A very-low-calorie ketogenic diet normalises obesity-related enhanced levels of erythropoietin compared with a low-calorie diet or bariatric surgery.

PURPOSE: Nutritional ketosis synergistically with body-weight loss induced by a very-low-calorie ketogenic diet (VLCKD) has proven to be effective in improving obesity-related pathophysiology. Recently, growing attention has been focused on the relation between erythropoietin (EPO) and obesity. Thus, this study aims to investigate whether nutritional ketosis and weight loss induced by a VLCKD modify the circulating levels of EPO in patients with obesity in comparison with the effect of low-calorie diet (LCD) or bariatric surgery (BS). METHODS: EPO levels, iron status and body composition parameters were evaluated in 72 patients with overweight or obesity and 27 normal-weight subjects at baseline and after the three different weight-reduction therapies (VLCKD, LCD and BS) in 69 patients with excess body weight. ß-hydroxybutyrate levels were also measured in the VLCKD group. The follow-up was established at 2-3 months and 4-6 months. RESULTS: It was found that EPO levels were higher in morbid obesity and correlated with higher basal weight, fat mass (FM) and fat-free mass (FFM) in the overall sample. High baseline EPO levels were also correlated with higher impact on the course of weight loss and changes in FM and FFM induced by the three weight-loss interventions. Furthermore, the VLCKD induced a decrease in EPO levels coinciding with maximum ketosis, which was maintained over time, while statistically significant changes were not observed after LCD and BS. CONCLUSION: The obesity-related increased EPO levels are restored after VLCKD intervention at the time of maximum ketosis, suggesting a potential role of the nutritional ketosis induced by the VLCKD. Baseline EPO levels could be a biomarker of response to a weight-loss therapy.

Plasma FGF21 levels in obese patients undergoing energy-restricted diets or bariatric surgery: a marker of metabolic stress?

BACKGROUND: Fibroblast growth factor 21 (FGF21) has been suggested to be an endocrine signal of nutritional status and an active regulator of metabolism. However, there is no agreement on the effect of weight-loss therapies on circulating levels of FGF21 in humans. OBJECTIVE: To assess FGF21 circulating levels in adiposity excess and after different weight-loss strategies prescribed in five different groups from four independent centers. SUBJECTS AND METHODS: Body composition, ketosis, insulin sensitivity and FGF21 were evaluated in 181 excess body weight and 14 normal-weight subjects. From the excess body weight patients, two independent groups (discovery cohort; n=20 and validation cohort; n=28) undertook a very low-calorie ketogenic (VLCK) diet, a third group followed a low-calorie (LC) diet (n=84) and other two groups underwent bariatric surgery (discovery cohort; n=24 and validation cohort; n=25). The follow-up was 4 to 6 or 12 months, respectively. RESULTS: FGF21 levels were higher in excess body weight patients than in normal-weight subjects. The energy-restriction therapy to lose weight induced a significant decrease, with respect to baseline, in circulating levels of FGF21 (VLCK: -62.5 pg ml-1 or -14.8 pg ml-1 and LC diet: -67.9 pg ml-1). There were no differences in FGF21 levels between both energy-restriction treatments. On the contrary, after bariatric surgery morbidly obese patients showed a significant increase in FGF21, especially 1 month after surgery (148.8 pg ml-1 higher than baseline). The FGF21 differential changes occur concomitantly with a non-induced ketosis situation (0.66±0.56 mm) in bariatric surgery, and an improvement in adiposity and insulin sensitivity induced by the three therapies. CONCLUSIONS: FGF21 levels were reduced after energy-restricted treatments and severely increased after bariatric surgery, independently of the weight reduction magnitude, insulin sensitivity or ketosis. Therefore, FGF21 appears to be a marker of severe nutritional stress.

DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients.

