Fig 1-2 Mechanism of osteoclast differentiation and activation (IFNγ = interferon-gamma; IL = interleukin; M-CSF = macrophage colony-stimulating factor; OPG = osteoprotegerin; RANKL = receptor activator of nuclear factor kappa B ligand; SPM = specialised pro-resolving mediators; TNF-α = tumour necrosis factor alpha).
Fig 1-3a and b a Osteoclast differentiation and activity. b Pathological bone resorption and the impact of obesity and DM on pro-inflammatory mediator and adipokine accumulation. (BMC = bone marrow cell; IL = interleukin; M-CSF = macrophage colony-stimulating factor; M-CSFR = M-CSF receptor; OB = osteoblast; OC = osteoclast; OPG = osteoprotegerin; RANK = receptor activator of nuclear factor kappa B; RANKL = RANK ligand; TNF-α = tumour necrosis factor alpha.)
1.3.3 Adipokines
Obesity, as a chronic condition, produces a low-grade inflammation, increased chronic oxidative stress, and activation of innate immune system that affects homeostasis over time141. Several chronic diseases are also the result of obesity (e.g., metabolic syndrome, DM, liver and cardiovascular diseases, and cancer) and associated with oxidative stress.
The obesity-induced pro-inflammatory status affects insulin resistance142 and secretion143 by production and release of adipokines144. Adipokines are a group of over 600 molecules produced by adipose tissue145. They act as paracrine and endocrine hormones146 and thus regulate processes like appetite and satiety, fat distribution, inflammation, blood pressure, haemostasis and endothelial function, acting in different organs including adipose tissue itself, brain, liver, muscle and blood vessels143,144. Among the adipokines, adiponectin, leptin, TNF-α, OPG, IL-6, resistin, IL-1, apelin, visfatin, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and retinol binding protein 4 (RBP4) have been widely investigated143,147. The overproduction of some adipokines in obese subjects is known to contribute to diabetes pathogenesis.
The mechanistic link between obesity, DM and adipose tissue inflammation was first proposed based on the finding that the level of the TNF-α, produced by macrophages, was increased in adipose tissue of obese rodents and humans and that its blockage led to improvement in insulin sensitivity148. Macrophages are able to infiltrate adipose tissue of obese mice and humans. Nearly 40% to 50% of total cells are macrophages in mice, and the major source of TNF-α149,150. TNF-α binds to TNF receptors 1 and 2, and mediates apoptosis, insulin resistance, lipolysis, inhibition of insulin-stimulated glucose transport and insulin receptor autophosphorylation146,150,151. In adipocytes, TNF-α reduces glucose transporter type (GLUT)-4 expression, leading to insulin resistance and atherogenic dyslipidaemia150.
IL-6 is also released by adipocytes, so it can be considered an adipokine. Obese individuals release greater amounts of IL-6 due to their larger amount and size of adipocytes, explaining a state of low-grade inflammation in these individuals152,153. IL-6 has multiple functions and its exact metabolic role is still controversial. For example, chronically elevated IL-6 levels lead to an impairment of the insulin-mediated glucose uptake by muscle cells154. On the other hand, acutely elevated IL-6 produced by skeletal muscle during exercise can increase glucose uptake and fatty acid oxidation in these cells152,155. TNF-α and IL-6 are also expressed by inflamed periodontal sites due to microbial stimuli. These mediators enter the systemic circulation, interfere with the function of insulin receptors and thereby derange the process of insulin signalling156.
Another adipokine, leptin, was the first adipokine known to be associated with direct pancreatic effects and is certainly the most studied of all adipokines. It has a potent inhibitory effect on insulin secretion from pancreatic β-cells, and has the additional effect of reducing pre-pro-insulin gene expression157; however, these observations are controversial. A study published by Brown et al158 demonstrated that leptin has a U-shape response in human islets, with lower concentrations inhibiting insulin release and higher levels having a relatively stimulatory effect. This finding provides an explanation for the existence of the conflicting reports158. Patients with periodontitis have reduced leptin levels in their GCF compared with periodontally healthy individuals159,160. On the other hand, periodontitis results in increased plasma levels of leptin, whereas periodontal therapy causes a decrease in the plasma leptin levels161,162. Adiponectin, on the other hand, has beneficial effects on obesity and diabetes. It improves insulin sensitivity and vascular function, thus being both anti-diabetes163 and anti-atherogenic164. It also inhibits apoptosis of β-cells and increases their proliferation. It is likely that the ratio of adiponectin to leptin (and other adipokines) is a determinant of the effects of the adiposity-induced altered adipokine levels on β-cell function165.
Another important adipokine is visfatin. It is increased in obesity and other systemic diseases. Visfatin can generate reactive oxygen species (ROS) comprising both superoxide and hydrogen peroxide (H2O2) and producing oxidative stress166. Nokhbehsaim et al167 observed that visfatin upregulates gene expressions of matrix-metalloproteinase (MMP)-1 and C-C motif chemokine ligand (CCL)-2 in periodontal ligament cells. MMP-1 plays a critical role in modelling and remodelling of the periodontal extracellular matrix by degradation of collagens167. Clinical studies have already demonstrated that gingival levels of MMP-1 are enhanced at sites of periodontitis and can be reduced by periodontal treatment168,