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Ana Carolina Proença da Fonseca,1,2 Gabriella de Medeiros Abreu,2 Lohanna Palhinha,1 Verônica Marques Zembrzuski,2 Mario Campos Junior,2 João Regis Ivar Carneiro,3 José Firmino Nogueira Neto,4 Fernanda Cristina C Mattos Magno,5 Eliane Lopes Rosado,5 Clarissa Menezes Maya-Monteiro,1 Giselda Maria Kalil de Cabello,2 Pedro Hernán Cabello,2,6 Patricia Torres Bozza1 1Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 2Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; 3Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 4Department of Pathology and Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil; 5Institute of Nutrition Josué de Castro, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 6Human Genetics Laboratory, Grande Rio University, Rio de Janeiro, BrazilCorrespondence: Ana Carolina Proença da FonsecaHuman Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, 4365 Brasil Avenue, Leônidas Deane Building – Office 611/615, Rio de Janeiro, RJ 21040-360, BrazilTel +552138658192Fax +552138658239Email ana.proenca@ioc.fiocruz.brBackground: Brain-derived neurotrophic factor (BDNF) is a pro-survival factor in the brain that also regulates energy balance. BDNF loss-of-function point mutations are responsible for haploinsufficiency, causing severe early-onset obesity. Up to date, only a few studies have sequenced this gene to search for rare mutations related to obesity. In this study, we aimed to investigate the prevalence of BDNF variants in a cohort of adults with severe obesity from Brazil.Material and Methods: This study comprised 201 adults with severe obesity (BMI ≥ 35.0 kg/m2) with onset during childhood- or adolescence/youth. As controls, 73 subjects with normal weight (18.5 ≤ BMI ≤ 24.9 kg/m2) were selected. The exclusion criteria were pregnancy, lactation, the use of medication to lose or gain weight, and the presence of symptoms suggestive of syndromic obesity (only for the case group). The coding region of the BDNF gene was screened by Sanger sequencing. Demographic, anthropometric, and blood pressure parameters were obtained from the participants as well as serum hormone and cytokines concentrations and biochemical values.Results: As a result, three missense variants [p.(Thr2Ile), p.(Val66Met), and p.(Arg209Gln)] and four synonymous variants (p.Leu107=, p.Thr149=, p.Ala150=, and p.Ser213=) were identified. The p.(Arg209Gln) was predicted as pathogenic by all in silico algorithms used and was not observed in the control group. The individuals carrying the p.(Val66Met) mutated allele had higher waist circumference, HDL-cholesterol and MCP1 levels, and reduced risk of developing metabolic syndrome.Conclusion: We observed that the common BDNF p.(Val66Met) variant has influenced waist circumference, HDL-cholesterol, and MCP1 levels. This polymorphism has also a protective effect on metabolic syndrome susceptibility. Additionally, we described for the first time a rare potentially pathogenic BDNF variant in a Brazilian patient with severe obesity and childhood-onset.Keywords: BDNF, severe obesity, rare mutation, early-onset obesity, metabolic syndrome

Ana Carolina Proença da Fonseca,1 Gabriella Medeiros Abreu,1 Verônica Marques Zembrzuski,1 Mario Campos Junior,1 João Regis Ivar Carneiro,2 José Firmino Nogueira Neto,3 Giselda Maria Kalil Cabello,1 Pedro Hernán Cabello1,41Human Genetics Laboratory, Oswaldo Cruz Institute/FIOCRUZ, Rio de Janeiro, Brazil; 2Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 3Department of Pathology and Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil; 4Human Genetics Laboratory, Grande Rio University, Rio de Janeiro, BrazilBackground: Obesity occurs due to the interaction between the genetic background and environmental factors, including an increased food intake and a sedentary lifestyle. Nowadays, it is clear that there is a specific circuit, called leptin-melanocortin pathway, which stimulates and suppresses food intake and energy expenditure. Therefore, the aim of this study was to evaluate the influence of genetic variants related to appetite regulation and energy expenditure on severe obesity susceptibility and metabolic phenotypes in a Brazilian cohort.Material and methods: A total of 490 participants were selected (298 severely obese subjects and 192 normal-weight individuals). Genomic DNA was extracted and polymorphisms in protein related to agouti (AGRP; rs5030980), ghrelin (GHRL; rs696217), neuropeptide Y (NPY; rs535870237), melanocortin 4 receptor (MC4R; rs17782313), brain-derived neurotrophic factor (BDNF; rs4074134) and fat mass and obesity-associated (FTO; rs9939609) genes were genotyped using TaqMan® probes. Demographic, anthropometric, biochemical and blood pressure parameters were obtained from the participants.Results: Our results showed that FTO rs9939609 was associated with severe obesity susceptibility. This polymorphism was also related to body weight, body mass index (BMI), waist to weight ratio (WWR) and inverted BMI. Individuals carrying the mutant allele (A) showed higher levels of BMI as well as lower values of WWR and inverted BMI.Conclusion: This study showed that FTO rs9939609 polymorphism plays a significant role in predisposing severe obesity in a Brazilian population.Keywords: leptin-melanocortin pathway, FTO, obesity, polymorphisms, hypothalamus

