Epidemiologic studies in different

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1 Effects of Scaling and Root Planing on Clinical Response and Serum Levels of Adipocytokines in Patients With Obesity and Chronic Periodontitis Tiago Eduardo Dias Goncxalves,* Magda Feres,* Glaucia Santos Zimmermann,* Marcelo Faveri,* Luciene Cristina Figueiredo,* Paloma Gralha Braga,* and Poliana Mendes Duarte* Background: Despite several investigations suggesting that obesity is a risk indicator for periodontitis, little is known about the effect of obesity on periodontal treatment response. The aim of this study is to evaluate the effects of scaling and root planing (SRP) on clinical parameters and circulating levels of leptin and adiponectin in patients with obesity with chronic periodontitis (CP). Methods: Twenty-four patients with obesity and CP and 24 patients without obesity with CP were submitted to SRP. Clinical parameters were assessed at baseline and 3 and 6 months after therapy. Serum levels of leptin and adiponectin were evaluated at all time points, using enzyme-linked immunosorbent assay. Results: SRP improved the clinical parameters of both groups at 3 and 6 months (P <0.05). Nonetheless, the patients without obesity presented a lower mean probing depth (PD) at 6 months after therapy and a greater reduction in PD from baseline to 6 months in the full-mouth analysis (primary outcome variable) and in initially deep sites (P <0.05). Leptin serum levels were higher in patients with obesity than in patients without obesity at all time points (P <0.05). No changes in the serum levels of leptin and adiponectin were observed in groups with and without obesity after therapy (P >0.05). Conclusions: Patients with obesity and CP presented lower reductions in PD than patients without obesity with CP at 6 months after SRP. Furthermore, the treatment did not affect the circulating levels of leptin and adiponectin in any group. J Periodontol 2015;86: KEY WORDS Adipokines; adiponectin; chronic periodontitis; Leptin; obesity; root planing. * Department of Periodontology, Dental Research Division, Guarulhos University, Guarulhos, São Paulo, São Paulo, Brazil. Department of Dentistry, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil. Epidemiologic studies in different populations and systematic reviews have demonstrated an association between obesity and periodontal diseases. 1-5 Evidence indicates a positive correlation between obesity and its anthropometric measurements (e.g., body mass index [BMI] and waist circumference) with periodontitis and clinical periodontal parameters (e.g., probing depth [PD], gingival inflammation, and clinical attachment loss). 1,2 The white adipose tissue, especially the visceral one, secretes several adipocytokines, including resistin, tumor necrosis factor-a, interleukin-6, leptin, and adiponectin. 6,7 Leptin and adiponectin are important adipocytokines that generally produce opposing molecular effects. Besides its role on energy homeostasis, as a cytokine, leptin presents proinflammatory biologic activities, stimulating secretion of several proinflammatory mediators related to the innate and T-helper-1 responses. 8,9 Instead, adiponectin provides multiple anti-inflammatory actions, including inhibition of proinflammatory cytokines, induction of anti-inflammatory mediators, downregulation of adhesion molecule expression, and antagonism of toll-like receptors and their ligands. 10,11 It is supposed that the imbalance in the production of proinflammatory and antiinflammatory adipocytokines may be a doi: /jop

2 Response of Patients With Obesity to Periodontal Therapy Volume 86 Number 1 possible link between obesity and periodontitis as a result of altered inflammatory and immune responses at systemic and/or periodontal levels. The obesity induces a chronic systemic inflammatory state that may negatively affect the onset and progression of periodontal disease, whereas periodontitis may adversely influence the systemic levels of adipocytokines in favor of proinflammation Despite numerous studies showing an association between obesity and periodontal diseases, few investigations to date have assessed the affect of obesity on periodontal treatment response Some reports have shown that obesity does not have a negative effect on the clinical response to periodontal treatment in the short term. 16,17,19 Conversely, Suvan et al. 20 showed that BMI and obesity are predictors of unfavorable responses to non-surgical periodontal treatment after 2 months. Furthermore, patients with obesity who had significant weight loss after bariatric surgery presented a short-term better clinical response to non-surgical periodontal therapy than those who did not have bariatric surgery. 