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The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis and are thought to contribute to the glucose-lowering effects of bariatric surgery.To establish the metabolomic effects of a combined infusion of GLP-1, OXM, and PYY (tripeptide GOP) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD).Subanalysis of a single-blind, randomized, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups.Twenty-five obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n = 14) or 0.9% saline control (n = 11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery.Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modeling approaches to identify similarities and differences between the effects of each intervention.Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB.Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated.

Nas últimas décadas, a obesidade tem se tornado um importante problema mundial de saúde pública, resultando no aumento da prevalência de doenças crônicas, geralmente associadas à obesidade, como a doença coronariana e o diabetes Mellitus do Tipo 2. Muitos estudos são desenvolvidos na tentativa de elaborar intervenções que possam bloquear ou minimizar as doenças metabólicas induzidas pela obesidade, em especial o diabetes Tipo 2. A restrição calórica (RC) reduz a adiposidade e melhora o metabolismo em pacientes com um ou mais sintomas da síndrome metabólica. No entanto, ainda não se sabe se os benefícios da RC em humanos são mediados pela restrição de calorias ou nutrientes. Este estudo foi realizado para identificar se a dieta isocalórica com restrição de proteína (RP) é capaz de conferir os efeitos benéficos da RC em pacientes com síndrome metabólica. Submetemos 21 indivíduos com diagnóstico de síndrome metabólica a restrição calórica de curto prazo (ou seja, 27 dias) (RC; n = 11) ou a dieta isocalórica com restrição de proteínas (RP; n = 10) e comparamos os resultados metabólicos e moleculares das intervenções. Assim como a RC, a RP promoveu perda de peso devido à redução da adiposidade e redução da glicemia, dos níveis lipídicos e da pressão arterial nesses indivíduos. Observamos redução na resistência insulínica, pelo aumento de 62,3% e 93,1% na taxa de infusão de glicose durante o clamp euglicêmico hiperinsulinêmico e redução de 61,1% e 56,6% no HOMA-IR, para RC e RP respectivamente. As assinaturas de expressão gênica no tecido adiposo subcutâneo (SAT) foram significativamente modificadas nas amostras de indivíduos dos grupos RC e RP. Observamos um aumento de expressão de mRNA principalmente em genes relacionados à função metabólica de adipócitos (Adipoq) e presença de nutrientes (AMPK, GCN2 e SIRT1). Não encontramos mudanças significativas na composição do microbioma intestinal após RP, embora 12 espécies, principalmente Firmicutes, tenham mudado consideravelmente. Nossos dados sugerem que a redução na ingestão de proteínas com um leve aumento na ingestão de carboidratos para manter o equilíbrio isocalórico da dieta é suficiente para melhorar o controle metabólico. A característica isocalórica da intervenção de RP torna essa abordagem uma estratégia dietética mais atrativa e menos drástica em ambientes clínicos e tem maior potencial para ser usada como terapia adjuvante no tratamento da síndrome metabólica. In recent decades, obesity has become an important public health problem worldwide, resulting in the increased prevalence of chronic diseases, generally associated with obesity, such as coronary heart disease and Type 2 diabetes mellitus. Many studies are carried out in an attempt to design interventions that can block or minimize obesity-induced metabolic diseases, especially Type 2 diabetes. Caloric restriction (CR) reduces adiposity and improves metabolism in patients with one or more symptoms of the metabolic syndrome. However, it is not known whether the benefits of CR in humans are mediated by caloric or nutrient restriction. This study was carried out to identify whether the isocaloric diet with protein restriction (PR) is able to confer the beneficial effects of CR in patients with metabolic syndrome. We subjected 21 individuals diagnosed with metabolic syndrome to shortterm (ie, 27 days) caloric restriction (CR; n = 11) or isocaloric diet with protein restriction (PR; n = 10) and compared the metabolic and molecular results of the interventions. Like CR, PR promoted weight loss due to reduced adiposity and reduced blood glucose, lipid levels and blood pressure in these individuals. We observed a reduction in insulin resistance, by an increase of 62.3% and 93.1% in the glucose infusion rate during the hyperinsulinemic euglycemic clamp and a reduction of 61.1% and 56.6% in the HOMA-IR, for CR and PR respectively. Gene expression signatures in subcutaneous adipose tissue (SAT) were significantly modified in samples from individuals in the CR and PR groups. We observed an increase in mRNA expression mainly in genes related to adipocyte metabolic function (Adipoq) and presence of nutrients (AMPK, GCN2 and SIRT1). We did not find significant changes in the composition of the gut microbiome after PR, although 12 species, mainly Firmicutes, changed considerably. Our data suggest that reducing protein intake with a slight increase in carbohydrate intake to maintain dietary isocaloric balance is sufficient to improve metabolic control. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has greater potential to be used as an adjunctive therapy in the treatment of metabolic syndrome.

