Impact of Bariatric Surgery on Circulating Metabolites and Cognitive Performance.

INTRODUCTION: Bariatric surgery is an effective intervention to reduce obesity and improve associated comorbidities. However, its effects on cognitive function are still the subject of debate. Given that the bioavailability of circulating metabolites can influence brain metabolism and cognitive performance, we aimed to assess the effects of bariatric surgery on plasma metabolic profiles and cognitive performance. METHODS: We recruited 26 women undergoing gastric bypass surgery. We conducted anthropometric assessments and collected plasma samples for metabolomic analysis. A set of 4 cognitive tests were used to evaluate cognitive performance. Participants were reevaluated 1 year post-surgery. RESULTS: After surgery, attention capacity and executive function were improved, while immediate memory had deteriorated. Regarding metabolic profile, reduction of beta-tocopherol and increase of serine, glutamic acid, butanoic acid, and glycolic acid were observed. To better understand the relationship between cognitive function and metabolites, a cluster analysis was conducted to identify more homogeneous subgroups based on the cognitive performance. We identified cluster 1, which did not show changes in cognitive performance after surgery, and cluster 2, which showed improved attention and executive function, but reduced performance in the immediate memory test. Thus, cluster 2 was more homogeneous group that replicated the results of non-clustered subjects. Analysis of the metabolic profile of cluster 2 confirmed serine, glutamic acid, and glycolic acid as potential metabolites associated with cognitive performance. CONCLUSIONS: Metabolites identified in this study have potential for biomarkers and alternative therapeutic target to prevent obesity-related cognitive decline. KEY POINTS: • Attention capacity and executive function were improved 12 months post bariatric surgery. • Immediate memory was worsened 12 months post bariatric surgery. • Serine, glutamic acid, and glycolic acid are potential metabolites linked to the alteration of cognitive performance.

Long-Term Treatment with Cannabidiol-Enriched Cannabis Extract Induces Synaptic Changes in the Adolescent Rat Hippocampus.

The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), phytocannabinoids have been increasingly used for the treatment of neurological disorders, even though little is known in terms of the long-term effect of these treatments on CNS development, mainly in the timeframe that comprises childhood and adolescence. Furthermore, an increased number of clinical trials using full-spectrum Cannabis extracts has been seen, rather than the isolated form of phytocannabinoids, when exploring the therapeutical benefits of the Cannabis plant. Thus, this study aims to evaluate the effect of cannabidiol (CBD)-enriched Cannabis extract on synaptic components in the hippocampus of rats from adolescence to early adulthood (postnatal day 45 to 60). Oral treatment of healthy male Wistar rats with a CBD-enriched Cannabis extract (3 mg/kg/day CBD) during 15 days did not affect food intake and water balance. There was also no negative impact on locomotor behaviour and cognitive performance. However, the hippocampal protein levels of GluA1 and GFAP were reduced in animals treated with the extract, whilst PSD95 levels were increased, which suggests rearrangement of glutamatergic synapses and modulation of astrocytic features. Microglial complexity was reduced in CA1 and CA3 regions, but no alterations in their phagocytic activity have been identified by Iba-1 and LAMP2 co-localization. Collectively, our data suggest that CBD-enriched Cannabis treatment may be safe and well-tolerated in healthy subjects, besides acting as a neuroprotective agent against hippocampal alterations related to the pathogenesis of excitatory and astrogliosis-mediated disorders in CNS.

Activation of cannabinoid type 1 receptor (CB1) modulates oligodendroglial process branching complexity in rat hippocampal cultures stimulated by olfactory ensheathing glia-conditioned medium.