The characterization of the epigenetic changes within the obesity-related adipose tissue will provide new insights to understand this metabolic disorder, but adipose tissue is not easy to sample in population-based studies. We aimed to evaluate the capacity of circulating leukocytes to reflect the adipose tissue-specific DNA methylation status of obesity susceptibility. DNA samples isolated from subcutaneous adipose tissue and circulating leukocytes were hybridized in the Infinium HumanMethylation 450 BeadChip. Data were compared between samples from obese (n = 45) and non-obese (n = 8-10) patients by Wilcoxon-rank test, unadjusted for cell type distributions. A global hypomethylation of the differentially methylated CpG sites (DMCpGs) was observed in the obese subcutaneous adipose tissue and leukocytes. The overlap analysis yielded a number of genes mapped by the common DMCpGs that were identified to reflect the obesity state in the leukocytes. Specifically, the methylation levels of FGFRL1, NCAPH2, PNKD and SMAD3 exhibited excellent and statistically significant efficiencies in the discrimination of obesity from non-obesity status (AUC > 0.80; p < 0.05) and a great correlation between both tissues. Therefore, the current study provided new and valuable DNA methylation biomarkers of obesity-related adipose tissue pathogenesis through peripheral blood analysis, an easily accessible and minimally invasive biological material instead of adipose tissue.

A role for novel adipose tissue-secreted factors in obesity-related carcinogenesis.

Obesity, a pandemic disease, is caused by an excessive accumulation of fat that can have detrimental effects on health. Adipose tissue plays a very important endocrine role, secreting different molecules that affect body physiology. In obesity, this function is altered, leading to a dysfunctional production of several factors, known as adipocytokines. This process has been linked to various comorbidities associated with obesity, such as carcinogenesis. In fact, several classical adipocytokines with increased levels in obesity have been demonstrated to exert a pro-carcinogenic role, including leptin, TNF-α, IL-6 and resistin, whereas others like adiponectin, with decreased levels in obesity, might have an anti-carcinogenic function. In this expanding field, new proteomic techniques and approaches have allowed the identification of novel adipocytokines, a number of which exhibit an altered production in obesity and type 2 diabetes and thus are related to adiposity. Many of these novel adipocytokines have also been identified in various tumour types, such as that of the breast, liver or endometrium, thereby increasing the list of potential contributors to carcinogenesis. This review is focused on the regulation of these novel adipocytokines by obesity, including apelin, endotrophin, FABP4, lipocalin 2, omentin-1, visfatin, chemerin, ANGPTL2 or osteopontin, emphasizing its involvement in tumorigenesis.

Interplay of atherogenic factors, protein intake and betatrophin levels in obese-metabolic syndrome patients treated with hypocaloric diets.

CONTEXT: The understanding of the potential role of betatrophin in human metabolic disorders is a current challenge. OBJECTIVE: The present research evaluated circulating betatrophin levels in obese patients with metabolic syndrome (MetSyn) features under energy-restricted weight-loss programs and in normal weight in order to establish the putative interplay between the levels of this hormone, diet and metabolic risk factors linked to obesity and associated comorbidities. SUBJECTS AND METHODS: One hundred forty-three participants were enrolled in the study (95 obese-MetSyn; age 49.5±9.4 years; body mass index (BMI) 35.7±4.5 kg m(-2) and 48 normal weight; age 35.71±8.8 years; BMI 22.9±2.2 kg m(-2)). A nutritional therapy consisting in two hypocaloric strategies (control diet based on the AHA recommendations and the RESMENA (MEtabolic Syndrome REduction in Navarra) diet, a novel dietary program with changes in the macronutrient distribution) was only prescribed to obese-MetSyn participants who were randomly allocated to the dietary strategies. Dietary records, anthropometrical and biochemical variables as well as betatrophin levels were analyzed before (pre-intervention, week 0), at 8 weeks (post-intervention, week 8) and after 4 additional months of self-control period (follow-up, week 24). RESULTS: Betatrophin levels were higher in obese-MetSyn patients than normal-weight subjects (1.24±0.43 vs 0.97±0.69 ng ml(-1), respectively, P=0.012), and levels were positively associated with body composition, metabolic parameters, leptin and irisin in all participants at baseline. Notably, low pre-intervention (week 0) betatrophin levels in obese patients were significantly associated with higher dietary-induced changes in atherogenic risk factors after 8 weeks. Moreover, protein intake, especially proteins from animal sources, was an independent determinant of betatrophin levels after dietary treatment (B=-0.27; P=0.012). CONCLUSIONS: Betatrophin is elevated in obese patients with MetSyn features and is associated with poorer nutritional outcomes of adiposity and dyslipidemia traits after a weight-loss program. Dietary protein intake could be a relevant modulator of betatrophin secretion and activity.

Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes.

BACKGROUND/OBJECTIVES: Obese adipose tissue, especially the visceral depot, exhibits altered production of several molecules that could have a role on the initiation/promotion of breast cancer development. The aim of this work was to evaluate the effect of excess adipose tissue and its secreted factors on the expression of genes involved in the early steps of tumor promotion on the mammary gland. SUBJECTS AND METHODS: Carcinogenesis-related gene expression was evaluated in mammary gland tissue from female diet-induced obese (DIO) Sprague-Dawley rats and circulating leukocytes isolated from a group of breast cancer diagnosed and non-diagnosed obese women and compared with their normal weight counterparts. In addition, the human non-tumoral mammary epithelial cell line MCF10A was treated in vitro with the visceral (retroperitoneal adipose tissue (RPAT)) or subcutaneous adipose tissue (SAT) secretome and with rising concentrations of the lipid peroxidation by-product 4-hydroxynonenal (4-HNE). RESULTS: DIO rats were classified as susceptible to DIO (DIO-S) or partially resistant to DIO (DIO-R) according to the maximum fat mass gain of the lean group as a cut-off. As compared with lean and DIO-R, the DIO-S group showed a higher fat mass and lower lean mass. The anatomical characteristic of DIO-S was correlated with differential expression of cellular proliferation (ALDH3A1 and MYC) and antioxidant and DNA protection (GSTM2, SIRT1), and tumor suppression (TP53, PTEN, TGFB1) genes. Remarkably, this carcinogenesis-related gene expression pattern was reproduced in MCF10A treated with the RPAT secretome from DIO-S rats and with the lipid peroxidation by-product 4-HNE. Moreover, this pattern was also detected in leukocytes from obese women compared with normal weight women without evidence of breast cancer. CONCLUSIONS: Lipid peroxides secreted by the obese visceral adipose tissue could be among the relevant factors that promote changes involved in the early steps of tumor development in mammary gland. These changes can be detected even before histological alterations and in circulating leukocytes.

Cerebral venous thrombosis in two patients with spontaneous intracranial hypotension.

Although few patients with spontaneous intracranial hypotension develop cerebral venous thrombosis, the association between these two entities seems too common to be simply a coincidental finding. We describe two cases of spontaneous intracranial hypotension associated with cerebral venous thrombosis. In one case, extensive cerebral venous thrombosis involved the superior sagittal sinus and multiple cortical cerebral veins. In the other case, only a right frontoparietal cortical vein was involved. Several mechanisms could contribute to the development of cerebral venous thrombosis in spontaneous intracranial hypotension. When spontaneous intracranial hypotension and cerebral venous thrombosis occur together, it raises difficult practical questions about the treatment of these two conditions. In most reported cases, spontaneous intracranial hypotension was treated conservatively and cerebral venous thrombosis was treated with anticoagulation. However, we advocate aggressive treatment of the underlying cerebrospinal fluid leak.

Ghrelin as a GH-releasing factor.

Growth hormone (GH) is secreted by the pituitary gland in a pulsatile manner. It is accepted that this pulsatility is primarily controlled by the hypothalamus, although this secretion can also be modulated by factors from GH-targeted organs, the pituitary and other regions of the central nervous systems, or by factors arriving from peripheral organs. In mammals, hypothalamic control of GH pulsatility is classically regulated by the interplay of two opposing hormones, stimulatory GHRH and inhibitory somatostatin (SS). Recognition of the gastric ghrelin peptide as the natural ligand for GH secretagogue receptor type 1a (GHS-R1a) added a new element to the complex physiological regulation of GH secretion and clarified some of its aspects that were previously not fully understood. In this review, we examine data that suggest that ghrelin may regulate GH secretion, as well as ghrelin's possible use as a therapeutic agent.

