor and Head, Department of Periodontics, MN DAV Dental College, Solan,

Solan -173223, Himachal Pradesh, India.

*Corresponding Author E-mail: sanjeelaguru@yahoo.co.in, suchetha70@gmail.com, drnitinsaroch@gmail.com

ABSTRACT:

Periodontitis is a disease of periodontium resulting from pathogenic microorganisms combined with other risk factors. For many years, the relationship of obesity with periodontal disease has been debated. Recently, obesity is considered a risk factor for periodontitis. The pathomechanistic association studies have shown a link between adipose tissue secreted adipokines and periodontal disease, although the inherent mechanisms are obscure. Thus, this review aims to get an overview of the association between adipokines and periodontal disease. Adipokines, bioactive molecules secreted by adipose tissue, regulate energy outflow and insulin sensitivity apart from modulation of inflammation and healing. Obesity causes chronic low-grade inflammation and increases adipokines. Recent studies have also shown that adipokines, such as leptin, adiponectin, and visfatin, could play a role in periodontal disease progression and may be used as biomarkers. They increase the production of pro-inflammatory factors, creating a hyperinflammatory state that affects systemic diseases and enhances the risk for periodontitis and compromises healing post periodontal therapy. Understanding the function of adipokines may better help us interpret the triad of obesity with periodontitis and type 2 diabetes. Moreover, periodontal disease treatment may imply positive effects on the overall health of the individual.

KEYWORDS: Adipokines, Periodontal disease, Inflammation, Obesity, Type 2 diabetes, cardiovascular diseases.

INTRODUCTION: 

Adipose tissue plays a significant role in the management of energy homeostasis. This functional endocrine organ secretes close to 600 biologically active substances, collectively labelled as adipokines. Among these, the well-investigated adipokines include pro-and anti-inflammatory cytokines including Interleukin-1 beta (IL-1β), Tumour necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6); growth factors including vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β); chemokines including monocyte chemotactic protein-1 (MCP-1) and Interleukin-8 (IL-8) and; hormones including leptin, adiponectin, visfatin, and resistin.

These molecules play a wide variety of overlapping roles in inflammatory diseases, among which periodontitis is very common. However, there is paucity in the available literature on the relationship between adipokines and periodontitis. The present review highlights this relationship and discusses the role of adipokines as biomarkers for periodontal disease progression.

Etiopathogenesis of periodontitis:

Periodontitis is a multifactorial, chronic inflammatory disease characterized by slow and progressive degradation of the periodontal ligament and associated supporting structures. Among the other risk factors, many putative periodontopathogens, including Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Aggregatibacter actinomycetemcomitans etc have been implicated in the etiopathogenesis of periodontal diseases.^1,2 The host-microbial interactions result in the release of various immunological mediators, which cause destruction of the periodontal tissues.^1,3 The most important mediators include IL-1β, IL-6, IL-8, TNF-α, Prostaglandin E2 (PGE2) and matrix metalloproteinases (MMPs). Furthermore, environmental factors like stress, smoking, and genetics also play a significant role in disease progression. It is evident that periodontal therapy decreases the microbial load in the periodontal arena, thereby restoring the balance between pro-and anti-inflammatory mediators of inflammation with a resultant halt in disease progression. Additionally, various host modulating therapeutic agents may also be used to reduce the periodontal destruction caused by the host immune response.

Association of periodontitis with obesity:

Although periodontitis was previously considered a separate disease entity, however with time, the direct or indirect link between periodontitis and many systemic conditions, including diabetes mellitus, coronary heart diseases, pregnancy, among others, has become more apparent.^4,5,6 Similarly, many studies have indicated the relationship between obesity and periodontitis. While Perlstein and Bissada in 1977 for the first time demonstrated that obesity contributes to the severity of periodontal disease in an animal model,⁷ Saito et al. in 1998 demonstrated this relationship in humans wherein the relative risk of periodontitis was higher among overweight and obese patients than underweight patients.⁸ Based on the United States National Health and Nutrition Examination Survey III, body fat is a strong predictor of periodontitis in young adults but not in middle-aged and older adults. Findings of the recent meta-analysis by Brum etal.⁹ confirmed that periodontitis alters the levels of the inflammatory markers in obese patients and vice versa. 