The endocannabinoid system (ECS) refers to a complex cell-signaling system highly conserved among species formed by numerous receptors, lipid mediators (endocannabinoids) and synthetic and degradative enzymes. It is widely distributed throughout the body including the CNS, where it participates in synaptic signaling, plasticity and neurodevelopment. Besides, the olfactory ensheathing glia (OEG) present in the olfactory system is also known to play an important role in the promotion of axonal growth and/or myelination. Therefore, both OEG and the ECS promote neurogenesis and oligodendrogenesis in the CNS. Here, we investigated if the ECS is expressed in cultured OEG, by assessing the main markers of the ECS through immunofluorescence, western blotting and qRT-PCR and quantifying the content of endocannabinoids in the conditioned medium of these cells. After that, we investigated whether the production and release of endocannabinoids regulate the differentiation of oligodendrocytes co-cultured with hippocampal neurons, through Sholl analysis in oligodendrocytes expressing O4 and MBP markers. Additionally, we evaluated through western blotting the modulation of downstream pathways such as PI3K/Akt/mTOR and ERK/MAPK, being known to be involved in the proliferation and differentiation of oligodendrocytes and activated by CB1, which is the major endocannabinoid responsive receptor in the brain. Our data show that OEG expresses key genes of the ECS, including the CB1 receptor, FAAH and MAGL. Besides, we were able to identify AEA, 2-AG and AEA related mediators palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in the conditioned medium of OEG cultures. These cultures were also treated with URB597 10-9 M, a FAAH selective inhibitor, or JZL184 10-9 M, a MAGL selective inhibitor, which led to the increase in the concentrations of OEA and 2-AG in the conditioned medium. Moreover, we found that the addition of OEG conditioned medium (OEGCM) enhanced the complexity of oligodendrocyte process branching in hippocampal mixed cell cultures and that this effect was inhibited by AM251 10-6 M, a CB1 receptor antagonist. However, treatment with the conditioned medium enriched with OEA or 2-AG did not alter the process branching complexity of premyelinating oligodendrocytes, while decreased the branching complexity in mature oligodendrocytes. We also observed no change in the phosphorylation of Akt and ERK 44/42 in any of the conditions used. In conclusion, our data show that the ECS modulates the number and maturation of oligodendrocytes in hippocampal mixed cell cultures.

Severe Obesity in Women Can Lead to Worse Memory Function and Iron Dyshomeostasis Compared to Lower Grade Obesity.

Objective: Obesity is one of the modifiable risk factors for dementia. Insulin resistance, the abundance of advanced glycated end-products, and inflammation are some of the mechanisms associated with the lower cognitive performance observed in obesity. This study aims to evaluate the cognitive function of subjects with distinct degrees of obesity, comparing class I and II obesity (OBI/II) to class III obesity (OBIII), and to investigate metabolic markers that can distinguish OBIII from OBI/II. Study Design. This is a cross-sectional study, in which 45 females with BMI varying from 32.8 to 51.9 kg/m2 completed a set of 4 cognitive tests (verbal paired-associate test, stroop color, digit span, and Toulouse-Pieron cancellation test) and their plasma metabolites, enzymes, and hormones related to glycemia, dyslipidemia, and liver function, as well as the biomarkers of iron status, were concomitantly analyzed. Results: OBIII showed lower scores in the verbal paired-associate test compared to OBI/II. In other cognitive tests, both groups showed similar performance. OBIII presented a lower iron status compared to OBI/II based on total iron binding capacity, degree of transferrin saturation, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. The levels of indicators for glycemia, liver function, and lipid metabolism were similar in both groups. Analysis of plasma metabolites showed that OBIII had lower levels of pyroglutamic acid, myoinositol, and aspartic acid and higher levels of D-ribose than OBI/II. Conclusion: Iron is an essential micronutrient for several metabolic pathways. Thus, iron dyshomeostasis observed in severe obesity may aggravate the cognitive impairment by altering metabolic homeostasis and enhancing oxidative stress. These findings can contribute to searching for biomarkers that indicate cognitive performance in the population with obesity.

Comparison of effect of crush or transection peripheral nerve lesion on lumbar spinal cord synaptic plasticity and microglial dynamics.

In an injury to the peripheral nervous system, the spinal cord and brain structure reorganize connections to optimize the function of the remaining parts. Many cell events are triggered in the spinal cord to support changes in the synaptic connections around motoneurons, where old connections are removed, and new ones created. Microglial cells are primitive macrophages that invade the central nervous system in early stages of neurodevelopment and have several functions, such as eliminating synapses. We investigated the synaptic plasticity after different types of peripheral (sciatic) nerve injury (crush or total transection), as well as the behavior of microglial cells for 2 weeks after a peripheral lesion. As expected, sciatic-nerve injury reduced motor performance in mice, but crushed animals regained partial motor control. Because of sciatic-nerve injury, pre-synaptic inputs decreased around the motoneurons in the ventro-lateral horn, while microglial cells increased around these cells. Microglial cells also exhibited altered morphology in both types of peripheral lesion, indicating a similar underlying mechanism of plasticity. To investigate the involvement of microglia in this scenario, microglial activation was modulated by daily administration of minocycline. The minocycline treatment directly affected the microglial response and impacted the synapse rearrangement in the spinal cord. Together, these results demonstrate that microglia cells are involved in synaptic plasticity in the lumbar spinal cord in both nerve-injury scenarios. SUMMARY OF STATEMENT: Here, we demonstrated that acute plasticity in the lumbar spinal cord (LSC) did not differ between crush and transection of peripheral nerve, and that microglial reactivity in the LSC was important after both injury types.