Oxidative stress associated to dysfunctional adipose tissue: a potential link between obesity, type 2 diabetes mellitus and breast cancer.

Diabetes mellitus and breast cancer are two important health problems. Type 2 diabetes (T2DM) and obesity are closely linked with both being associated with breast cancer. Despite abundant epidemiological data, there is no definitive evidence regarding the mechanisms responsible for this association. The proposed mechanisms by which diabetes affects breast cancer risk and prognosis are the same as the mechanisms hypothesised for the contribution of obesity to breast cancer risk. The obesity-induced inflammation promoted by adipose tissue dysfunction is a key feature, which is thought to be an important link between obesity and cancer. Inflammation induces an increase in free radicals and subsequently promotes oxidative stress, which may create a microenvironment favourable to the tumor development in obese persons. Oxidative stress is also proposed as the link between obesity and diabetes mellitus. Therefore, obesity-related oxidative stress could be a direct cause of neoplastic transformation associated with obesity and T2DM in breast cancer cells. This review is focused on the role of obesity-related oxidative stress in the context of chronic inflammation, on the time of breast cancer onset and progression, which provide targets for preventive and therapeutic strategies in the fields of diabetes and obesity-related breast cancer.

Encefalopatía de Wernicke en pacientes no alcohólicos: una serie de 8 casos / Wernicke's encephalopathy in non-alcoholic patients: a series of 8 cases

Introduction: Wernicke's encephalopathy (WE) is an underdiagnosed condition, usually associated with alcoholism, and has a worse prognosis if there is a delay in diagnosis. A series of 8 non-alcoholic patients with WE is presented and an assessment is made on whether a delay in diagnosis leads to a worse prognosis. Patients and methods:The clinical records of patients admitted to 2 university hospitals between 2004 and 2009 with the diagnosis of WE, excluding those with a history of alcoholism, were retrospectively reviewed. Results:The study included 4 men and 4 women aged 35-82 of whom 7 had a history of gastrointestinal pathology, and persistent vomiting was the precipitating factor in 7. Encephalopathy was the most frequent onset symptom (4). The classical triad was present in seven patients. Thiamine levels were low in 3/6 and normal in 3/6 cases. MRI was abnormal in seven patients, with high signal intensity in the diencephalon and mammillary bodies (7), periaqueductal grey matter (6), cortex (3) and cerebellum (1). Seven improved with thiamine. Sequelae were mild in 6, and severe in 2 after 6-12 months of follow-up. All patients with a diagnostic delay less than 18 days had mild sequelae.Conclusions: Non-alcoholic WE frequently occurs after gastrointestinal disturbances that could result in lower thiamine absorption. Whereas thiamine levels can be normal in many cases, in almost all cases the MRI shows signal alterations in typical locations. A delay in the diagnosis, and therefore, in treatment leads to a worse prognosis

Introducción: La encefalopatía de Wernicke (EW) es una entidad infradiagnosticada, generalmente asociada a alcoholismo, que tiene peor pronóstico si existe retraso diagnóstico. Se presenta una serie de 8 pacientes no alcohólicos con EW y se evalúa si el retraso en el diagnóstico implica un peor pronóstico. Pacientes y métodos:Revisión retrospectiva de las historias clínicas de pacientes ingresados en dos hospitales universitarios entre 2004 y 2009 con diagnóstico de EW, excluidos aquéllos con historia de alcoholismo.Resultados: Se incluyó a 4 varones y 4 mujeres, con edades comprendidas entre los 35 y los 82 años; 7 tenían antecedentes patológicos gastrointestinales y los vómitos persistentes fueron el desencadenante en 7 casos. La encefalopatía fue la forma de inicio más frecuente (4 casos). La tríada clásica llegó a estar presente en 7 pacientes. Los niveles de tiamina fueron bajos en 3/6 y normales en 3/6 pacientes. La RM fue patológica en 7 pacientes, con hiperintensidad en diencéfalo y cuerpos mamilares (7), sustancia gris periacueductal (6), corteza (3) y cerebelo (1). Siete pacientes mejoraron tras el tratamiento con tiamina. Las secuelas fueron leves en 5 casos y graves en 3 pacientes. Todos los pacientes con un retraso diagnóstico inferior a 18 días tuvieron secuelas leves.Conclusiones: En la EW no alcohólica son frecuentes los antecedentes gastrointestinales que podrían condicionar una menor absorción de tiamina. Mientras que los niveles de tiamina pueden ser normales en muchos casos, la RM casi siempre muestra alteración de señal en localizaciones típicas. El retraso en el diagnóstico y, por tanto, en el tratamiento podría implicar un peor pronóstico (AU)