Ana Carolina Proença da Fonseca,1 Gabriella de Medeiros Abreu,1 Verônica Marques Zembrzuski,1 Mario Campos Junior,1 João Regis Ivar Carneiro,2 Fernanda Cristina C Mattos Magno,3 Eliane Lopes Rosado,3 José Firmino Nogueira Neto,4 Giselda Maria Kalil de Cabello,1 Pedro Hernán Cabello1,5 1Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil; 2Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 3Institute of Nutrition Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 4Department of Pathology and Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil; 5Human Genetics Laboratory, Grande Rio University, Rio de Janeiro, Brazil Background: Melanocortin 4 receptor gene (MC4R) is an important regulator of food intake, body weight, and blood pressure. Mutations in MC4R are associated with the most common form of nonsyndromic monogenic obesity. MC4R variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding MC4R variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the MC4R gene in a Brazilian cohort of severely obese adults and to investigate the phenotype–genotype correlation within MC4R variant carriers. Methods: This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0–11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12–21 years). The entire coding region of MC4R gene was screened by Sanger sequencing. Results: As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of MC4R. It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with MC4R missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying MC4R variants had higher median of waist–hip ratio when compared to noncarriers (P=0.048). These missense variants were also associated with hypertension (P=0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers (P=0.020 and P=0.065, respectively). Val103Ile was also associated with hypertension (P=0.003). Conclusion: This study showed the prevalence of MC4R variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of MC4R on body fat distribution and blood pressure. Keywords: MC4R, severe obesity, mutation, start lost, blood pressure

Fernanda Cristina Carvalho Mattos Magno,1 Helena Chrispim Guaraná,1 Ana Carolina Proença Fonseca,2 Giselda Maria Kalil Cabello,2 João Régis Ivar Carneiro,3 Aline Pereira Pedrosa,1 Ana Carolina Ximenes,1 Eliane Lopes Rosado1 1Institute of Nutrition, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 2Oswaldo Cruz Foundation (FIOCRUZ), Oswaldo Cruz Institute (IOC), Human Genetics Laboratory, Rio de Janeiro, RJ, Brazil; 3Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Service of Nutrology, Rio de Janeiro, RJ, Brazil Background: The fat mass and obesity-related (FTO) gene has a strong relationship with obesity, extreme obesity and inflammatory state, and may also be associated with food intake regulation.Objective: The aim of the present study was to evaluate the influence of the rs9939609 single-nucleotide polymorphism of the FTO gene on appetite, ghrelin, leptin, interleukin 6 (IL6), tumor necrosis factor α (TNFα) levels and food intake of morbidly obese women.Materials and methods: The study comprised 70 women, aged between 20 and 48 years, from Rio de Janeiro, Brazil. The participants were selected according to the body mass index between 40 and 60 kg/m2. Anthropometric and biochemical data were measured during fasting. Hormones and inflammatory data were measured before and after the participants ate an isocaloric meal. Dietary records were calculated and analyzed using a nutritional assessment program. Visual analog scales were used for behaviors of the sensations of appetite and food preferences. The FTO rs9939609 variant was genotyped using real-time polymerase chain reaction.Results: Participants with the AA genotype had lower values of ghrelin and IL6 and higher values of leptin than those with TT and TA in the postprandial period. Comparing the plasma concentrations of ghrelin, insulin, IL6 and TNFα intragenotypes, it was observed that those with TT had decreased leptin and increased IL6 at the postprandial period. Subjects with TA showed increased postprandial IL6, and those with AA had decreased postprandial ghrelin. There was no difference in TNFα intra- and intergenotypes. The postprandial sensations of hunger were lower in AA than those with TT. There were differences between genotypes regarding ingested grams of protein by weight, cholesterol, B3, B5, B6 and B12 vitamins, and selenium potassium and sodium minerals.Conclusion: These findings suggest that genetics may exert an influence on physiologic factors and might alter eating behavior. Keywords: obesity, rs9939609, hormones, inflammatory cytokines, food intake, binge eating