A freeze-and-thaw-induced fragment of the microtubule-associated protein tau in rat brain extracts: implications for the biochemical assessment of neurotoxicity.

Tau is a microtubule-associated protein (MAP) responsible for controlling the stabilization of microtubules in neurons. Tau function is regulated by phosphorylation. However, in some neurological diseases Tau becomes aberrantly hyperphosphorylated, which contributes to the pathogenesis of neurological diseases, known as tauopathies. Western blotting (WB) has been widely employed to determine Tau levels in neurological disease models. However, Tau quantification by WB should be interpreted with care, as this approach has been recognized as prone to produce artifactual results if not properly performed. In the present study, our goal was to evaluate the influence of a freeze-and-thaw cycle, a common procedure preceding WB, to the integrity of Tau in brain homogenates from rats, 3xTg-AD mice and human samples. Homogenates were prepared in ice-cold RIPA buffer supplemented with protease/phosphatase inhibitors. Immediately after centrifugation, an aliquot of the extracts was analyzed via WB to quantify total and phosphorylated Tau levels. The remaining aliquots of the same extracts were stored for at least 2 weeks at either -20 or -80°C and then subjected to WB. Extracts from rodent brains submitted to freeze-and-thaw presented a ∼25 kDa fragment immunoreactive to anti-Tau antibodies. An in-gel digestion followed by mass spectrometry (MS) analysis in excised bands revealed this ∼25 kDa species corresponds to a Tau fragment. Freeze-and-thaw-induced Tau proteolysis was detected even when extracts were stored at -80°C. This phenomenon was not observed in human samples at any storage condition tested. Based on these findings, we strongly recommend the use of fresh extracts of brain samples in molecular analysis of Tau levels in rodents.

Antibody Fragments as Tools for Elucidating Structure-Toxicity Relationships and for Diagnostic/Therapeutic Targeting of Neurotoxic Amyloid Oligomers.

The accumulation of amyloid protein aggregates in tissues is the basis for the onset of diseases known as amyloidoses. Intriguingly, many amyloidoses impact the central nervous system (CNS) and usually are devastating diseases. It is increasingly apparent that neurotoxic soluble oligomers formed by amyloidogenic proteins are the primary molecular drivers of these diseases, making them lucrative diagnostic and therapeutic targets. One promising diagnostic/therapeutic strategy has been the development of antibody fragments against amyloid oligomers. Antibody fragments, such as fragment antigen-binding (Fab), scFv (single chain variable fragments), and VHH (heavy chain variable domain or single-domain antibodies) are an alternative to full-length IgGs as diagnostics and therapeutics for a variety of diseases, mainly because of their increased tissue penetration (lower MW compared to IgG), decreased inflammatory potential (lack of Fc domain), and facile production (low structural complexity). Furthermore, through the use of in vitro-based ligand selection, it has been possible to identify antibody fragments presenting marked conformational selectivity. In this review, we summarize significant reports on antibody fragments selective for oligomers associated with prevalent CNS amyloidoses. We discuss promising results obtained using antibody fragments as both diagnostic and therapeutic agents against these diseases. In addition, the use of antibody fragments, particularly scFv and VHH, in the isolation of unique oligomeric assemblies is discussed as a strategy to unravel conformational moieties responsible for neurotoxicity. We envision that advances in this field may lead to the development of novel oligomer-selective antibody fragments with superior selectivity and, hopefully, good clinical outcomes.

CXCR4 and MIF are required for neutrophil extracellular trap release triggered by Plasmodium-infected erythrocytes.