Adipokines and metabolism:

In humans, there are two types of adipose tissues: brown and white. The brown adipose tissue has a significant role in tissue thermogenic activity while the white adipose tissue is the major storage of unit of energy.¹⁰ Adipose tissue is involved in the production and secretion of various proteins, including adipokines. The following section discusses the major adipokines:

1. Leptin:

Leptin, a 16 kDa non-glycosylated peptide hormone, is categorised as a cytokine due to its resemblance to long-chain helical cytokine family, specifically IL-6, IL-12, and granulocyte colony-stimulating factor.¹¹ Since the secretion of leptins is directly correlated to the size and number of adipocytes, plasma leptin levels are higher in obese individuals and lower during weight loss and lean individuals.¹² Leptin regulates metabolic activities such as appetite inhibition and stimulates energy use. It also modulates haematopoiesis, coagulation cascade, bone metabolism, insulin regulation and lipid metabolism. Leptin primarily has pro-inflammatory actions. It regulates T lymphocyte proliferation, activation, and cytokine production, chemotaxis and phagocytosis by macrophages(Table 1).^13,14

Table 1: Effects of adipokines on the innate and adaptive immune response

Leptin (Pro-inflammatory activity)^11-13	Innate immunity	Adaptive immunity
	↑ TNF ↑ IL-6 ↑ IL-12 ↑ Neutrophil activation ↑ Reactive oxygen species ↑ Chemotaxis ↑ NK-cell function	↑ Lymphopoiesis ↑ Thymocyte survival ↑ T-cell proliferation ↑ TH1 response (IL-2 and IFNγ) ↓ TH2 response (IL-4)
Adiponectin (anti-inflammatory activity)^26,28 (Pro-inflammatory activity)^25	↓ TNF-α ↓NF-kB ↓IL-6 ↑ IL-10 ↑ IL-1 RA ↓monocyte adhesion to endothelial cells ↓conversion of macrophage to foam cells ↓LPS stimulated osteoclast formation	↓T cell response ↓ lymphopoeisis
Resistin (Pro-inflammatory activity)^35,36	↑ TNF [36, 38] ↑ IL-1β [38] ↑ IL-6 ↑ IL-12 ↑ NF-κB ↑ Endothelial adhesion molecules (VCAM1 and ICAM1)	Not described yet
Visfatin^42,45 (Activity not established)	↑ IL-6 ↑ IL-8 ↓ Apoptosis of neutrophils	Not described yet
Apelin (anti-inflammatory activity)^48,49	↓ TNF-α ↓IL-1β ↓IL-6 ↓macrophage inflammatory protein-1a ↓vascular endothelial cadherin	Not described yet
Omentin (anti-inflammatory activity)^53,54	↓TNF-α induced cyclooxygenase expression ↓IL-6	Not described yet

During acute inflammation, the presence of inflammatory mediators such as cytokines and lipopolysaccharides stimulate the production of leptins levels. Multiple studies have reported altered leptin levels in saliva,¹⁶ gingival crevicular fluid (GCF)^16,17and plasma^18,19 during active periodontitis, which reverses after periodontal treatment. Selvarajan et al.²⁰ observed a substantial reduction in leptin levels in the GCF of patients with gingivitis and periodontitis. There was progressive decrease in leptin levels with disease progression. According to Shi et al.²¹ elevated plasma leptin levels in aggressive periodontitis patients was associated with increased systemic pro-inflammatory markers including Il-1β, Il-6, TNF-α. Similarly, Purwar et al.¹⁵ also reported increased serum leptin concentrations in periodontitis patients with significantly higher BOP, PI, PD and CAL. On the other hand, salivary leptin levels were significantly lower in periodontitis patients than healthy individuals. Apart from restoring the periodontal health, periodontal therapy also restored the serum and salivary leptin levels. Kardeşler et al.¹⁹ observed a significant decrease in the serum leptin levels in type-2 diabetes mellitus (T2DM) patients with periodontitis at three months following non-surgical periodontal treatment. On the other hand, Teres et al.²² and Goncalves et al.²³ did not observe an alteration in the leptin levels or other adipokines in the serum after periodontal therapy. Despite its pro-inflammatory properties and evidenced role in systemic inflammatory conditions, the exact role of leptins as an inflammatory marker in periodontitis needs to be validated.