18 Because the results of the few studies assessing obesity as a possible modifying factor in the response to periodontal therapy are contradictory, additional studies on this topic are still necessary. Therefore, the aim of this study is to evaluate the effects of scaling and root planing (SRP) on clinical response and circulating levels of leptin and adiponectin in patients with obesity and chronic periodontitis (CP) up to 6 months after therapy. MATERIAL AND METHODS Sample Size Calculation The ideal sample size to ensure adequate power in this study was calculated considering differences of 0.5 mm between groups for full-mouth mean PD change from baseline to 6 months and a standard deviation of 0.5 mm. 20 Based on these data, it was determined that 18 patients per group would be necessary to provide an 85% power with an a of However, based on an anticipated attrition rate of 25%, 24 patients per group were included in this study. Population Patients with and without obesity with CP (26 males and 22 females, aged 33 to 70 years; mean age: 48.7 years) were selected from the population referred to the Dental Clinic of Guarulhos University, São Paulo, Brazil. All eligible patients were invited to participate in the study, and detailed medical and dental records were obtained. Patients were informed of the nature, potential risks, and benefits of their participation in the study and signed an informed consent. The Guarulhos University Ethics Committee in Clinical Research had previously approved the study protocol. Inclusion and Exclusion Criteria Inclusion criteria included: 1) aged >30 years; 2) 15 teeth excluding third molars and teeth with advanced decay indicated for exodontia; 3) diagnosis of generalized CP 21 (>30% of the sites with concomitant PD and clinical attachment level [CAL] 4mm and a minimum of six teeth distributed in the different quadrants presenting at least one site with PD and CAL 5 mm and bleeding on probing [BOP] at baseline); 4) glycated hemoglobin A1c (HbA1c) <6.5%; 5) fasting plasma glucose (FPG) of 70 to 99 mg/dl; and 6) C-reactive protein (CRP) <6 mg/l. The levels of HbA1c (high-performance liquid chromatography method), FPG (glucose oxidase method), and CRP (latex agglutination test) were all assessed by the Guarulhos University Clinical Analysis Laboratory during patient screening. Exclusion criteria included: 1) pregnancy; 2) lactation; 3) current smoking and smoking within the past 10 years; 4) any medical condition requiring prophylactic antibiotic coverage before dental treatment; 5) subgingival periodontal therapy in the previous 12 months; 6) antimicrobial, anti-inflammatory, immunosuppressive, and lipid-lowering (e.g., statins) therapies during the previous 6 months; 7) regular use of mouthrinses containing antimicrobials; and 8) use of orthodontic appliances. Patients reporting the presence of systemic conditions that could affect the progression of periodontitis and/or gain/ loss of weight (e.g., diabetes mellitus, immunologic disorders, osteoporosis, hypothyroidism, or hyperthyroidism) were also excluded. Anthropometric Measurements and Experimental One trained examiner (PGB) performed all anthropometric measurements, including weight (kilograms), height (meters), waist (centimeters), and hip circumferences (centimeters). BMI was calculated as theweightdividedbythesquareofheight(kilograms/ square meters). The waist-to-hip ratio (WHR) was calculated as the ratio of waist-to-hip circumference. Patients with obesity were defined as having BMI 30 and <40 kg/m 2 and concomitant WHR 0.85 for females and WHR 0.90 for males. Patients without obesity were defined as having BMI ranging from 20 to 29.9 kg/m 2 and WHR below that determined for obesity (i.e., WHR <0.85 for women and WHR <0.90 for men). 22 The anthropometric measurements were reassessed at all follow-up visits to verify whether the patients did not change their obese or non-obese status during the study. Non-Surgical Periodontal Therapy Initially, all patients received supragingival plaque and calculus removal, exodontia, provisional restoration, and filling overhang removal, as necessary. 54

3 Goncxalves, Feres, Zimmermann, et al. They were also instructed regarding brushing technique and use of dental floss. A trained periodontist (GSZ) performed SRP in four to six appointments lasting 1 hour each, using manual curets and an ultrasonic device under local anesthesia. Periodontal therapy was completed in 14 days. The endpoint for each SRP appointment was smoothness of the scaled roots. Local and systemic antimicrobials were not used. All patients received periodontal maintenance at 3 and 6 months after therapy, including: 1) professional plaque control with abrasive sodium carbonate air-powder system; 2) reinstruction of oral hygiene; and 3) subgingival debridement of deep sites presenting BOP. Clinical Monitoring Patients received clinical monitoring at baseline and 3 and 6 months after therapy. One calibrated examiner (TEDG) performed all the clinical examinations. After a calibration exercise, the standard error of measurement was calculated. Intraexaminer