Neutrophil extracellular traps (NETs) evolved as a unique effector mechanism contributing to resistance against infection that can also promote tissue damage in inflammatory conditions. Malaria infection can trigger NET release, but the mechanisms and consequences of NET formation in this context remain poorly characterized. Here we show that patients suffering from severe malaria had increased amounts of circulating DNA and increased neutrophil elastase (NE) levels in plasma. We used cultured erythrocytes and isolated human neutrophils to show that Plasmodium-infected red blood cells release macrophage migration inhibitory factor (MIF), which in turn caused NET formation by neutrophils in a mechanism dependent on the C-X-C chemokine receptor type 4 (CXCR4). NET production was dependent on histone citrullination by peptidyl arginine deiminase-4 (PAD4) and independent of reactive oxygen species (ROS), myeloperoxidase (MPO) or NE. In vitro, NETs functioned to restrain parasite dissemination in a mechanism dependent on MPO and NE activities. Finally, C57/B6 mice infected with P. berghei ANKA, a well-established model of cerebral malaria, presented high amounts of circulating DNA, while treatment with DNAse increased parasitemia and accelerated mortality, indicating a role for NETs in resistance against Plasmodium infection.

Mesenchymal Stromal Cells Protect the Blood-Brain Barrier, Reduce Astrogliosis, and Prevent Cognitive and Behavioral Alterations in Surviving Septic Mice.

OBJECTIVES: Survivors of sepsis are frequently left with significant cognitive and behavioral impairments. These complications derive from nonresolving inflammation that persists following hospital discharge. To date, no study has investigated the effects of mesenchymal stromal cell therapy on the blood-brain barrier, astrocyte activation, neuroinflammation, and cognitive and behavioral alterations in experimental sepsis. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Government-affiliated research laboratory. SUBJECTS: Male Swiss Webster mice (n = 309). INTERVENTIONS: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. All animals received volume resuscitation (1 mL saline/mouse subcutaneously) and antibiotics (meropenem 10 mg/kg intraperitoneally at 6, 24, and 48 hours). Six hours after surgery, mice were treated with mesenchymal stromal cells IV (1 × 10 cells in 0.05 mL of saline/mouse) or saline (0.05 mL IV). MEASUREMENTS AND MAIN RESULTS: At day 1, clinical score and plasma levels of inflammatory mediators were increased in cecal ligation and puncture mice. Mesenchymal stromal cells did not alter clinical score or survival rate, but reduced levels of systemic interleukin-1ß, interleukin-6, and monocyte chemoattractant protein-1. At day 15, survivor mice completed a battery of cognitive and behavioral tasks. Cecal ligation and puncture mice exhibited spatial and aversive memory deficits and anxiety-like behavior. These effects may be related to increased blood-brain barrier permeability, with altered tight-junction messenger RNA expression, increased brain levels of inflammatory mediators, and astrogliosis (induced at day 3). Mesenchymal stromal cells mitigated these cognitive and behavioral alterations, as well as reduced blood-brain barrier dysfunction, astrocyte activation, and interleukin-1ß, interleukin-6, tumor necrosis factor-α, and interleukin-10 levels in vivo. In cultured primary astrocytes stimulated with lipopolysaccharide, conditioned media from mesenchymal stromal cells reduced astrogliosis, interleukin-1ß, and monocyte chemoattractant protein-1, suggesting a paracrine mechanism of action. CONCLUSIONS: In mice who survived experimental sepsis, mesenchymal stromal cell therapy protected blood-brain barrier integrity, reduced astrogliosis and neuroinflammation, as well as improved cognition and behavior.

Homeostasis Model Assessment-Adiponectin: the role of different types of physical exercise in obese adolescents.

BACKGROUND: Homeostasis Model Assessment-Adiponectin (HOMA-AD) is suggesting a new biomarker of insulin resistance in obese population. In this way, the purpose of this study was to investigate the effects of different kinds of exercise in the sensitive index predictor of insulin resistance. METHODS: A total of 148 obese adolescents were enrolled in the program. They aged 15-19 y, with Body Mass Index (BMI) ≥P95th and were submitted to 1 year of interdisciplinary weight loss therapy, randomized in two groups, aerobic training (AT) (N.=51) and aerobic plus resistance training (N.=97). Blood samples were collected to analyze adiponectin, glucose and insulin concentrations. The insulin resistance was measured by HOMA-AD and Homeostasis Model Assessment Insulin Resistance Index (HOMA-IR). RESULTS: Both kinds of exercise training promoted a decrease in body mass, body mass index, fat mass, visceral and subcutaneous fat. However, only aerobic plus resistance training was effective to reduce HOMA-AD, insulin and glucose concentration; and increase insulin sensibility and adiponectin concentration. CONCLUSIONS: The aerobic plus resistance training was more effective than AT alone to improve the HOMA-AD, suggesting clinical application on obesity, diabetes, atherosclerosis and metabolic syndrome control in the pediatric population.