2. Adiponectin:

Adiponectin, also known as Acrp30, apM1 or GBP28, is an important polypeptide adipokine having a molecular weight of 30-kDa and gene located on chromosome 3 at 3q27.²⁴ Based on the molecular weight, adiponectin is categorized into trimeric, hexameric and multimeric forms having low (LMV), medium (MMW) and high molecular weight (HMV), respectively.²⁴It plays a vital role in homeostasis control of glucose, energy and lipid metabolism and regulates glycemia, lipidemia, endothelial dysfunction and pro-inflammatory mechanisms. Serum adiponectin levels are inversely related to insulin resistance, increased fat and blood lipid levels; hence, markedly decreased levels are seen in patients with insulin resistance and T2DM, atherosclerosis, fatty liver disease(non-alcoholic) and obese individuals with visceral and central obesity.²⁵ Consequently,weight loss and normal BMI are important up-regulators of adiponectin synthesis.

Adiponectin has both pro-and anti-inflammatory properties. Predominant immunomodulatory properties include attenuation of TNF-α, inhibiting nuclear factor-kB, IL-6 production, and stimulating the anti-inflammatory cytokines such as IL-10 and IL-1 receptor antagonist (Table 1).^25,26 TNF-α, in turn, downregulates the transcription of adiponectin through the adipocytes in obese individuals, resulting in reduced serum adiponectin levels.²⁷ In oral cavity of healthy individuals, adiponectin receptors are widely expressed on oral epithelial cells, gingival fibroblasts, periodontal ligament cells, osteoblasts and bone marrow macrophages.²⁸Adiponectin inhibits the adhesion of monocyte to endothelial cells and down-regulates macrophage conversion to foam cells. Additionally, it downregulates lipopolysaccharides (LPS) stimulated osteoclast formationand stimulates the proliferation, differentiation and mineralization of osteoblasts.²⁹ HMW adiponectin has pro-inflammatory properties, and it may directly correlate with an inflammatory condition like periodontitis as well as systemic conditions including obesity and T2DM.

During periodontitis and inflammation, the expression of adiponectin decreases. In a recent meta- analysis Zhu et al.,³⁰ supported the decreased serum adiponectin levels in obese periodontitis patients than controls with lower BMI levels. As obesity is directly linked to decrease adiponectin levels, controlling obesity and weight loss (≥10%) alleviates the periodontal disease burden in chronic periodontitis patients.³¹ Conversely, Duzagac et al.³² reported similar response to periodontal therapy in periodontitis patients with or without obesity and no significant improvement in GCF adiponectin levels in obese periodontitis patients. Abdella et al.³³ demonstrated a positive correlation between periodontal therapy and improved glycaemic control, periodontal status with associated increase in serum adiponectin levels in T2DM patients with periodontitis. Although adiponectin is thought to inhibit alveolar bone loss in periodontitis patients, and has a protective role; however, a definite relationship between periodontal diseases and serum adiponectin levels has not been demonstrated so far.

3. Resistin:

The name ‘resistin’ was based on the original observation that it initiated insulin resistance in mice. Resistin, a 12.5 kDa cysteine-rich secretory protein with 108 amino acids, is primarily expressed in monocytes, macrophages, and bone marrow and very little is expressed in adipocytes.³⁴ Increased expression of resistin in the peripheral blood mononuclear cells (PBMCs) are stimulated by bacterial LPS, IL-1β, IL-6, and TNF-α, and the effects of resistin are mediated through the NF-κB signalling pathway. On the other hand, the pro-inflammatory nature of resistin triggers the production and secretion of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12, and monocyte chemoattractant protein (MCP)-1 (Table 1).³⁵Apart from its well-known role in insulin resistance and obesity, elevated levels of resistin in circulation are found in patients with cardiovascular disease, chronic kidney diseases, rheumatoid arthritis.³⁶

Previous studies have evaluated the associations of serum/GCF levels of resistin and periodontitis. Furugenet al.³⁷ demonstrated a positive correlation between gingival bleeding on probing and serum resistin levels in chronic periodontitis patients. While, Zimmermann et al.³⁸ suggested a positive relationship between circulating resistin levels and periodontitis. Offenbacher et al.³⁹ demonstrated the role of GCF resistin as an inflammatory mediator in the induction and resolution of experimental gingivitis in humans. Similarly, Thommesen et al.⁴⁰ reported a correlation between osteoclast differentiation and increased resistin levels, suggesting the potential role of resistin in bone metabolism. However, the exact mechanism of action of resistin in periodontal diseases is yet to be elucidated.