variability was 0.22 mm for PD and 0.24 mm for CAL. The agreement for categorical variables (e.g., BOP) was >85%, as calculated by the k-light test. The following parameters were assessed at six sites (mesio-buccal, mid-buccal, disto-buccal, mesio-lingual, mid-lingual, and disto-lingual) per tooth, excluding third molars, using a manual periodontal probe i :1) visible plaque accumulation (presence or absence); 2) marginal bleeding (MB) (presence or absence); 3) BOP (presence or absence); 4) suppuration (SUP) (presence or absence); 5) PD (distance between the gingival margin and the bottom of the sulcus/pocket [millimeters]); and 6) CAL (distance between the cemento-enamel junction and the bottom of the sulcus/pocket [millimeters]). Leptin and Adiponectin Monitoring Fasting peripheral blood was sampled on the days of the clinical examinations into appropriate tubes. Immediately after blood collection, the serum was separated from blood by centrifugation (10 min at 1,300 rpm) and stored in aliquots at -80 C. Aliquots of serum were analyzed by enzyme-linked immunosorbent assay (ELISA) at baseline and 3 and 6 months using commercially available kits for detecting adiponectin # and leptin**. ELISA procedures were performed according to the recommendations of the manufacturer using human recombinant standards. According to the manufacturer, the minimum detectable dose for adiponectin is ng/ml and for leptin is <7.8 pg/ml. The optical density was measured at 450 nm. The adipocytokine results were reported in concentration per milliliter of serum (picograms or nanograms per milliliter). A masked operator (PMD) performed all assays. Statistical Analyses The primary outcome variable was the difference between groups for full-mouth PD change between baseline and 6 months. Non-parametric statistical tests were used to evaluate the data that did not achieve normal distribution by Shapiro-Wilk test. The following were computed for each patient: 1) percentages of sites with plaque accumulation MB; BOP; SUP; PD 5 mm and PD 7 mm; 2) the mean number of sites with PD 5 mm and PD 7 mm; 3) the full-mouth mean PD and CAL; 4) BMI; 5) WHR; 6) the glycemic parameters; and 7) adipocytokines. Subsequently, all data were averaged between groups. Changes in PD and CAL in the full-mouth and at initially moderate and deep sites were averaged per patient and then across patients within each group. The significance of differences between groups for age, anthropometric, and glycemic parameters at baseline were compared by unpaired Student t test. The significance of differences between groups for clinical parameters and adipocytokine levels at each time point were compared using the Mann-Whitney U test. The Friedman test was used to detect differences within each group over time for the clinical parameters and the serum levels of adipocytokines. Analysis of covariance (ANCOVA) with adjustments for baseline values was used to detect differences between groups in the mean changes of PD and CAL. The x2 test was used to compare the frequency of sex and the number of patients with low (no more than four sites with PD 5 mm), moderate (five to eight sites with PD 5 mm), or high (at least nine sites with PD 5 mm) risk for disease progression. 23 The level of significance was set at 5%. RESULTS Retention This study was conducted from March 2012 to July Figure 1 presents the flowchart of the study. Of the 480 individuals screened, 432 were excluded for not meeting the inclusion criteria, and 48 entered the study (24 with and 24 without obesity). Three patients from the group without obesity and six from the group with obesity did not return for the 3-month follow-up visit and were excluded from the statistical analysis. Demographic, Anthropometric, and Glycemic Results There were no significant differences between groups for sex, age, and glycemic parameters at baseline Hu-Friedy, Chicago, IL. Cavitron Select SPC, DENTSPLY, York, PA. i UNC15, Hu-Friedy. Serum BD Vacutainer Plus plastic serum tubes, BD Biosciences, Franklin Lakes, NJ. # Quantikine, R&D Systems, Minneapolis, MN. ** Quantikine, R&D Systems. 55

4 Response of Patients With Obesity to Periodontal Therapy Volume 86 Number 1 56 Figure 1. Flowchart of the study. Table 1. Demographic Characteristics and Anthropometric and Glycemic Parameters of the Study Population at Baseline (mean 6 SD) Variable Without Obesity (n = 21) (P >0.05) (Table 1). As expected, BMI and WHR were higher in the obese than in the non-obese group (P <0.001) (Table 1). Clinical Parameters SRP yielded statistically significant improvements in all clinical parameters of both groups at 3 and 6 months compared with baseline (P <0.05) (Table 2). However, patients without obesity presented additional improvements in mean PD and CAL and in the mean number and percentage of sites with PD 5 mm between 3 and 6 months (P <0.05) (Table 2). With Obesity (n = 18) P Sex (% male) Age (years) BMI (kg/m 2 ) <0.001 WHR <0.001 HbA1c (%) FPG (mg/dl) P <0.05 indicates differences between groups by the unpaired Student t test. There were no differences between groups for sex ( x2 test, P >0.05). The group without obesity also presented a lower full-mouth mean PD than the group with obesity at 6 months after treatment (P <0.05) (Table 2). Table 3 presents the mean PD reduction and CAL gain from baseline to 3 months and to 6 months. Patients without obesity had a statistically significantly greater reduction in mean PD than the patients with obesity from baseline to the 6-month time point, considering the full-mouth and the initially deep site evaluations (P <0.05). Table 4 presents data for residual sites at the patient level. Patients presenting at most four, from five to eight, or at least nine sites with PD 5 mm after treatment were categorized as being at low, moderate, or high risk, respectively, for future disease progression. 23 Nine (42.8%) patients in the group without obesity and 13 patients (72.2%) in the group with obesity were at high risk for disease progression at 6 months after therapy (P >0.05). In addition, seven (33.3%) and five (23.8%) patients without obesity and four (22.2%) and one (5.5%) patients with obesity were at low and moderate risk for disease progression, respectively, at 6 months after therapy (P >0.05). Serum Adipocytokines Table 5 presents the serum levels of leptin and adiponectin for both groups at baseline and 3 and 6 months after therapy. Leptin serum levels were higher in patients with obesity than in patients without obesity at all time points (P <0.05). Adiponectin levels did not differ between groups at any time point (P >0.05). In addition, there were no changes in the serum levels of leptin and adiponectin for either group after SRP (P >0.05). DISCUSSION Despite several investigations suggesting that obesity is a risk indicator for periodontitis, 1,2 little is known about the effect of obesity on periodontal treatment response. Therefore, this study evaluates the clinical

5 Goncxalves, Feres, Zimmermann, et al. Table 2. Mean 6 SDs of Full-Mouth Clinical Parameters for Both at Baseline and at Follow-Up Visits Time Point Without Obesity (n = 21) With Obesity (n = 18) P % of sites with plaque accumulation Baseline a a months b b months b b 0.38 % of sites with MB Baseline a a months b b months b b 0.13 % of sites with BOP Baseline a a months b b months b b 0.55 % of sites with SUP Baseline a a months b b months b b 0.40 Mean PD (mm) Baseline a a months b b months c b 0.04 Mean CAL (mm) Baseline a a months b b months c b 0.08 Number of sites with PD 5 mm Baseline a a months b b months c b 0.34 % of sites with PD 5 mm Baseline a a months b b months c b 0.35 Number of sites with PD 7 mm Baseline a a months b b months b b 0.37 % of sites with PD 7 mm Baseline a a months b b months b b 0.34 Superscript letters indicate significant differences over time within the same group (Friedman test, P <0.05). P <0.05 indicates differences between groups at each time point (Mann-Whitney U test, P <0.05). response of patients with obesity and CP to non-surgical periodontal therapy up to 6 months when compared with age- and sex-matched patients without obesity. Furthermore, the possible effects of nonsurgical periodontal therapy on serum levels of leptin and adiponectin were also assessed at 3 and 6 months in both groups. Overall, the results demonstrated that SRP was effective in improving clinical parameters in patients with and without obesity. However, patients with obesity exhibited lower reductions in PD at 6 months after therapy, indicating that obesity may, to some extent, negatively affect the clinical response to non-surgical periodontal therapy. In addition, periodontal treatment did not yield any changes in adiponectin and leptin levels in any group, suggesting that SRP was not able to modulate these adipocytokines at the systemic level. Patients with obesity exhibited significantly greater mean PD (Table 2) and lower reduction in PD in the full-mouth analysis and at initially deep sites compared with patients without obesity at 6 months after treatment (Table 3). Patients without obesity, but not those with obesity, presented statistically significant gradual improvements from baseline to 3and6monthsinmeanPDandCAL and in the number and percentage of sites with PD 5 mm (Table 2). To date, few studies have evaluated the response of patients with obesity to periodontal therapy. Some investigations 16,17,19 have shown that patients with and without obesity did not differ in their clinical response to non-surgical periodontal therapy. Conversely, a previous study 18 showed an improved clinical response to SRP in patients with obesity that lost weight after bariatric surgery when compared with obese controls not submitted to bariatric surgery. Furthermore, a recent study 20 reported that BMI and obesity were associated with mean PD and mean percentage of sites with PD >4 mm at 2 months after 57