The role of multicomponent therapy in the metabolic syndrome, inflammation and cardiovascular risk in obese adolescents.

Obesity is characterised by low-grade inflammation, which increases the metabolic syndrome (MetS) and cardiovascular risks. The aim of the present study was to verify the role of multicomponent therapy in controlling the MetS, inflammation and carotid intima-media thickness (cIMT) in obese adolescents. The second aim was to investigate the relationships between adipokines, the MetS parameters and cIMT. A total of sixty-nine obese adolescents participated in the present study and completed 1 year of multicomponent therapy (a combination of strategies involving nutrition, psychology, physical exercise and clinical therapy), and were divided according to their MetS diagnosis as follows: MetS (n 19); non-MetS (n 50). Blood analyses of glucose, lipid and adipokine concentrations (adiponectin, leptin, plasminogen activator inhibitor 1 (PAI-1) and C-reactive protein) were collected. Insulin resistance was assessed using the homeostasis model assessment for insulin resistance, quantitative insulin sensitivity check index and homeostasis model assessment-adiponectin. cIMT and visceral and subcutaneous fat were estimated using ultrasonography. At baseline, the MetS group presented higher waist circumference, glucose and insulin levels, and systolic and median blood pressures compared with the non-MetS group. After therapy, both groups showed improvements in the anthropometric profile, body composition, insulin level, insulin resistance, insulin sensibility, TAG and VLDL-cholesterol, adiponectin, leptin and PAI-1 levels, blood pressure and cIMT. The prevalence of the MetS was reduced from 27·5 to 13·0 %. Metabolic syndrome patients showed resistance in the attenuation of total cholesterol and LDL-cholesterol (LDL-C) levels and leptin:adiponectin and adiponectin:leptin ratios. In the MetS group, the variation in the adiponectin:leptin ratio was correlated with variations in glucose, insulin sensibility, total cholesterol, LDL-c and systolic blood pressure. Additionally, the number of MetS parameters was correlated with the carotid measurement. Moreover, the variation in cIMT was correlated with the variations in insulin sensibility, total cholesterol and LDL-c. For the entire group, the number of MetS alterations was correlated with the leptin level and leptin:adiponectin ratio and adiponectin:leptin ratio after therapy. In conclusion, multicomponent therapy was effective in controlling the MetS, inflammation and cIMT in the obese adolescents. However, the MetS patients showed resistance in the attenuation of the atherogenic lipid profile and leptin:adiponectin ratio and adiponectin:leptin ratio. These results suggest that the MetS patients have increased cardiovascular risks, and that it is important to attempt to control the inflammatory process that occurs due to obesity in clinical practice in order to improve the health of adolescents.

Association of nonalcoholic fatty liver disease with cardiovascular risk factors in obese adolescents: the role of interdisciplinary therapy.

BACKGROUND: Obesity is associated with several cardiovascular risk factors, including nonalcoholic fatty liver disease (NAFLD). These risk factors can induce changes in the arteries such as an increase in the carotid intima-media thickness (cIMT), which contributes to the early development of atherosclerosis. OBJECTIVE: To determine whether NAFLD is associated with an atherogenic lipid profile, inflammatory markers, or cIMT in obese adolescents and to compare the effects of therapeutic lifestyle changes in NAFLD and non-NAFLD groups. METHODS: A total of 79 obese adolescents were divided into two groups: 33 NAFLD and 46 non-NAFLD. They were submitted to an interdisciplinary therapy involving diet exercise and psychological support during the course of 1 year. The cIMT and estimates of fat mass (liver, intra-abdominal, and subcutaneous) were determined ultrasonographically. Body composition, glucose, lipid profile, and adipokines were analyzed before and after the therapy. RESULTS: At baseline, only in the NAFLD group was the homeostasis model assessment of insulin resistance positively correlated with cIMT and triglyceride/high-density lipoprotein cholesterol ratio. Therapy was associated with an increase in adiponectin concentrations and reduced visceral fat, cIMT, leptin, and plasminogen activator inhibitor-1 concentrations, as well as the ratios of total cholesterol/high-density lipoprotein cholesterol and triglycerides/high-density lipoprotein cholesterol in both groups. Only in the non-NAFLD group did therapy result in a reduction in the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio and increased high-density lipoprotein cholesterol concentration. CONCLUSIONS: In obese adolescents, NAFLD is associated with cardiovascular risk factors and inflammatory markers of atherosclerosis that were positively correlated with cIMT only in the NAFLD group. Nevertheless, the strength of the present study is that the interdisciplinary therapy effectively improved cIMT and other proinflammatory adipokines in both groups.