Several single nucleotide polymorphisms (SNPs) could indirectly, as well directly, influence metabolic parameters related to health effects in response to selenium (Se) supplementation. This study aimed to investigate whether the selenoprotein SNPs were associated with the response of Se status biomarkers to the Brazil nut consumption in patients using statins and if the variation in Se homoeostasis could affect antioxidant protection, lipid profile, muscle homoeostasis and selenoproteins mRNA. The study was performed in the Ribeirão Preto Medical School University Hospital. Thirty-two patients using statins received one unit of Brazil nut daily for 3 months. Body composition, blood Se concentrations, erythrocyte glutathione peroxidase (GPX) activity, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triacylglycerol (TAG), creatine kinase (CK) activity and gene expression of GPX1 and selenoprotein P (SELENOP) were evaluated before and after Brazil nut consumption. The volunteers were genotyped for SNP in GPX1 (rs1050450) and SELENOP (rs3877899 and rs7579). SNPs in selenoproteins were not associated with plasma and erythrocyte Se, but SNPs in SELENOP influenced the response of erythrocyte GPX activity and CK activity, TAG and LDL after Brazil nut consumption. Also, Brazil nut consumption increased GPX1 mRNA expression only in subjects with rs1050450 CC genotype. SELENOP mRNA expression was significantly lower in subjects with rs7579 GG genotype before and after the intervention. Thus, SNP in SELENOP could be associated with interindividual differences in Se homeostasis after Brazil nut consumption, emphasising the involvement of genetic variability in response to Se consumption towards health maintenance and disease prevention.

Made available in DSpace on 2021-06-25T10:59:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Several single nucleotide polymorphisms (SNPs) could indirectly, as well directly, influence metabolic parameters related to health effects in response to selenium (Se) supplementation. This study aimed to investigate whether the selenoprotein SNPs were associated with the response of Se status biomarkers to the Brazil nut consumption in patients using statins, and if the variation in Se homeostasis could affect antioxidant protection, lipid profile, muscle homeostasis, and selenoproteins mRNA. The study was performed in the Ribeirão Preto Medical School University Hospital. Thirty-two patients using statins received one unit of Brazil nut daily for three months. Body composition, blood Se concentrations, erythrocyte glutathione peroxidase (GPX) activity, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), creatine kinase (CK) activity, and gene expression of GPX1 and selenoprotein P (SELENOP) were evaluated before and after Brazil nut consumption. The volunteers were genotyped for SNPs in GPX1 (rs1050450) and SELENOP (rs3877899 and rs7579). SNPs in selenoproteins were not associated with plasma and erythrocyte Se, but SNPs in SELENOP influenced the response of erythrocyte GPX activity and CK activity, triglycerides, and LDL after Brazil nut consumption. Also, Brazil nut consumption increased GPX1 mRNA expression only in subjects with rs1050450 CC genotype. SELENOP mRNA expression was significantly lower in subjects with rs7579 GG genotype before and after the intervention. Thus, SNPs in SELENOP could be associated with interindividual differences in Se homeostasis after Brazil nut consumption, emphasizing the involvement of genetic variability in the response to Se consumption toward health maintenance and disease prevention. Department of Internal Medicine Ribeirão Preto Medical School University of São Paulo - FMRP/USP Department of Clinical and Toxicological Analyses and Bromatology Faculty of Pharmaceutical Sciences of Ribeirão Preto University of São Paulo - FCFRP/USP Department of Pediatrics Ribeirão Preto Medical School University of São Paulo - FMRP/USP Department of Health Sciences Division of Nutrition and Metabolism Ribeirão Preto Medical School University of São Paulo - FMRP/USP Department of Food and Nutrition Faculty of Pharmaceutical Sciences São Paulo State University - UNESP Department of Food and Nutrition Faculty of Pharmaceutical Sciences São Paulo State University - UNESP

BackgroundBariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective and durable treatment option for severe obesity. The mechanisms involving adipose tissue may be important to explain the effects of surgery.MethodsWe aimed to identify the genetic signatures of adipose tissue in patients undergoing RYGB. We evaluated 13 obese, non-diabetic patients (mean age 37 years, 100% women, Body mass index (BMI) 42.2 kg/m2) one day before surgery, 3 and 6 months (M) after RYGB.ResultsAnalysis of gene expression in adipose tissue collected at surgery compared with samples collected at 3 M and 6 M Post-RYGB showed that interleukins [Interleukin 6, Tumor necrosis factor-α(TNF-α), and Monocyte chemoattractant protein-1(MCP1)] and endoplasmic reticulum stress (ERS) genes [Eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) and Calreticulin (CALR)] decreased during the follow-up (P ≤ 0.01 for all). Otherwise, genes involved in energy homeostasis [Adiponectin and AMP-activated protein kinase (AMPK)], cellular response to oxidative stress [Sirtuin 1, Sirtuin 3, and Nuclear factor erythroid 2-related factor 2 (NRF2)], mitochondrial biogenesis [Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)] and amino acids metabolism [General control nonderepressible 2 (GCN2)] increased from baseline to all other time points evaluated (P ≤ 0.01 for all). Also, expression of Peroxisome proliferator-activated receptor gamma (PPARϒ) (adipogenesis regulation) was significantly decreased after RYGB (P ConclusionsOur findings demonstrate that weight loss is associated with amelioration of inflammation and ERS and increased protection against oxidative stress in adipose tissue. These observations are strongly correlated with a decrease in BMI and essential genes that control cellular energy homeostasis, suggesting an adaptive process on a gene expression level during the caloric restriction and weight loss period after RYGB.Trial registrationCAAE: 73,585,317.0.0000.5440

Roux-en-Y gastric bypass (RYGB) is the most effective and durable treatment option for reducing adiposity and control abnormalities of metabolic syndrome in patient with severe obesity. Some studies have shown that the initial effect of RYGB on improving metabolic parameters is due to caloric restriction. However, the impact of RYGB on adipose tissue is still under debate. We evaluated 13 obese, nondiabetic patients (mean age 37 years, 100% women, BMI 42.2 kg/m2) one day before surgery, 3 and 6 months (M) after RYGB. Changes in anthropometric, biochemical e gene expression were evaluated with ANOVA and Pearson’s correlation analysis. BMI, fat mass and blood pressure decreased after 3M and 6M (P≤0.05 for all) compared with baseline. Analysis of gene expression in adipose tissue collected at surgery compared with samples collected at 3M and 6M Post-RYGB showed that interleukins (IL6, TNF-α, and MCP1) and endoplasmic reticulum stress (ERS) genes (EIF2AK3 and CALR) decreased during the follow-up (P≤0.01 for all). Nonetheless, genes involved in energy homeostasis (ADIPOQ and AMPK), cellular response to oxidative stress (SIRT1, SIRT3, and NRF2), regulation of adipogenesis (PPARγ), mitochondrial biogenesis (PGC1α) and amino acid metabolism (GCN2) increased from baseline to all other time points evaluated (P≤0.01 for all). We also observed a strong positive correlation between PGC1α, SIRT1, and AMPK with BMI at 3M (P≤0.01 for all) and ADIPOQ and SIRT1 with BMI at 6M (P≤0.01 for all). Our findings demonstrate that weight loss is associated with amelioration of inflammation and ERS and increased protection against oxidative stress in adipose tissue. These observations are strongly correlated with a decrease in BMI and essential genes that control cellular energy homeostasis, suggesting an adaptive process, in a gene expression level, during the caloric restriction and weight loss period after RYGB in patients without diabetes. Disclosure R. Ferraz-Bannitz: None. C.R. Welendorf: None. P.O. Coelho: None. W. Salgado Jr.: None. C.B. Nonino: None. R.A. Beraldo: None. M. Foss-Freitas: None. Funding Ribeirao Preto Clinical Hospital-FAEPA