Introduction: Obesity is a multifactorial disease associated with the development of many comorbidities. This disease is associated with several metabolic alterations; however, it has been shown that some individuals with obesity do not exhibit metabolic syndrome. Adipose tissue neutralizes the detrimental effects of circulating fatty acids, ectopic deposition, and inflammation, among others, through its esterification into neutral lipids that are stored in the adipocyte. However, when the adipocyte is overloaded, i.e., its expansion capacity is exceeded, this protection is lost, resulting in fatty acid toxicity with ectopic fat accumulation in peripheral tissues and inflammation. In this line, this study aimed to investigate whether polymorphisms in genes that control adipose tissue fat storage capacity are potential biomarkers for severe obesity susceptibility and also metabolic complications., Methods: This study enrolled 305 individuals with severe obesity (cases, BMI≥35 kg/m 2 ) and 196 individuals with normal weight (controls, 18.5≤BMI≤24.9 kg/m 2 ). Demographic, anthropometric, biochemical, and blood pressure variables were collected from the participants. Plasma levels of leptin, resistin, MCP1, and PAI1 were measured by Bio-Plex 200 Multiplexing Analyzer System. Genomic DNA was extracted and variants in DBC1 (rs17060940), SIRT1 (rs7895833 and rs1467568), UCP2 (rs660339), PPARG (rs1801282) and ADRB2 (rs1042713 and rs1042714) genes were genotyped by PCR allelic discrimination using TaqMan ® assays., Results: Our findings indicated that SIRT1 rs7895833 polymorphism was a risk factor for severe obesity development in the overdominant model. SIRT1 rs1467568 and UCP2 rs660339 were associated with anthropometric traits. SIRT1 rs1467568 G allele was related to lower medians of body adipose index and hip circumference, while the UCP2 rs660339 AA genotype was associate with increased body mass index. Additionally, DBC1 rs17060940 influenced glycated hemoglobin. Regarding metabolic alterations, 27% of individuals with obesity presented balanced metabolic status in our cohort. Furthermore, SIRT1 rs1467568 AG genotype increased 2.5 times the risk of developing metabolic alterations. No statistically significant results were observed with Peroxisome Proliferator-Activated Receptor Gama and ADRB2 polymorphisms., Discussion/conclusion: This study revealed that SIRT1 rs7895833 and rs1467568 are potential biomarkers for severe obesity susceptibility and the development of unbalanced metabolic status in obesity, respectively. UCP2 rs660339 and DBC1 rs17060940 also showed a significant role in obesity related-traits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 da Fonseca, Assis, Salum, Palhinha, Abreu, Zembrzuski, Campos Junior, Nogueira-Neto, Cambraia, Souza Junior, Maya-Monteiro, Cabello, Bozza and Carneiro.)

This systematic review aimed to answer the focused question: "What are the benefits of subgingival periodontal therapy on blood hematological and biochemical index, biomarkers of inflammation and oxidative stress, quality of life, and periodontal pathogen counts in patients with obesity and periodontitis?". A systematic literature search was performed in six databases: PubMed, Embase, LILACS, Web of Science, Cochrane and SCOPUS and other sources, and a manual search was conducted as well. Inclusion criteria were randomized and non-randomized clinical trials, and before-and-after studies on patients with obesity subjected to periodontal therapy. The results were synthesized qualitatively. Risk of bias within studies was assessed using RoB 2 and ROBINS-I tools. The certainty of evidence was evaluated following the GRADE approach. Three randomized controlled trials and 15 before-and-after studies were included. Randomized controlled trials were considered to have a low risk of bias, as compared to before-and-after studies assessed as having low, serious, and critical risks of bias. Non-surgical periodontal therapy plus azithromycin, chlorhexidine, and cetylpyridinium chloride reduced blood pressure and decreased serum levels of HbA1c, hsCRP, IL-1β, and TNF-α. Salivary resistin level also decreased in patients with obesity and periodontitis after therapy and chlorhexidine mouth rinse. Before-and-after data suggest an improvement in total cholesterol, LDL, triglycerides, insulin resistance, C3, GCF levels of TNF-α, chemerin, vaspin, omentin-1, visfatin, 8-OHdG, and periodontal pathogen counts after therapy.