Aerobic plus resistance training improves bone metabolism and inflammation in adolescents who are obese.

Obesity is a worldwide epidemic with a high prevalence of comorbidities, including alterations in bone mineral metabolism. The purpose of this yearlong study was to evaluate the role of 2 types of exercise training (aerobic and aerobic plus resistance exercise) on adipokines parameters and bone metabolism in adolescents who are obese. This was a clinical trial study with interdisciplinary weight loss therapy. Forty-two postpubertal adolescents who are obese were subjected to interdisciplinary weight loss therapy with physical exercise, medical monitoring, nutritional intervention, and psychological intervention. Data were collected from serum analyses of leptin, ghrelin, adiponectin, glucose, and insulin. Anthropometric measurements of body composition, bone mineral density, visceral, and subcutaneous fat were also performed. Statistical tests were applied using repeated-measures analysis of variance. Correlations were established using the Pearson test, and dependencies of variables were established using simple linear regression test. Both training types promoted reductions in body mass index, total central, visceral and subcutaneous fat, insulin concentration, and homeostasis model assessment insulin resistance (HOMA-IR) index, but only aerobic plus resistance training showed statistical improvements in the bone mineral content, adiponectin concentration, and lean tissue. Effective reduction in the visceral/subcutaneous ratio, central/peripheral ratio, and leptin concentration was observed. Insulin and the HOMA-IR index were negative predictors of bone mineral content in the combined training group. Moreover, fat distribution was a negative predictor for bone mineral density in both groups. Aerobic plus resistance training promotes a protective role in bone mineral content associated with an improvement in adiponectin and leptin concentrations, favoring the control of the inflammatory state related to obesity in adolescents. Aerobic plus resistance training combined with interdisciplinary interventions provides important strategies to approach obesity, and these strategies may contribute to clinical practice.

Hyperleptinemia: implications on the inflammatory state and vascular protection in obese adolescents submitted to an interdisciplinary therapy.

The low-grade systemic inflammation seen in obesity may affect the actions of some adipose tissue-derived adipokines that are involved in the regulation of vascular function. We sought to verify whether hyperleptinemia may influence the inflammatory and atherogenic responses in obese adolescents undergoing interdisciplinary therapy. Thirty-four obese adolescents underwent interdisciplinary therapy for 1 year. Subjects were considered hyperleptinemic if they had baseline values of leptin above 20 ng/mL for boys and 24 ng/mL for girls. Both groups showed an improvement in body composition and a reduction in carotid intima-media thickness. However, only subjects in the non-hyperleptinemic group showed an increase in adiponectin concentration after therapy. Moreover, leptin concentration was positively correlated with adiponectin and inversely correlated with PAI-1 in this group. Hyperleptinemic state may impair the attenuation of inflammation in obese adolescents undergoing interdisciplinary therapy, particularly by impeding the increase in adiponectin concentration, which is directly involved in vascular protection.

Interaction of bone mineral density, adipokines and hormones in obese adolescents girls submitted in an interdisciplinary therapy.

Obesity is a chronic inflammatory condition with numerous metabolic consequences to the organism, highlighting its influence on bone mass. Therefore, the aim of this study was to verify the role of visceral fat, leptin, adiponectin and ghrelin on bone mineral density in obese post-puberty adolescents girls, submitted to an interdisciplinary therapy. The study involved 20 post-puberty obese adolescent girls: 16±1.5 years of age, 98.9±15.8 kg (weight), 1.60±0.72 m (height) and 37.2±4.8 kg/m2 [body mass index (BMI)]. Anthropometric measurements, body composition, visceral fat, subcutaneous fat, bone mineral density and content were determined. Ghrelin, leptin and adiponectin were analyzed and the leptin/adiponectin ratio was calculated. Our findings showed a significant increase in adiponectin concentration and a reduction in body weight, BMI, total fat mass, visceral and subcutaneous fat. In addition, ghrelin (r2=-0.53; p=0.02) visceral fat (r2=-0.46, p=0.04) (r2 -0.66, p=0.001) and leptin/adiponectin ratio (r2 -0.56, p=0.01) were negative predictors for bone mineral density and content in obese adolescent girls, respectively. It provides a novel physiologically concept that may shed light on the etiology of osteoporosis and help to identify new therapeutic targets. However this should be confirmed in a large cohort study.