One severe complication of gastrointestinal and bariatric surgery is post-bariatric hypoglycemia (PBH). Affected patients may develop severe hypoglycemia, typically 1-3 hours after meals. While exaggerated postprandial incretin hormone and insulin secretion has been implicated, additional contributors to hypoglycemia remain uncertain. We performed untargeted semiquantitative metabolomic analysis of plasma samples collected in the fasting state and at 30 and 120 minutes after a liquid mixed meal (Ensure) in 13 individuals with PBH post-RYGB, 10 asymptomatic post-RYGB, and 8 overweight/obese individuals without history of gastrointestinal surgery. Multiple analytes were reduced in the fasting state in PBH, including 10 amino acids (Leu, Ile, Val, Ala, Phe, Tyr, Met, Trp, Thr, Asn, nominal p Disclosure R. Ferraz-Bannitz: None. C.M. Mulla: None. J. Dreyfuss: None. H. Pan: None. M. Patti: Consultant; Self; Fractyl Laboratories, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, American Diabetes Association, American Society of Metabolic and Bariatric Surgery, Endocrine Society, Insulet Corporation, King Abdullah International Medical Research Center, SUNY Downstate. Funding National Institutes of Health (R01DK121995, P30DK046200)

Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of metabolic syndrome. Nonetheless, it remains elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. This study was conducted to determine whether isocaloric dietary protein restriction is sufficient to confer the beneficial effects of dietary restriction in patients with metabolic syndrome. We performed a prospective, randomized controlled dietary intervention under constant nutritional and medical supervision. Twenty-one individuals diagnosed with metabolic syndrome were randomly assigned for caloric restriction (CR; n = 11, diet of 5941 ± 686 KJ per day) or isocaloric dietary protein restriction (PR; n = 10, diet of 8409 ± 2360 KJ per day) and followed for 27 days. Like CR, PR promoted weight loss due to a reduction in adiposity, which was associated with reductions in blood glucose, lipid levels, and blood pressure. More strikingly, both CR and PR improved insulin sensitivity by 62.3% and 93.2%, respectively, after treatment. Fecal microbiome diversity was not affected by the interventions. Adipose tissue bulk RNA-Seq data revealed minor changes elicited by the interventions. After PR, terms related to leukocyte proliferation were enriched among the upregulated genes. Protein restriction is sufficient to confer almost the same clinical outcomes as calorie restriction without the need for a reduction in calorie intake. The isocaloric characteristic of the PR intervention makes this approach a more attractive and less drastic dietary strategy in clinical settings and has more significant potential to be used as adjuvant therapy for people with metabolic syndrome.