[Wernicke's encephalopathy in non-alcoholic patients: a series of 8 cases]. / Encefalopatía de Wernicke en pacientes no alcohólicos: una serie de 8 casos.

INTRODUCTION: Wernicke's encephalopathy (WE) is an underdiagnosed condition, usually associated with alcoholism, and has a worse prognosis if there is a delay in diagnosis. A series of 8 non-alcoholic patients with WE is presented and an assessment is made on whether a delay in diagnosis leads to a worse prognosis. PATIENTS AND METHODS: The clinical records of patients admitted to 2 university hospitals between 2004 and 2009 with the diagnosis of WE, excluding those with a history of alcoholism, were retrospectively reviewed. RESULTS: The study included 4 men and 4 women aged 35-82 of whom 7 had a history of gastrointestinal pathology, and persistent vomiting was the precipitating factor in 7. Encephalopathy was the most frequent onset symptom (4). The classical triad was present in seven patients. Thiamine levels were low in 3/6 and normal in 3/6 cases. MRI was abnormal in seven patients, with high signal intensity in the diencephalon and mammillary bodies (7), periaqueductal grey matter (6), cortex (3) and cerebellum (1). Seven improved with thiamine. Sequelae were mild in 6, and severe in 2 after 6-12 months of follow-up. All patients with a diagnostic delay less than 18 days had mild sequelae. CONCLUSIONS: Non-alcoholic WE frequently occurs after gastrointestinal disturbances that could result in lower thiamine absorption. Whereas thiamine levels can be normal in many cases, in almost all cases the MRI shows signal alterations in typical locations. A delay in the diagnosis, and therefore, in treatment leads to a worse prognosis.

Metabolic implications of growth hormone therapy.

GH regulates important physiological processes, including somatic growth and development, and carbohydrate and lipid metabolism. GH deficiency and GH replacement therapy exert opposite effects on body composition and fat accumulation, suggesting that GH may directly regulate adipocyte functions. Multiple studies have shown that in tissues previously deprived of GH, short-term stimulation with GH is able to mimic the actions of insulin, including stimulation of amino-acid and glucose transport, and lipogenesis. However, the antagonistic effects of GH on insulin-mediated metabolic responses are well-documented: GH excess in patients with GH-producing pituitary tumors causes hyperinsulinemia, insulin resistance, and even clinical diabetes mellitus. These apparently contradictory effects may be explained at the molecular level by the complex interplay between GH and insulin signaling. In this review, we examine the consequences of acute and chronic effects of GH on visceral fat and on metabolic responses in adipocytes, and discuss experimental data illustrating the integrated crosstalk between GH and insulin.

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Aspectos morfológicos e quetotáxicos de larvas de Argas (Persicargas) miniatus (Acari: Argasidae) no Brasil / Morphology and chaetotaxy aspects of larvae of Argas (Persicargas) miniatus (Acari: Argasidae) in Brazil

Eggs were obtained from female Argas (Persicargas) miniatus parasitizing chickens after natural ovoposition. The larvae from eggs were sacrificed, prepared for and mounted onto slides. Morphological and chaetotaxic studies enabled the following observation: idiosome and gnathosome shape; presence or absence of scutum, eyes and anal setae; number of palpi segments; number of files of teeth on the hypostoma; number of denticles on the apical crow; number of cheliceral digits; number of teeth in each hypostoma file; disposition and shape of opistosoma and podosoma setae in ventral and dorsal view. Based on these morphological features analyzed, it is concluded that the larvae of A. (P.) miniatus present variations in morphology and chaetotaxy that are useful to separate the larvae of the subgenus Persicargas.