The effect of weight loss magnitude on pro-/anti-inflammatory adipokines and carotid intima-media thickness in obese adolescents engaged in interdisciplinary weight loss therapy.

BACKGROUND: Obesity is a chronic disease defined by an excess amount of adipose tissue and presents a low-grade inflammatory state, increasing cardiovascular risk. OBJECTIVE: To assess the effect of weight loss magnitude on the inflammatory profile and carotid intima-media thickness (cIMT) in obese adolescents engaged in interdisciplinary therapy. DESIGN AND PATIENTS: Seventy-seven postpubertal obese adolescents with a BMI greater than the 95th percentile (37·18 ± 5·14), of both genders and between the ages of 14 and 19 years (16·74 ± 1·59) were subjected to a 1-year period of interdisciplinary intervention (nutrition, psychology, physical exercise and clinical support). MEASUREMENTS: Blood samples were collected to analyse glucose, lipid and adipokine concentrations. Body composition, anthropometric profiles and cIMT were measured. The results are presented according to quartiles of weight loss: 1st (≤5·80 kg) = low; 2nd (5·80-10·90 kg) = low to moderate; 3rd (10·90-15·90 kg) = moderate; and 4th (>15·90 kg) = massive. RESULTS: Leptin, the leptin/adiponectin ratio and plasminogen activator inhibitor 1 (PAI-1) were decreased significantly in the low-to-moderate weight loss. The cIMT was reduced in the moderate weight loss. Moreover, adiponectin was increased only in the massive weight loss. Additionally, weight loss was an independent predictor of changes in leptin level, the adiponectin/leptin ratio (A/L ratio) and PAI-1 when the data were adjusted for age and gender. BMI changes were predictors of changes in leptin and PAI-1 levels. A/L ratio was associated with lean body mass (%), independent of gender and age. In addition, changes in A/L ratio were independent predictors of cIMT alterations. CONCLUSIONS: Interdisciplinary therapy may reduce cardiovascular risk factors among adolescents depending on their degree of weight loss (moderate to massive) and when correlated with their inflammatory profile, metabolic state and cIMT.

Long-term effects of aerobic plus resistance training on the adipokines and neuropeptides in nonalcoholic fatty liver disease obese adolescents.

OBJECTIVE: To compare the effects of aerobic training (AT) with aerobic plus resistance training (AT+RT) in nonalcoholic fatty liver disease (NAFLD) obese adolescents. DESIGN: Long-term interdisciplinary weight-loss therapy (1 year of clinical, nutritional, psychological, and exercise-related intervention). PARTICIPANTS: Fifty-eight postpubertal obese adolescents were randomized to AT or AT+RT according to NAFLD diagnosis. Adipokine and neuropeptide concentrations were measured by enzyme-linked immunosorbent assay, visceral fat by ultrasound, and body composition by plethysmography. RESULTS: The NAFLD group that followed the AT+RT protocol presented lower insulin, homeostasis model assessment-insulin resistance (HOMA-IR), and alanine transaminase (ALT) values after intervention compared with AT. It was verified that there was a higher magnitude of change in the subcutaneous fat, glycemia, total cholesterol (TC), low-density lipoprotein-cholesterol, ALT, and adiponectin in response to AT+RT than in the control group (AT). All patients who underwent the AT+RT exhibited significantly higher adiponectin, leptin, and Δadiponectin and lower melanin-concentrating hormone (MCH) concentrations after therapy compared with the AT group. In the simple linear regression analysis, changes in glycemia, insulin, and HOMA-IR were independent predictors of significant improvement in adiponectin concentration. Indeed, ΔAST (aspartate transaminase) and ΔGGT (γ-glutamyl transpeptidase) were independent predictors of ΔALT, while Δfat mass and ΔAgRP (agouti-related protein) were independent predictors of ΔMCH. Although the number of patients was limited, we showed for the first time the positive effects of AT+RT protocol in a long-term interdisciplinary therapy to improve inflammatory biomarkers and to reduce orexigenic neuropeptide concentrations in NAFLD obese adolescents. CONCLUSION: The long-term interdisciplinary therapy with AT+RT protocol was more effective in significantly improving noninvasive biomarkers of NAFLD that are associated with the highest risk of disease progression in the pediatric population.

Influence of visceral and subcutaneous fat in bone mineral density of obese adolescents.