Background: Dietary restriction (DR) reduces adiposity and improves metabolism in patients with one or more symptoms of the metabolic syndrome. Nonetheless, it remained elusive whether the benefits of DR in humans are mediated by calorie or nutrient restriction. Methods: Here we subjected 21 individuals diagnosed with the metabolic syndrome to short-term (i.e., 27-days) caloric restriction (CR; n = 11) or isocaloric dietary protein restriction (PR; n = 10) and compared the metabolic outcomes of the interventions. Findings: Like CR, PR promoted weight loss due to reduction in adiposity, and reduced blood glucose, lipid levels and blood pressure in these individuals. Hence, a reduction in calorie intake is not necessary to confer the metabolic benefits of DR. Instead, a reduction in protein intake with a mild increase in carbohydrate intake to maintain the caloric balance of the diet is sufficient to improve metabolic control in patients with the metabolic syndrome. Interpretation: Because PR is a less drastic food intervention to be conducted, it has a greater potential to be used as an adjuvant therapy to treat the metabolic syndrome. Trial Registration: This study is registered at the Brazilian Clinical Trials, ensaiosclinicos.gov.br, number RBR-3HKNRW. Funding Statement: This work was supported by grant 2015/12133-0 and 2017/01184-9 of Sao Paulo Research Foundation (FAPESP). Declaration of Interests: The authors declare they have no competing financial interests. Ethics Approval Statement: This study was approved by the Research Ethics Committee of the Clinics Hospital of Ribeirao Preto and by the Plataforma Brasil. The Helsinki Declaration Guidelines have been followed and the reports in this article are aligned with the CONSORT standards. All participants were informed about the procedures and signed a study consent form.

Although the mechanisms by which statins promote muscle disorders remain unclear, supplementation with dietary antioxidants may mitigate statins' side effects. This study aimed to investigate whether the consumption of Brazil nuts modulates serum creatine kinase (CK) activity in patients regularly using statins.The study was performed in the Ribeirão Preto Medical School University Hospital. Thirty-two patients in regular use of statins were divided according to CK activity levels (G1: increased or G2: normal) and received one unit of Brazil nut daily for 3 months. Body composition, blood selenium (Se) concentrations, erythrocyte glutathione peroxidase (GPX) activity, oxidative stress parameters, and CK activity were evaluated before and after supplementation.In both groups, supplementation with one Brazil nut daily for 3 months contributed to achieve decreased levels of CK activity in serum, with positive changes in plasma and erythrocyte Se concentrations (p 0.0001), and increased levels of GPX activity. Among the parameters related to curbing of oxidative stress, we observed reduced levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in both groups after supplementation. We also found a moderately negative association between CK and GPX activity (r = -41; p 0.02). Expression of selenoproteins GPX1, SELENOP, and SELENON after Brazil nut supplementation was unchanged.Brazil nut consumption enhanced the control of CK activity by improving oxidative stress biomarkers in patients using statins but did not modulate mRNA expression of selenoproteins.

Objectives Dietary omega-3 fatty acids have been efficacious in decreasing serum cholesterol levels and reducing the risk of cardiovascular disease. However, the metabolic and molecular changes induced by the omega-3 fatty acid α-linolenic acid (ALA), which is found in linseed oil, are not fully understood. In this study, we showed a correlation between ALA and insulin resistance, inflammation and endoplasmic reticulum stress (ERS). Methods We studied 40 male mice (C57/BL6) divided into 4 groups: a control (C) group, a control + omega-3/ALA (CA) group, a high-fat diet (HFD) (H) group and a high-fat diet + omega-3/ALA (HA) group. For 8 weeks, the animals in the H and HA groups were fed a high-fat (60%) diet, while the animals in the C and CA groups received regular chow. The diets of the CA and HA groups were supplemented with 10% lyophilized ALA. Results ALA supplementation improved glucose tolerance and reduced insulin resistance, as measured by intraperitoneal glucose tolerance tests and the homeostasis model assessment for insulin resistance, respectively. In addition, ALA reduced hepatic steatosis and modified the standard fat concentration in the liver of animals fed an HFD. Dietary ALA supplementation reduced the serum levels of interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and monocyte chemoattractant protein-1 (MCP-1), increased the expression of important chaperones such as binding immunoglobulin protein (BIP) and heat shock protein 70 (HSP70) and reduced the expression of C/EBP-homologous protein (CHOP) and X-box binding protein 1 (XBP1) in hepatic tissues, suggesting an ERS adaptation in response to ALA supplementation. Conclusions Dietary ALA supplementation is effective in preventing hepatic steatosis; is associated with a reduction in insulin resistance, inflammation and ERS; and represents an alternative for improving liver function and obtaining metabolic benefits.