6 Response of Patients With Obesity to Periodontal Therapy Volume 86 Number 1 Table 3. Mean 6 SEM PD Reduction and CAL Gain From Baseline to 3 and 6 Months for Full-Mouth and Initially Moderate and Deep Sites PD Category Without Obesity (n = 21) With Obesity (n = 18) P Reduction in PD (mm) Full-mouth sites 0 to 3 months to 6 months Initially moderate sites (PD of 4 to 6 mm) 0 to 3 months to 6 months Initially deep sites (PD 7 mm) 0 to 3 months to 6 months Gain in CAL (mm) Full-mouth sites 0 to 3 months to 6 months Initially moderate sites (PD of 4 to 6 mm) 0 to 3 months to 6 months Initially deep sites (PD 7 mm) 0 to 3 months to 6 months P <0.05 indicates differences between groups at each time point by ANCOVA. Table 4. Number and Percentage of Patients Presenting Low, Moderate, or High Risk for Disease Progression 23 at 6 Months Post-therapy Risk for Disease Progression Without Obesity (n = 21) Low risk ( 4 sites with PD 5 mm) 7 (33.3%) 4 (22.2%) 0.49 Moderate risk (5 to 8 sites with PD 5 mm) 5 (23.8%) 1 (5.5%) 0.19 High risk ( 9 sites with PD 5 mm) 9 (42.8%) 13 (72.2%) 0.25 non-surgical periodontal therapy. In that study 20, patients with obesity had 3.2% more sites with PD >4 mm and 0.14 mm greater mean PD at 2 months after therapy than patients with normal BMI. Unfortunately, significant methodologic differences among the studies hamper a more direct comparison with the results of the present study. First, all of the abovementioned investigations have limited their clinical monitoring period to a maximum of 3 months. In addition, studies differed considerably regarding the non-surgical periodontal therapy protocol used (i.e., quadrant-wise SRP or SRP within 24 hours with or without local antimicrobials), the parameter used to define obesity (i.e., BMI and/or waist circumference), the inclusion/exclusion criteria used (e.g., smokers and patients with diabetes), and the severity With Obesity (n = 18) P of obesity (e.g., inclusion or exclusion of Class III obesity). One could argue that the worse mean PD observed in the patients with obesity after therapy could be attributed to their poorer compliance with oral hygiene and/or greater degree of gingival inflammation. However, it is important to observe that patients with and without obesity did not differ in terms of plaque accumulation, MB, and BOP at any time point (Table 2). Studies in the medical field have proposed that patients with obesity present altered immune inflammatory responses and adipocytokine signaling, which may increase the susceptibility to infection and impair would healing. 24,25 However, at this stage, the mechanisms that could explain the worse clinical 58

7 Goncxalves, Feres, Zimmermann, et al. Table 5. Serum Levels of Adipocytokines (mean 6 SD) for Both at Baseline and at Follow-Up Visits Adipocytokines ( 10 2 ) Without Obesity (n = 21) With Obesity (n = 18) P Leptin (pg/ml) Baseline months months Adiponectin (ng/ml) Baseline months months There were no significant differences over time within each group by the Friedman test. P <0.05 indicates differences between groups at each time point by the Mann-Whitney U test. response of patients with obesity to periodontal therapy are still unknown. Additional evaluations performing local immunologic and microbiologic analyses and longer follow-up periods are still needed to clarify this issue. Adipose tissue acts as an endocrine organ by secreting several proinflammatory and anti-inflammatory factors, called adipocytokines, that are able to stimulate molecular events in inflammatory and/or autoimmune conditions. 6,7 Leptin is an adipocytokine with proinflammatory properties that has a fundamental role in regulating appetite and energy expenditure but also in controlling immunity and inflammation. 8,9,11 Recent evidence has suggested that leptin may play a role in the metabolism, defense, and regeneration of the dental and periodontal tissues. 26 In addition, dental and periodontal tissues seem to be important sources of leptin not only locally but also systemically. 26 Adiponectin is an adipocytokine with anti-inflammatory properties that is related to the improvement of insulin sensitivity, antiatherogenic actions, and regulation of metabolic homeostasis. 10,11 In the present study, serum levels of leptin are increased in patients with obesity at all time points, corroborating previous evidence that leptin concentrations are mostly higher in patients with obesity compared with normal-weight patients, with or without periodontitis. 