OBJECTIVE: To verify the influence of visceral and subcutaneous fat, as well adipokines in bone mineral density (BMD) in obese adolescents. SUBJECTS AND METHODS: The study involved 125 postpubertal obese adolescents (45 boys and 80 girls). Anthropometric measurements, body composition, visceral and subcutaneous fat, and BMD were determined. Leptin, adiponectin, and insulin levels also analyzed. RESULTS: Data demonstrated a negative relationship between BMD with insulin resistance, visceral fat and leptin concentration; and bone mineral content with visceral/subcutaneous ratio. Positive association between BMD and subcutaneous fat was observed. CONCLUSIONS: Visceral fat and insulin resistance, as well as visceral/subcutaneous ratio and leptin concentration, were negative predictors of BMD in boys and girls, respectively. However, subcutaneous fat had a protective influence in BMD only in boys.

The role of pro/anti-inflammatory adipokines on bone metabolism in NAFLD obese adolescents: effects of long-term interdisciplinary therapy.

To investigate the role of pro- and anti-inflammatory adipokines in the bone metabolism of non-alcoholic fatty liver disease (NAFLD) obese adolescents as well as the effects of long-term interdisciplinary therapy on metabolic-related risk factors. Forty post-puberty obese adolescents were randomly assigned into two groups: (1) NAFLD group and (2) non-NAFLD group (diagnosis by ultrasonography) and submitted to a weight loss therapy. Body composition was analyzed by air displacement plethysmography, bone mineral density (BMD) and content by dual-energy X-ray absorptiometry, blood samples were collected to measure lipid profile, hepatic enzymes, and adipokines. Leptin and adiponectin concentrations were measured by ELISA. A decrease in total body mass, BMI, body fat, visceral and subcutaneous fat, insulin concentration, HOMA-IR, total cholesterol and an increase in lean body mass were observed in both groups after therapy. It was found positive correlation between the Δ BMD and the Δ fat mass (%) (r = 0.31, P = 0.01) and negative correlations between Δ BMC with Δ HOMA-IR (r = -0.34, P = 0.02) and Δ HOMA-IR with Δ leptin (r = -0.34, P = 0.02). In addition, increased levels of adiponectin and reduction in leptin concentrations were observed in NAFLD group. In the simple regression analysis, the HOMA-IR was an independent predictor changes in BMC in total obese adolescents and in the non-NAFLD group. One year of interdisciplinary weight loss therapy for obese adolescents with or without NAFLD, could regulate bone mineral metabolism as result of an increased BMC and improved inflammatory state.

Influence of visceral and subcutaneous fat in bone mineral density of obese adolescents / A influência da gordura visceral e subcutânea na densidade mineral óssea de adolescentes obesos

OBJECTIVE: To verify the influence of visceral and subcutaneous fat, as well adipokines in bone mineral density (BMD) in obese adolescents. SUBJECTS AND METHODS: The study involved 125 postpubertal obese adolescents (45 boys and 80 girls). Anthropometric measurements, body composition, visceral and subcutaneous fat, and BMD were determined. Leptin, adiponectin, and insulin levels also analyzed. RESULTS: Data demonstrated a negative relationship between BMD with insulin resistance, visceral fat and leptin concentration; and bone mineral content with visceral/subcutaneous ratio. Positive association between BMD and subcutaneous fat was observed. CONCLUSIONS: Visceral fat and insulin resistance, as well as visceral/subcutaneous ratio and leptin concentration, were negative predictors of BMD in boys and girls, respectively. However, subcutaneous fat had a protective influence in BMD only in boys.

OBJETIVO: Verificar a influência da gordura visceral e subcutânea, assim como das adipocinas na densidade mineral óssea (DMO) em adolescentes obesos. SUJEITOS E MÉTODOS: O estudo envolveu 125 adolescentes obesos pós-púberes. Medidas antropométricas, composição corporal, gordura visceral e subcutânea e DMO foram determinadas. Níveis de leptina, adiponectina e insulina foram analisados. RESULTADOS:Os dados demonstraram associação negativa entre DMO com resistência insulínica, gordura visceral e concentração de leptina; e conteúdo mineral ósseo com a razão visceral/subcutânea. Associação positiva entre DMO e gordura subcutânea foi observada. CONCLUSÕES: Gordura visceral, resistência insulínica, razão visceral/subcutânea e concentração de leptina foram preditores negativos da DMO em meninos e meninas, respectivamente. Entretanto, a gordura subcutânea demonstrou exercer influência positivamente na DMO somente nos meninos.