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Interleukin 6, Matrix Metalloproteinase-8 and Tissue Inhibitor-1 Levels in Obesity

Obesity is a nutritional disease characterized by excess of adipose tissue. It is
recognized as a low-grade chronic inflammation state characterized by increased
serum levels of acute phase proteins such as interleukins (ILs) and cytokines. IL-6 is
a proinflammatory cytokine, which is involved in the regulation of lipid metabolism
associated with obesity and inflammation. It plays numerous proinflammatory roles.
However, IL-6 may also play an anti-inflammatory role. Matrix metalloproteinases
(MMPs) participate in several physiological processes such as remodeling of extracellular
matrix (ECM), healing, angiogenesis and apoptosis. They are regulated by specific tissue
inhibitors (TIMPs) which block access to the active site of MMPs. A dual role for MMP-8
has been described under specific conditions: MMP-8 plays a role in the development
of the inflammatory response but appears to play an anti-inflammatory role during
recovery and may be crucial for this process.


Introduction
Obesity is a nutritional disorder characterized by excess of adipose tissue. The development of this disorder is associated with coordinated cellular processes, including adipocyte hypertrophy followed by recruitment of adipocyte precursors, and new fat cell differentiation. These processes are also accompanied by neovascularization, which is essential for generation and function of the tissue [1]. The development of obesity involves processes like adipogenesis and extracellular matrix (ECM) remodeling [2].
This disorder is recognized as a low-grade chronic inflammatory state, characterized by the increase of serum levels of acute phase proteins, such as C-reactive protein (CRP), and other interleukins and cytokines [3]. Evidences support that many co-morbidities of obesity, including type 2 diabetes mellitus, nonalcoholic fatty liver disease, steatohepatitis, asthma, cancer, cardiovascular diseases and neurodegenerative diseases, are related to the development of this low-grade chronic inflammation [4]. The primary cause of inflammation induced by obesity is not yet fully understood. The rapid expansion of the adipose tissue may produce intrinsic signals which might trigger an inflammatory response.
These signals include adipocyte death, hypoxia and mechanotransduction resulting from cells and ECM interactions [4]. Another explanation for this trigger may be endoplasmic reticulum stress [4][5][6]. Adipocyte hyperplasia and hypertrophy may cause mitochondrial and endoplasmic stress, which during fat overload releases additional inflammatory cytokines that can attract macrophages. During adipocyte hypertrophy the expression of Tumor Necrosis Factor α, Interleukin 6 (IL-6), Interleukin 1β and Prostaglandin E2 are induced, adipocyte die, and neutrophils, monocytes and T cells are consistently activated [5]. Out of all cytokines deregulated in obesity, IL-6 is one of the most common.
The high levels of this interleukin are consistently seen in obese rats and humans [7]. IL-6 is a proinflammatory cytokine, produced by several types of cells, including bone marrow cells and hepatocytes.
Some of the proinflammatory roles of this cytokine are B and T lymphocyte activation, growth and differentiation [8]. However, IL-6 may also have an anti-inflammatory role [9]. This cytokine is involved in the regulation of lipid metabolism associated with obesity and inflammation [10].
Matrix metalloproteinases (MMPs) are zinc and calcium dependent endopeptidases, which participate in several physiological processes such as ECM remodeling, wound repair, angiogenesis and apoptosis. MMPs are able to increase matrix plasticity, enabling adipose tissue remodeling and/or adipocyte hypertrophy [1]. They are secreted by various types of cells, such as inflammatory, neoplastic and epithelial cells, in the form of proenzymes, which require activation by proteolysis. This process is controlled by MMPs specific tissue inhibitors (TIMPs) [11]. TIMPs block access to the MMPs activation site. There are 4 known TIMPs (TIMP -1, -2, -3 e -4), that share similar structural characteristics and have an inhibitory specificity capable of inhibiting most of human MMPs [12]. ECM degradation, in addition to enabling cell migration, also leads to the release of signaling molecules such as chemokines, cytokines and growth factors. It has become widely accepted that MMPs play a central role in the direct activation of signaling molecules, which shows that MMPs also contribute to various aspects of immunity [13].
Recent data suggest that MMPs play an important role in inflammation and the regulation of the immune response. MMPs have been proposed as inflammation regulators, through proteolysis of chemokines, growth factors, receptors and their binding proteins, proteases and protease inhibitors, as well as intracellular multifunctional proteins, resulting in pro-or anti-inflammatory functions leading to tissue homeostasis or to pathology [14].
MMP-8, also known as collagenase-2 or neutrophils collagenase, plays different roles in regulating of inflammatory response. This MMP is quickly released when neutrophils are activated, in order to ensure their availability in inflammatory sites. A dual function has been described for MMP-8 under specific conditions: it plays a role in the development of the inflammatory response, but it seems to play an anti-inflammatory role during recovery and seems to be crucial to this process [13]. MMP-8 deficient mice showed delayed in the beginning and a slow clearance of local inflammatory infiltrates. Several immunological mediators, such as Macrophage Inflammatory Protein 1α, Interleukin 10 and Lipopolysaccharide-Induced Cytokine, were involved in that characteristic pattern and showed to be substrates of MMP-8 [15].

