Inflammation and Bone Turnover Markers in Adult Obesity
Corresponding author: Dr. F. Hümeyra Yerlikaya, N. Erbakan Universitesi, Meram Tıp Fakültesi, Biyokimya Anablim Dalı, Konya-TURKEY Tel 0 332 / 223 77 61; E-mail: firstname.lastname@example.org
Obesity is a condition of abnormally increased body fat, resulting from increased energy intake relative to energy expenditure . Excess body weight is a risk factor for many somatic and psychological disorders, including cardiovascular disease, type 2 diabetes mellitus, osteoarthritis and several cancer types . Vitamin D3 and parathyroid hormone (PTH) are well known for their essential role in bone metabolism and calcium homeostasis . Obese individuals, as a group, have low plasma concentrations of Vitamin D3, which are associated with increased plasma concentrations of PTH [4-6].
In isolated adipocytes, it has been demonstrated that PTH increases the cytosolic calcium level, which may impede the catecholamine-induced lipolysis and also promote expression of fatty acid synthase. This would lead to accumulation of fat, and accordingly, it has been hypothesized that PTH and vitamin D3 may be of importance for the development of obesity .
Bone metabolism, bone turnover, and mineral content are altered in severe obesity [5,8]. Not only do bones produce a protein hormone, osteocalcin, that regulates bone formation, but this hormone also protects against obesity and glucose intolerance by increasing proliferation of pancreatic beta cells and their subsequent secretion of insulin. Osteocalcin was also found to increase the body’s sensitivity to insulin and as well as reducing its fat stores . Alkaline phosphatase (ALP) is a membrane-bound enzyme found in a wide variety of tissues, including liver. The existence of ALP in human preadipocytes is of interest because it is conceivable that adipose tissue might be a source of serum ALP [10,11].
Numerous articles have published that obese subjects had significantly lower 25-OH Vit D3 concentrations as compared with normal weight subjects [4,12-14] and obese children . Since, 25-OH Vit D3 concentrations increased after reduction of overweight, this finding points a consequence rather than a cause of overweight . The low levels of 25-OH Vit D3 may be attributed to several factors such as decreased exposure to sunlight in obese subjects due to limited mobility, lifestyle, body shape, sensitivity or cultural reasons for precluding skin exposure to view, or the excessive deposition of vitamin D in adipose tissue [3,12]. The increase in serum 25-OH Vit D3 after sun exposure was reported to be 57% less in obese compared with normal weight people. Also, adipose tissue is a major storage site of vitamin D .
In addition, obesity-associated vitamin D insufficiency may be due to the decreased bioavailability of vitamin D3 from cutaneous and dietary sources because of its deposition in body fat compartments . The finding of most studies have reported that elevated PTH levels in obese people [7,14]. Kamycheva et al. and Ahlström et al. have also observed that serum PTH concentrations were positively associated with BMI [15,16].
Obesity, older age, and reduced daily intakes of calcium and vitamin D are associated with higher levels of PTH. Accordingly, weight reduction and higher intakes of calcium and vitamin D have been associated with decreases in PTH levels . Increased PTH promotes calcium influx into the adipocytes. In these cells, intracellular calcium enhances lipogenesis, and therefore, PTH excess may promote weight gain .
Osteocalcin, secreted by osteoblasts, is also involved in the regulation of body energy in that it modulates fat and glucose metabolism . Holecki et al. have found that serum osteocalcin concentration was significantly lower in obese perimenopausal women than in control subjects . Im et al. have reported a statistically significant negative correlation between serum osteocalcin levels and BMI . On the other hand, Perfetto et al.  have found no significant difference between serum osteocalcin concentrations of the obese and nonobese women groups. Sayinalp et al.  have reported no correlation between weight or BMI and osteocalcin. Although the relationship between serum osteocalcin and obesity was not fully understood, Lee et al.  have found that mice with high levels of osteocalcin did not gain weight even when they were fed a high fat diet, which demonstrated the anti-obesity action of osteocalcin.