Introduction: Few studies have evaluated the impact of bariatric surgery (BS) on thyroid function and morphology, and how it correlates to inflammatory and metabolic markers. We aimed to evaluate all those parameters together., Methods: A longitudinal study included 70 patients with severe obesity. The bariatric group (BG) enrolled 40 patients who underwent BS, and the control group (CG) enrolled 30 patients who did not undergo BS. Both were submitted (pre- and 2nd-year) to thyroid ultrasound and laboratory analyses to determine the levels of thyroid hormones, inflammatory, and metabolic markers., Results: Thyroid volume (TV) decreased after BS (-1.5 cm 3 ), differing significantly from the CG (+0.6 cm 3 ; p = 0.003). ΔTV was independently and positively correlated with ΔHOMA-IR (0.41 (0.11/7.16) p = 0.007) and ΔIL6 (0.02 (0.01/0.3) p = 0.016). A nonsignificant correlation between ΔTV and ΔBMI was detected (0.38 (-0.01/0.09) p = 0.152). We also observed a negative correlation between ΔTV and ΔTSH (-2.03 (-2.87/-1.19) p = 0.000) and ΔT3/T4 ratio (-0.06 (-0.09/-0.02) p = 0.001). TSH had a nonsignificant reduction with BS (-0.3872 vs. -0.2483 p = 0.128). The conversion of T4 to T3 had a significant increase after BS, as demonstrated by the T3/T4 ratio (+5.16 p = 0.01). Despite an increase in the prevalence of thyroid nodules in the BG, it was not statistically significant (p = 0.340)., Conclusion: BS was associated with a reduction in TV and a nonstatistically significant reduction in TSH. The variations in TV were related to the metabolic markers and inflammatory changes. An increase in the conversion of T4 to T3 with BS was detected, possibly related to inflammatory improvement., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: SH2B1 gene encodes an important adaptor protein to receptor tyrosine kinases or cytokine receptors associated with Janus kinases. This gene has been associated with the structural and functional modulation of neurons and other cells, and impacts on energy and glucose homeostasis. Several studies suggested that alterations in this gene are strong candidates for the development of obesity. However, only a few studies have screened SH2B1 point variants in individuals with obesity. Therefore, the aim of this study was to investigate the prevalence of SH2B1 variants in a Brazilian cohort of patients with severe obesity and candidates to bariatric surgery., Methods: The cohort comprised 122 individuals with severe obesity, who developed this phenotype during childhood. As controls, 100 normal-weight individuals were included. The coding region of SH2B1 gene was screened by Sanger sequencing., Results: A total of eight variants were identified in SH2B1, of which p.(Val345Met) and p.(Arg630Gln) variants were rare and predicted as potentially pathogenic by the in the silico algorithms used in this study. The p.(Val345Met) was not found in either the control group or in publicly available databases. This variant was identified in a female patient with severe obesity, metabolic syndrome and hyperglycemia. The p.(Arg630Gln) was also absent in our control group, but it was reported in gnomAD with an extremely low frequency. This variant was observed in a female patient with morbid obesity, metabolic syndrome, hypertension and severe binge-eating disorder., Conclusion: Our study reported for the first time two rare and potentially pathogenic variants in Brazilian patients with severe obesity. Further functional studies will be necessary to confirm and elucidate the impact of these variants on SH2B1 protein function and stability, and their impact on energetic metabolism., Level of Evidence: Level V, cross-sectional descriptive study., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Salum, Rolando, Zembrzuski, Carneiro, Mello, Maya-Monteiro, Bozza, Kohlrausch and da Fonseca.)