4. Visfatin:

Visfatin was first identified by Fukuhara et al. in 2005.⁴¹ It is a 52-KDa protein that up-regulates pre-B-cell colony release by lymphocytes and enhances B-lymphocyte maturation.It is secreted by both visceral adipose tissue and macrophages and present in bone marrow, muscle and dendritic cells. In addition to its cytokine-like effects, it also plays a role in energy metabolism. Visfatin enhances IL-1 β, IL-6 and TNF-α production secondary to infection and inflammation (Table 1).⁴² Since it inhibits the biosynthesis of nicotinamide adenine dinucleotide, it is identified as nicotinamide phosphoribosyltransferase. Visfatin is present in both GCF and saliva; its levels vary depending on physiological and pathological condition. In a comparative analysis between periodontitis patients and healthy individuals, Özcan et al.⁴³ reported a possible relationship between GCF visfatin levels and counts of Prevotella intermedia, Porphyromonas gingivalis, Prevotella nigrescense and Epstein-Barr virus (EBV). Moreover, visfatin levels increased with the presence of EBV, suggesting a positive association.

During periodontitis, visfatin stimulates the periodontal ligament cells to produce pro-inflammatory and proteolytic molecules. A positive correlation between serum and GCF visfatin concentrations and periodontitis has been suggested previously; wherein, the serum and GCF visfatin increased progressively with the severity of periodontal disease from gingivitis to severe periodontitis. Furthermore, elevated visfatin levels in periodontitis patients with T2DM as compared to those without T2DM.⁴⁴ Özcan et al.⁴⁵ investigated the relationship between visfatin levels and NF-κB (NF-κB1 and NF-κB2), TNF-α, IL-1 β and PI3k in tissues of periodontitis patients and healthy individuals. They reported an increased expression of NF-κB and PI3k directly proportional to the increasing visfatin levels, suggesting visfatin’s possible immunomodulatory role during the inflammatory process. Raghavendra et al.⁴⁶ and Abolfazli et al.⁴⁷ reported a significant reduction in the serum, GCF and salivary visfatin levels following periodontal therapy. In periodontitis patients with T2DM highest visfatin levels were reported despite periodontal therapy, implying that T2DM patients with high visfatin levels are at increased risk of periodontitis. However, with limited data and prospective trials, the role of visfatin in periodontal diseases is not well established yet, and further research is warranted in this field to establish the association if any.

5. Apelin:

Apelin is a short peptide released from adipocytes upon stimulation. Currently, three forms of apelin containing 13, 17, or 36 amino acids have been identified, derived from a common precursor containing 77 amino acids. Receptors for apelin are found in many vital tissues such as the heart, skeletal muscle, lungs, brain, etc. It exerts varied physiological effects on individual systems, primarily the cardiovascular system. Apart from modulating insulin secretion, apelin also plays a role in glucose and lipid metabolism. Insulin stimulates apelin synthesis, and increased plasma apelin levels are seen during obesity, obesity-associated insulin resistance and hyperglycaemia (T2DM).⁴⁸

Koguchi et al.⁴⁹ classified apelin as an anti-inflammatory cytokine. It supresses the pro-inflammatory factor expression including, TNF-α and IL-1β during inflammation. Leeper et al.,⁵⁰ in an animal model, demonstrated a significant reduction in the macrophage colony-stimulating factor, monocyte chemoattractant protein-1, IL-6, macrophage inflammatory protein-1a and TNF-a TNF-α mRNA following apelin treatment (Table 1). They further highlighted that apelin suppresses hyper-permeability by inhibiting vascular endothelial cadherin confirming the anti-inflammatory action of apelin. These findings were supported by Visser et al.⁵¹ who advocated the therapeutic use of apelin in suppressing inflammation.On the contrary, Heinonen et al.⁵² reported pro-inflammatory properties of apelin in patients with metabolic syndrome post-diet-induced weight loss. At present, the function of apelin in acute and chronic inflammation, particularly in periodontal diseases, is not clearly established, and further investigations are required in this field.