Khan et al. have reported that an ALP isozyme was found to be expressed in adipocytes, which is implicated to raise fat depots during the course of enhanced adipogenesis in obesity . This high fat deposition might add surplus leptin into the blood circulation of the obese subjects. The presence of an ALP isozyme in adipocytes is conceivable that adipose tissue might be a source of serum ALP. Furthermore, increased serum ALP concentration in obese versus non-obese subjects is a clue for additional release of ALP from adipose tissue in obesity . Ali et al.  have found that serum ALP levels was positively associated with obesity. Choi has  observed that serum ALP levels was positively associated with BMI in overweight women. In another study, serum ALP levels was found to be positively correlated with visceral adipose tissue in overweight and obese patients .
The existence of ALP in human preadipocytes is of interest because it is possible that adipose tissue might be a source of serum ALP. Furthermore, the positive relationship between measures of abdominal obesity and serum liver enzyme levels demonstrates that adipose tissue mass also can influence the release of liver products into the circulation. It is possible that the higher level of liver ALP in obese than in normal weight subjects is a result of ALP release from adipose tissue .
Obesity, in general, is thought to be associated with a chronic inflamatory state [23,24]. The adipocyte is an important source of cytokines, namely interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-alpha, and their levels are significantly higher in the plasma of obese patients [25,26]. The rise of these cytokines, such as IL-1 β and TNF-alpha induce ferritin production within macrophages, hepatocytes and adipocytes [27,28], and especially in IL-6, triggers an increased synthesis of CRP [25,26]. The neutrophil ALP source is used in the diagnosis of hematological diseases. ALP is often raised in sepsis together with CRP . Hanley et al  and Kim et al  have found that CRP and ALP are both elevated in atherosclerosis. The result of previos reports showing a raised serum ALP level in obese subjects [29, 32]. According to their hypothesis, ALP may be another marker of systemic inflammation in morbid obese subjects.
White blood cell count is also routinely measured marker of systemic inflammation . Wilson et al. have reported that white blood cell count was positively correlated with percentage body fat and leptin concentration . Obesity may expose bone marrow to higher concentrations of leptin, which increases the proliferation of myeloid stem cells, resulting in higher white blood cell count . Vitamin D3 protects endothelial cells by suppressing the proliferation and inhibiting the development of inflammation . Bednarek-Skublewska et al. have found that plasma 25-OH Vit D3 levels negatively correlated IL-6 levels in hemodialysis patients . Gertz et al. have reported that white blood cell count, which may be a surrogate marker of inflammation, was significantly associated with percent change in bone mineral content in postmenopausal women .
Activities of osteoblasts and osteoclasts are controlled by various hormones and cytokines [37,38]. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin pathwayn . In many studies investigated biological markers that are thought to be responsible for bone loss, are osteoprotegerin (OPG), RANKL, RANK. RANKL, its receptor RANK–stimulating osteoclast maturation- and decoy receptor OPG –inhibiting RANKL to induce osteoclastogenesis- are key molecules that modulation of osteoclast differentiation and function [39,40]. Several potential mechanisms link obesity and metabolic dysregulation to bone metabolism, including chronic inflammation.
Cytokine production in adipose tissue induces chronic inflammation that has been implicated in bone loss  and lower bone mineral density in obesity . Inflammatory markers including TNF-alpha, IL-1β, and IL-6 can stimulate osteoclast activity via increased proliferation of preosteoclastic cells and upregulated RANKL expression . In addition, obese individuals show abnormal circulating levels of adiponectin and leptin. Leptin which has been found to stimulate inflammatory responses, plays a role in osteoblast differentiation and suppresses resorption by osteoclasts [42-44]. Mechanism of action of leptin in increasing bone mass is also done by increasing OPG, which would inhibit osteoclastogenenesis through the mediation RANK/RANK ligand or OPG ligand/OPG . OPG functions as a soluble decoy receptor for RANKL and acts by competing with RANK, which is expressed on osteoclasts and dendritic cells for specifically binding to RANKL . The binding of RANKL to OPG would inhibit RANKL binding to RANK which then inhibits osteoclastogenesis. In contrast adiponectin acts as an anti-inflammatory cytokine which suppresses TNF-α-induced NF-κB activation (Figure 1.) .
In conclusion, further research is needed to examine the interrelationship among markers of inflammation and bone turnover marker to determine whether treatment to reduce inflammation would be an appropriate approach for reducing the rate of bone loss in obese people.
Figure 1. Bone metabolism and adipose tissue
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