Purpose: Monogenic forms of obesity are caused by single-gene variants which affect the energy homeostasis by increasing food intake and decreasing energy expenditure. Most of these variants result from disruption of the leptin-melanocortin signaling, which can cause severe early-onset obesity and hyperphagia. These mutation have been identified in genes encoding essential proteins to this pathway, including leptin (LEP), melanocortin 2 receptor accessory proteins 2 (MRAP2) and proopiomelanocortin (POMC). We aimed to investigate the prevalence of LEP, MRAP2 and POMC rare variants in severely obese adults, who developed obesity during childhood. To the best of our knowledge, this is the first study screening rare variants of these genes in patients from Brazil., Methods: A total of 122 Brazilian severely obese patients (BMI ≥ 35 kg/m 2 ) were screened for the coding regions of LEP, MRAP2 and POMC by Sanger sequencing. All patients are candidates to the bariatric surgery. Clinical characteristics were described in patients with novel and/or potentially pathogenic variants., Results: Sixteen different variants were identified in these genes, of which two were novel. Among them, one previous variant with potentially deleterious effect in MRAP2 (p.Arg125Cys) was found. In addition, two heterozygous mutations in POMC (p.Phe87Leu and p.Arg90Leu) were predicted to impair protein function. We also observed a POMC homozygous 9 bp insertion (p.Gly99_Ala100insSerSerGly) in three patients. No pathogenic variant was observed in LEP., Conclusion: Our study described for the first time the prevalence of rare potentially pathogenic MRAP2 and POMC variants in a cohort of Brazilian severely obese adults., Level of Evidence: Level V, cross-sectional descriptive study.

Purpose: The rs17782313 variant of the MC4R gene plays an important role in the obesity phenotype. Studies that evaluate environmental factors and genetic variants associated with obesity may represent a great advance in understanding the development of this disease. This work seeks to assess the association of the polymorphism of MC4R rs17782313 on plasma parameters, including leptin, ghrelin, tumor necrosis factor (TNFα) and interleukin 6 (IL6), and on the eating behaviors of morbidly obese women., Methods: 70 adult women with BMI between 40 and 60 kg/m 2 were recruited. Laboratory and anthropometric data were recorded. Using a visual analog scale (VAS), the feelings of hunger and satiety were evaluated. The presence or absence of binge eating was evaluated through the Binge Eating Scale (BES) questionnaire. Habitual food intake was analyzed using 3-day dietary records. TaqMan ® assays were conducted using real-time PCR to assess genotype polymorphism variants from peripheral blood DNA., Results: This study found that female patients with the MC4R rs17782313 polymorphism had high levels of ghrelin and reduced levels of IL6 in the postprandial period. We observed a higher prevalence of severe binge eating in more than 50% of women with at least one risk allele., Conclusion: Our hypothesis is that the MC4R rs17782313 polymorphism may influence the release of ghrelin, even without being associated with feelings of hunger and satiety. More than half of women with this polymorphism exhibited severe binge eating., Level of Evidence: Level III: case-control analytic study.

Background: The melanocortinergic pathway orchestrates the energy homeostasis and impairments in this system often lead to an increase in body weight. Rare variants in the melanocortin 4 receptor ( MC4R ) gene resulting in partial or complete loss of function have been described with autosomal co-dominant inheritance. These mutations are the most common cause of non-syndromic monogenic obesity. In this context, this study aimed to sequence the MC4R gene in a Brazilian cohort of adults with severe obesity., Methods: This study included 163 unrelated probands with Body Mass Index (BMI) ≥ 35 kg/m 2 , stratified into three groups, according to the period of obesity onset. From the total sample, 25 patients were enrolled in the childhood-onset group (0-11 years), 19 patients in the adolescence/youth-onset group (12-21 years), and 119 patients in the adult-onset group (>21 years). Blood pressure, anthropometric and biochemical characteristics were obtained, and the MC4R coding region of each subject's DNA was assessed using automated Sanger sequencing., Results: Significant anthropometric differences between the groups were observed. Higher body weight and BMI medians were found in patients with childhood-onset or adolescence/youth-onset when compared to the adulthood-onset obesity group. A total of five mutations were identified, including four missense variants: p.Ser36Thr, p.Val103Ile, p.Ala175Thr, and p.Ile251Leu. Additionally, we observed one synonymous variant (p.Ile198=). The p.Ala175Thr variant was identified in a female case with severe obesity and adulthood-onset. This variant was previously described as a partial loss-of-function mutation, in which the minor allele poses dominant-negative effect, probably resulting in reduced cAMP activity., Conclusion: This study showed a prevalence of common and rare variants in a cohort of Brazilian adults with severe obesity and candidates to bariatric surgery. We have identified a rare potentially pathogenic MC4R variant in a Brazilian patient with severe and adulthood-onset obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Salum, de Souza, Abreu, Campos Junior, Kohlrausch, Carneiro, Nogueira Neto, Magno, Rosado, Palhinha, Maya-Monteiro, Cabello, Cabello, Bozza, Zembrzuski and da Fonseca.)