6. Omentin 1:

Omentin or intelectin is a 40 kDa protein is made up of 313 amino acids.  It is a product of adipose tissue stromal cells, first identified during the cDNA library evaluation of the visceral adipose tissue. In humans, two forms of omentin are identified:  omentin-1 and omentin-2. Among them, Omentin-1 is the key form found in circulating blood. Obesity reduces the secretion and serum concentrations of omentin.⁵³ By increasing insulin-facilitated glucose uptake by subcutaneous tissue and omental adipocytes,omentin enhances insulin actions. It also exhibits anti-inflammatory, anti-diabetic and anti-atherogenic characteristics.⁵³ Immunomodulatory properties of omentin-1 include, inhibiting pro inflammatory cytokines such as IL-6, TNF-α and TNF-α-induced cyclooxygenase (COX2) expression.^54,55

The role of omentin-1 in the modulation of bone metabolism is ambiguous. While few studies conducted on mice⁵⁶ and patients with multiple sclerosis⁵⁷ reported the ability of omentin-1 in suppressing bone resorption thereby, preventing bone loss, osteoporosis and promoting bone formation.Other studies have reported a negative effects of omentin-1 on bone turnover markers which inhibited bone formation at various skeletal sites.⁵⁸ Doğan et al.⁵⁹ reported significantly lower GCF omentin-1 levels in periodontitis patients than healthy patients and the omentin-1 levels increased following periodontal therapy. These findings suggest the potential use of omentin as an inflammatory marker of diabetes, periodontal disease and treatment outcome. However, further studies are warranted to evaluate the exact role of omentin-1 on bone metabolism and periodontitis.

7. Adipocyte-derived plasminogen activator inhibitor-1 (PAI-1):

Plasminogen activator inhibitor-1 (PAI-1) secreted by the adipocytes is a crucial inhibitor of plasminogen activators. It belongs to the serine proteinase inhibitor family, and majority of PAI-1 are secreted by the white adipose tissue, specifically visceral adipose tissue, compared to subcutaneous adipose tissue. Along with inhibiting fibrinolysis, PAI-1 also has a complex interaction with cellular matrices and further inhibits proteolysis. PAI-1 levels in the plasma are related to overall fatness (BMI), particularly the omental fat and are elevated in obese individuals. PAI-1 is known to be associated with metabolic syndrome in obesitywhich is characterized by dyslipidemia, hypertension, and glucose intolerance.⁶⁰ During inflammation, increased TNF-α expression and increased infiltration of the adipose tissue by macrophages result in lipolysis, thereby causing increased release of PAI-1.Studies on plasminogen activating systems in GCF and gingival tissues have remonstrated higher levels of PAI-2 and t-PA, and lower levels at localized gingival inflammatory sites. Debnath et al.⁶¹ demonstrated that impaired PAI-1 is associated with increased risk of chronic periodontitis and associated alveolar bone loss. However, the role on PAI-1 in periodontitis is yet to be elucidated. 

Biological significance of adipokines in periodontal disease progression:

As already discussed in the previous sections, adipokines are bioactive molecules that have an active role in the genesis of inflammation and insulin resistance associated with obesity. At present, there is evidence that obesity-related diseases could be a result of dysregulated production of adipocytokines. TNF-α, leptin, and resistin affect insulin sensitivity in the whole body.⁶² It is a well-established fact now that increased production of TNF-α is associated with insulin resistance. Hence, it is clear from the above discussion that certain risk factors for T2DM and periodontitis are the same. The association of adipokines and periodontal disease progression has been a focus of research for the last few years. Different researchers have made multiple observations and at present, there is insufficient data to establish a well-defined relationship between various adipokines and periodontitis. As already stated, there are multiple adipokines in white adipose tissue. Only a few of them have been studied so far. Hence, this field is wide open for research.

CONCLUSION:

Periodontal diseases are primarily inflammatory diseases and have multifactorial aetiology. Various biological mediators such as cytokines, chemokines, and locally secreted enzymes by various immune cells play a vital role in periodontal disease progression. Various adipokines are biologically active molecules and are associated with insulin resistance and T2DM. Hence, these may also participate in periodontal disease progression. The role of leptin, adiponectin, resistin, visfatin, apelin and omentin 1 have been described in the inflammatory process. Only a few studies have been undertaken so far to evaluate the association between these mediators and their possible role in the periodontal inflammatory process. Thus, more research is desired to clarify various aspects of adipokines in periodontal health and disease in the future.

CONFLICT OF INTEREST:

The Authors declare that they have no conflict of interest

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Received on 28.10.2021            Modified on 10.05.2022

Accepted on 18.09.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(4):2061-2067.

DOI: 10.52711/0974-360X.2023.00339