12,27-29 Because previous studies have linked periodontitis with high serum levels of leptin and lower levels of adiponectin, changes in the circulating levels of these adipocytokines would be expected after periodontal treatment. However, in this study, although SRP yielded clinical improvements, it did not affect the circulatory levels of leptin and adiponectin in either group. Some studies have demonstrated a decrease in serum levels of leptin in patients with 19 or without obesity 14 after SRP. Conversely, in agreement with the present results, other investigations 29,30 have also failed to show changes in the serum levels of leptin and adiponectin in patients with periodontitis after nonsurgical periodontal therapy. Although the patients of the present study were engaged in a maintenance therapy at 3-month intervals, the majority of them still retained several residual pockets (PD 5 mm) after the proposed nonsurgical periodontal therapy (Tables 2 and 4), which reflects the failure of this therapy in promoting a periodontal condition comparable with that of the periodontally healthy patients. Possibly these residual infected/inflamed sites could be enough to maintain a systemic load able to sustain the leptin and adiponectin levels unchanged despite periodontal treatment. Furthermore, a pre-existing susceptibility for systemic inflammation, possibly unrelated to periodontal infection, may be another explanation for the unchanged levels of adipocytokines after therapy, because previous evidence has identified groups of patients that are resistant to systemic anti-inflammatory effects after periodontal therapy. 30 The main strength of this study is to be the first investigation, to the best of the authors knowledge, to follow the response of patients with obesity to SRP up to 6 months after therapy. In addition, some aspects related to participant selection could also be considered strengths of the present investigation. Patients with and without obesity were classified considering both WHR and BMI, which take into consideration body fat distribution and abdominal obesity. To avoid interference of other risk factors for periodontitis, patients with diabetes and smokers were not included in this study, and all patients presented low levels of CRP (<6 mg/l). Previous 59

8 Response of Patients With Obesity to Periodontal Therapy Volume 86 Number 1 evidence has demonstrated that CRP directly binds leptin in extracellular settings, impairing its biologic actions. 31 Therefore, the chronic elevation of CRP, commonly observed in patients with obesity, may worsen leptin resistance. 31 Finally, anthropometric measurements were revised at all follow-up visits to ensure that patients maintained their obese or nonobese status over the course of the study. Conversely, this study has some limitations that should be taken into consideration. First, four patients fell into the BMI classification of overweight (BMI from 26.7 to 27.8 Kg/m 2 ), although their WHRs were below those determined for obesity. Second, there was a pronounced dropout in the group with obesity, which ended up with 18 patients. Fortunately, the sample size calculation estimated that 18 patients per group would be enough to provide an 85% statistical power. Furthermore, based on the periodontitis and obesity profiles of the present study population, these results cannot be extrapolated to patients with milder periodontitis and Class III obesity (i.e., BMI 40 kg/m 2 ). Finally, this study is not considered masked. Because obesity is an obvious characteristic, both the operator and examiner could certainly deduce the patient group, which may be a possible bias. CONCLUSIONS Patients with obesity presented a worse response to SRP than patients without obesity at 6 months after therapy. In addition, this treatment did not affect the circulating levels of leptin and adiponectin in patients with or without obesity and CP. ACKNOWLEDGMENTS This study was supported by São Paulo State Research Foundation Grant 2011/ The authors report no conflicts of interest related to this study. REFERENCES 1. Chaffee BW, Weston SJ. Association between chronic periodontal disease and obesity: A systematic review and meta-analysis. 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9 Goncxalves, Feres, Zimmermann, et al. tissues of primates. Cell Tissue Res 2014;355: El-Haschimi K, Lehnert H. Leptin resistance Or why leptin fails to work in obesity. Exp Clin Endocrinol Diabetes 2003;111: Considine RV. Human leptin: An adipocyte hormone with weight-regulatory and endocrine functions. Semin Vasc Med 2005;5: Teles FR, Teles RP, Martin L, Socransky SS, Haffajee AD. Relationships among interleukin-6, tumor necrosis factor-a, adipokines, vitamin D, and chronic periodontitis. J Periodontol 2012;83: Behle JH, Sedaghatfar MH, Demmer RT, et al. Heterogeneity of systemic inflammatory responses to periodontal therapy. J Clin Periodontol 2009;36: Hribal ML, Fiorentino TV, Sesti G. Role of C reactive protein (CRP) in leptin resistance. Curr Pharm Des 2014;20: Correspondence: Dr. Poliana Mendes Duarte, Universidade Guarulhos, Centro de Pós-Graduacxão e Pesquisa, Pracxa Teresa Cristina, 229, Centro, Guarulhos, São Paulo, Brazil Fax: ; pduarte@ ung.br. Submitted May 5, 2014; accepted for publication July 31,