Obesity is a major public health problem worldwide. It has a complex etiology, influenced by environmental and genetic factors. FTO has been recognized as an important genetic factor for obesity development. This study evaluated the contribution of FTO polymorphisms (rs9939609 and rs17817449) for extreme obesity in terms of the period of obesity onset, anthropometric, and biochemical parameters. The haplotype and the combined effects of FTO risk alleles on obesity susceptibility were evaluated. We investigated 169 normal-weight subjects (body mass index, BMI: 22.8 [21.0; 24.0] kg/m2) and 123 extremely obese individuals (BMI: 47.6 [44.1; 53.1] kg/m2). Genotyping was performed by real time PCR. Our results showed a strong association between FTO variants and extreme obesity. Carriers of the AT haplotype had an increased risk for extreme obesity. Gene scores suggested that the risk of developing extreme obesity was increased 1.37-fold per risk allele added. Both polymorphisms also influenced BMI and body weight. Additionally, rs17817449 influenced triglyceride levels. No effect of FTO variants on the period of obesity onset was found. In conclusion, the FTO polymorphisms showed a strong association with development of extreme phenotype of obesity and adiposity modulation in a Brazilian population.

Background: Regular physical activity has an important role in energy expenditure and combats the development of obesity. During exercise, PPARGC1A is overexpressed, stimulating an increase of the expression of FNDC5. This protein is cleaved to release the hormone irisin, which activates a browning process in white adipose tissue through an increase in UCP1 expression. As a result, irisin leads to mitochondrial heat production and energy expenditure., Objectives: The aim of this study was to investigate whether genetic variants in genes related to browning are associated with severe obesity and obesity-related features. This case-control study comprised 210 individuals with severe obesity (median body mass index [BMI] 45.6 [range 40.5-52.2]) and 191 normal-weight subjects (BMI 22.8 [21.1-23.9])., Methods: Genomic DNA was extracted from peripheral blood and the genotypes of the PPARGC1A(rs8192678, rs3736265, rs2970847, and rs3755863) and UCP1 (rs6536991 and rs12502572) genes were obtained using Taqman® assay. For the FNDC5 gene, screening of exons 3-5 as well as their intron-exon boundaries was performed using automatic sequencing., Results: Our results demonstrated that PPARGC1Ars2970847 and UCP1rs12502572 are associated with severe obesity. Furthermore, these polymorphisms influence anthropometric traits, such as BMI, body weight, and body adiposity index. Our findings also showed a dose-effect relationship between PPARGC1A rs8192678 and fasting plasma glucose. Finally, 5 rare mutations were identified in FNDC5, and 1 of these is a novel missense mutation., Conclusion: This study shows that genetic variants in the activation of brown-like adipocyte pathway play an important role in the susceptibility to severe obesity., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Bariatric surgery has been recognized as the gold standard treatment for severe obesity. Although postbariatric surgery patients usually achieve and maintain substantial weight loss, a group of individuals may exhibit weight regain. Several factors are proposed to weight regain, including psychiatric comorbidity. The objective of the study is to conduct a systematic review and meta-analysis of studies investigating the relationship between psychiatric comorbidity and weight regain. A systematic review through PubMed, Web of Science, Cochrane Library, Scopus, and PsycINFO was performed, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). After a stepwise selection, 13 articles were included in the qualitative analysis and 5 were included for a meta-analysis. Women was majority in most of the studies (87.6%), and a bypass procedure was the bariatric intervention most evaluated (66.8%), followed by gastric banding (32.1%) and sleeve (1.1%). Higher rates of postbariatric surgery eating psychopathology were reported in patients with weight regain. However, the association between general psychopathology and weight regain was not consistent across the studies. In the meta-analysis, the odds of eating psychopathology in the weight regain group was higher compared with the nonweight regain group (OR = 2.2, 95% CI 1.54-3.15). Postbariatric surgery eating psychopathology seems to play an important role in weight regain., (© 2019 World Obesity Federation.)