Discussion
Obesity is considered as a state of inflammation, in which adipose tissue and the liver are the main sources of cytokines and inflammatory proteins. This inflammation is local and is usually triggered and secondary to metabolic changes [18].

Expansion of adipose cells involves adipogenesis, angiogenesis
and ECM remodeling. This remodeling is carried out by MMPs, which are regulated through gene expression levels, by activating proenzymes and by TIMPs [19]. MMPs, in addition to playing their role in the degradation of ECM, are also considered inflammation markers [1,14]. Regarding the study population, participants were grouped according to body fat mass percentage. The group of obese individuals had a higher percentage of fat mass compared to normal weighted individuals, this difference being statistically significant (p ≤ 0,001). In relation to visceral fat mass percentage, the group of obese individuals had a higher percentage of visceral fat mass compared to individuals with excess weight, this difference being statistically significant (p < 0,05). This difference was even more significant between obese individuals and standard weighted individuals (p ≤ 0,001).
Although little is known about the biological effects of MMP-8, some studies have shown elevated levels of MMP-8 in atherosclerosis, childhood obesity and metabolic syndrome [20][21][22].
In the study by Andrade et al. lower serum MMP-8 levels were found in a population of obese women without comorbidities compared to the control group (19). Another study established evidence that, through its negative regulation, MMP-8 may have a protective or anti-inflammatory potential in human inflammatory diseases [23]. Lauhio et al. presented serum levels of MMP-8 significantly elevated in relation to standard weighted individuals [24]. In this study, MMP-8 levels were higher in the group of overweight individuals, compared to the group of standard weight and the group of obese individuals ( Figure 2). These discrepant results suggest that there are different mechanisms of ECM remodeling that can be activated in different diseases [19]. Proinflammatory cytokines, such as IL-6, can influence adipocyte function, lipid metabolism, homeostasis, blood pressure and insulin sensitivity, therefore they play an important role in the development of diabetes, atherosclerosis and cardiovascular diseases [3]. Studies is described as an adipokine and the increase in its expression is related to obesity, so it was expected a significant increase in its expression in the group of obese individuals, which was not verified [25]. This contradiction shows that different mechanisms may be involved in the regulation of TIMP-1 expression [26]. Total adipose tissue and visceral adipose tissue have been shown to be associated differently with glucose-insulin metabolism in standard weight and obese individuals. While total adipose tissue is the best predictor of insulin sensitivity in normal weighted individuals, visceral adipose tissue is the parameter that correlates most strongly with the variables related to glucose-insulin metabolism in obese individuals [27]. A study of obese Caucasian and African women showed that visceral adipose tissue was the strongest predictor of changes in glucose metabolism [28].
The moderate positive correlation between serum glucose levels and visceral fat mass percentage (r = 0,6112; p ≤0,0001) ( Figure 5) is in line with the study by Ross et al., who showed an association between visceral fat mass and blood glucose [27].

Park et al. showed a significant correlation between IL-6 levels
and visceral fat mass percentage [29]. In the study by Ghoski, et al. IL-6 mRNA expression in mouse models with polycystic ovary syndrome was increased in visceral adipose tissue compared to the control group [30]. In this study, a weak correlation was observed between IL-6 levels and visceral fat mass percentage (r = 0,2887; p = 0,0832) ( Figure 6). These results may be related to the fact that adipose tissue is endocrine and produces numerous factors that contribute to systemic inflammation [29]. Gonçalves et al.
showed high levels of MMP-8 in patients with metabolic syndrome, compared to the control group. This change was associated with increased concentrations of some inflammatory mediators, such as IL-6 [21]. In this study, a moderate positive correlation was observed between the serum levels of MMP-8 and the serum levels of IL-6 (r= 0,4510; p≤0.05) (Figure 7). This may indicate that they can be stimulated by the same mechanisms in the inflammation process.