Background: Melanocortin 4 receptor gene ( MC4R ) is an important regulator of food intake, body weight, and blood pressure. Mutations in MC4R are associated with the most common form of nonsyndromic monogenic obesity. MC4R variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding MC4R variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the MC4R gene in a Brazilian cohort of severely obese adults and to investigate the phenotype-genotype correlation within MC4R variant carriers., Methods: This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0-11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12-21 years). The entire coding region of MC4R gene was screened by Sanger sequencing., Results: As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of MC4R . It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with MC4R missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying MC4R variants had higher median of waist-hip ratio when compared to noncarriers ( P =0.048). These missense variants were also associated with hypertension ( P =0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers ( P =0.020 and P =0.065, respectively). Val103Ile was also associated with hypertension ( P =0.003)., Conclusion: This study showed the prevalence of MC4R variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of MC4R on body fat distribution and blood pressure., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: The aim of this study was to evaluate the relationship between inflammatory cytokines, placental weight, glycated hemoglobin and adverse perinatal outcomes (APOs) in women with gestational diabetes mellitus (GDM)., Subjects and Methods: This was a prospective, longitudinal and observational study conducted from April 2004 to November 2005 in Bauru, Brazil. Included patients had singleton pregnancies and performed a 100 g OGTT and had the levels of C-reactive protein (CRP), interleukin (IL)-6, TNF alfa and glycated hemoglobin (HbA1c) determined at 24-28th gestation weeks., Results: A total of 176 patients were included, of whom 78 had the diagnosis of GDM (44.3%). Multivariate analysis demonstrated that HbA1c, age, body mass index (BMI) and previous history of GDM were independent predictors for GDM diagnosis. ROC curve indicated that HbA1C levels ≥ 5.1% at 24-28 weeks gestation were associated with GDM. No difference was found in IL-6, tumor necrosis factor alpha (TNF-alpha) and CRP serum levels in women with and without GDM. Multivariate analysis showed that placental weight was significantly associated with APOs (p < 0.005), with a cut-off value of 610 grams as demonstrated by the ROC curve., Conclusion: Placental weight ≥ 610 grams and HbA1C ≥ 5.1% were found to be associated with APOs and GDM, respectively, and their evaluation should be part of prenatal care routine.

Objective: Roux-en-Y gastric bypass (RYGB) reduces body weight and the comorbidities associated with obesity. The aim of this study was to evaluate whether glucose and lipid profiles were maintained during a 5-year follow-up period after RYGB., Subjects and Methods: Anthropometric and laboratory data from 323 patients who had undergone this operation were analyzed. Differences in laboratory variables between the baseline and 12, 24, 36, 48 and 60 months postoperatively (PO) were assessed using a one-way ANOVA test to compare the three groups. Delta significance using one-way ANOVA was performed to assess anthropometric variable in the postoperative period (p < 0.05)., Results: 77 patients (24%) were included in Group 1 (G1), 101 (32%) in Group 2 (G2), and 141 (44%) in Group 3 (G3). The majority of patients, 71.7% in G1, 82.8% in G2, and 70% in G3, showed high triglycerides (TG) before surgery. A decrease in weight loss was observed in all groups followed by an increase in body weight in G2 and G3 at 36, 48 and 60 months. Laboratory results for G1, G2 and G3 showed no significant differences between groups at baseline and during the post-operative period., Conclusion: Our results suggest that weight regain after RYGB has no significant impact on the long-term evolution of the lipid profile and glycemia.

Obesity is the most common nutritional disorder. This disease is a multifactorial disease influenced by environmental and genetic factors. This study investigated the relationship between common variants of adiponectin ( ADIPOQ ), retinoic acid receptor responder 2 ( RARRES2 ), and peroxisome proliferator-activated receptor- γ coativator-1 ( PPARGC1 ) and obesity-related traits and susceptibility. A total of 167 individuals with obesity and 165 normal-weight subjects were recruited. Genotype frequencies of rs182052 in ADIPOQ differed significantly between the groups. Genotype AA was observed at a higher frequency in case than in control subjects. Association analysis showed that the A allele was a risk factor for obesity. This polymorphism was associated with body weight, body mass index (BMI), and waist circumference. After stratification by BMI, eutrophic individuals with AA or AG genotypes had higher body weights and waist circumferences than those with GG genotypes. In the case group, no associations were observed, except for stratified subjects with morbid obesity that exhibited a progressive increase of body weight, BMI, and waist circumference when rs182052 A was present. No associations were observed between SNPs in RARRES2 and PPARGC1 and obesity or any other studied variables. The rs182052 polymorphism in ADIPOQ is associated with a higher risk for obesity and obesity-related parameters.