Claudio Gonzalez

Obesity prevalence and trends in Latin-American countries.

The prevalence of obesity in some lower‐income and transitional countries is as high as, or even higher than, the prevalence reported in developed nations, and it seems to be increasing rapidly. In most countries, the prevalence of obesity is higher in women than in men, and higher in urban than in rural areas. Preobesity prevalence is very high in most Latin‐American countries. Sixty per cent of the population in Venado Tuerto (Argentina) has a body mass index (BMI) of ≥25 kg m−2, as do 35% of the population in Brazil, 60% in Mexico, 68% in Paraguay and 53% in Peru. Trends are available from Brazil, where marked increases in the prevalence of obesity have occurred, except in women from higher‐income groups. Women from the higher‐income quartiles in urban regions experienced a marked reduction in obesity prevalence from 1989 to 1997 (12.8 to 9.2%). Although data in children is scant, the prevalence of undernutrition is decreasing and the prevalence of obesity is high also in Latin‐American children. The prevalence of obesity is high even in minority Indian groups. Rapid changes in dietary structure (in particular associated with urbanization) and major changes in the levels of physical activity, both occupationally and during leisure time, may explain these changes.

Effects of rotating shift work on biomarkers of metabolic syndrome and inflammation

Objective.  The major function of the circadian system is the internal cycling of physiological and metabolic events. The present study sought to explore the effect of rotating shift work schedule on leucocyte count and its relationship with risk factors of metabolic syndrome (MS).

The Pancreatitis-induced Vacuole Membrane Protein 1 Triggers Autophagy in Mammalian Cells

Autophagy is a degradation process of cytoplasmic cellular constituents, which serves as a survival mechanism in starving cells, and it is characterized by sequestration of bulk cytoplasm and organelles in double-membrane vesicles called autophagosomes. Autophagy has been linked to a variety of pathological processes such as neurodegenerative diseases and tumorigenesis, which highlights its biological and medical importance. We have previously characterized the vacuole membrane protein 1 (VMP1) gene, which is highly activated in acute pancreatitis, a disease associated with morphological changes resembling autophagy. Here we show that VMP1 expression triggers autophagy in mammalian cells. VMP1 expression induces the formation of ultrastructural features of autophagy and recruitment of the microtubule-associated protein 1 light-chain 3 (LC3), which is inhibited after treatment with the autophagy inhibitor 3-methiladenine. VMP1 is induced by starvation and rapamycin treatments. Its expression is necessary for autophagy, because VMP1 small interfering RNA inhibits autophagosome formation under both autophagic stimuli. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes. It interacts with Beclin 1, a mammalian autophagy initiator, through the VMP1-Atg domain, which is essential for autophagosome formation. VMP1 endogenous expression co-localizes with LC3 in pancreas tissue undergoing pancreatitis-induced autophagy. Finally, VMP1 stable expression targeted to pancreas acinar cell in transgenic mice induces autophagosome formation. Our results identify VMP1 as a novel autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process.

The emerging role of autophagy in the pathophysiology of diabetes mellitus

An emerging body of evidence supports a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus. Persistent high concentrations of glucose lead to imbalances in the antioxidant capacity within the cell resulting in oxidative stress-mediated injury in both disorders. An anticipated consequence of impaired autophagy is the accumulation of dysfunctional organelles such as mitochondria within the cell. Mitochondria are the primary site of the production of reactive oxygen species (ROS), and an imbalance in ROS production relative to the cytoprotective action of autophagy may lead to the accumulation of ROS. Impaired mitochondrial function associated with increased ROS levels have been proposed as mechanisms contributing to insulin resistance. In this article we review and interpret the literature that implicates a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus as it applies to β-cell dysfunction, and more broadly to organ systems involved in complications of diabetes including the cardiovascular, renal and nervous systems.

Zymophagy, a Novel Selective Autophagy Pathway Mediated by VMP1-USP9x-p62, Prevents Pancreatic Cell Death

Autophagy has recently elicited significant attention as a mechanism that either protects or promotes cell death, although different autophagy pathways, and the cellular context in which they occur, remain to be elucidated. We report a thorough cellular and biochemical characterization of a novel selective autophagy that works as a protective cell response. This new selective autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration to sequester and degrade potentially deleterious activated zymogen granules. We have coined the term “zymophagy” to refer to this process. The autophagy-related protein VMP1, the ubiquitin-protease USP9x, and the ubiquitin-binding protein p62 mediate zymophagy. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. Zymophagy is activated by experimental pancreatitis in genetically engineered mice and cultured pancreatic acinar cells and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. Together, these data reveal a novel selective form of autophagy mediated by the VMP1-USP9x-p62 pathway, as a cellular protective response.

Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns.

We explored peroxisome proliferator‐activated receptor‐γ co‐activator 1α gene (PPARGC1A), peroxisome proliferator‐activated receptor‐γ gene (PPARG), and transcription factor A mitochondrial gene (Tfam) promoter DNA methylation in newborns between both extremes of abnormal fetal growth: Small (SGA) and large for gestational age (LGA) in relation to the mothers characteristics. We further sought for the association of rs9930506 variant at FTO gene and the promoter patterns of DNA methylation in the aforementioned genes, in relation to the offsprings birth weight. In a cross‐sectional study, 88 healthy pregnant women and their babies were included. According to the offspring birth weight, there were 57 newborns with appropriate weight for gestational age (AGA), 17 SGA, and 14 LGA. After bisulphite treatment of umbilical cord genomic DNA, a real‐time methylation‐specific PCR was used to determine the promoter methylation status in selected CpGs. Promoter methylated DNA/unmethylated DNA ratio, expressed as mean ± s.e., was 0.82 ± 0.15 (45% of alleles) for PPARGC1A, and 0.0044 ± 0.0006 (0.4% of alleles) for Tfam. PPARG promoter was almost 100% methylated in all samples. In univariate analysis, there was no association among characteristics of the newborn and gene promoter methylation. None of the maternal features were related with the status of promoter methylation, except for a positive correlation between maternal BMI and PPARGC1A promoter methylation in umbilical cord (Pearson correlation coefficient r = 0.41, P = 0.0007). Finally, FTO rs9930506 AA homozygous in the LGA group showed decreased levels of methylated PPARGC1A in comparison with AG + GG genotypes and AGA and SGA infants. In conclusion, our findings suggest a potential role of promoter PPARGC1A methylation in metabolic programming.

Association of the C-344T aldosterone synthase gene variant with essential hypertension: a meta-analysis.

Background The CYP11B2 gene (CYP11B2) encoding aldosterone synthase has been associated with essential hypertension and some, but not all, studies have reported that the C−344T variant may influence the risk of the disease. Objective We performed a systematic review of the literature by means of a meta-analysis to evaluate the influence of the C−344T CYP11B2 polymorphism on arterial hypertension and intermediate phenotypes. Methods From 485 reports, we included 42 observational studies, case–control and cohort at baseline. Fixed and random effect models were used to pool data from individual studies. Results From 19 heterogeneous studies including 5343 essential hypertensive and 5882 control subjects, we found a significant association between hypertension and the C−344T variant in fixed but not in random effect models [for homozygous CC: odds ratio (OR), 0.834; 95% confidence interval (CI), 0.760–0.914; P < 0.0001, n = 11 225]. Besides, homozygous CC subjects had lower plasma renin activity (D, −0.161; 95% CI, −0.279 to −0.043; P < 0.01, n = 1428) but no difference in plasma aldosterone levels (D, −0.006; 95% CI, −0.081 to 0.07; P = 0.88, n = 2872). Limiting the quantitative analysis of blood pressure to 13 studies including only untreated individuals, no significant association was found for systolic arterial blood pressure (D, 0.042; 95% CI, −0.057 to 0.141; P = 0.41, n = 1775) and diastolic arterial blood pressure (D, 0.026; 95% CI, −0.073 to 0.125; P = 0.61, n = 1775). Conclusion Homozygous individuals for the −344C CYP11B2 allele are at 17% lower risk of hypertension with respect to homozygous TT subjects.

Gemcitabine Induces the VMP1-Mediated Autophagy Pathway to Promote Apoptotic Death in Human Pancreatic Cancer Cells

Background/Aim: Autophagy is a degradation process of cytoplasmic cellular constituents. We have described the vacuole membrane protein-1 (VMP1) whose expression triggers autophagy in mammalian cells. The aim of this study was to analyze the role of autophagy in human pancreatic cancer cell death. Methods/Results: Here we show that gemcitabine, the standard chemotherapy for pancreatic cancer, induced autophagy in PANC-1 and MIAPaCa-2 cells, as evidenced by the accumulation of acidic vesicular organelles, the recruitment of microtubule-associated protein-1 light chain-3, and electron microscopy. In addition, gemcitabine treatment induced early expression of VMP1 in cancer cells. Gemcitabine also induced apoptosis detected by morphology, annexin V-positive cells, and cleavage of caspase-3. Surprisingly, 3-methyladenine, an autophagy inhibitor, decreased apoptosis in gemcitabine-treated cells, showing that autophagy leads to cancer cell apoptotic death. Finally, VMP1 knockdown decreased autophagy and apoptosis in gemcitabine-treated cancer cells. Conclusions: The VMP1-autophagy pathway promotes apoptosis in pancreatic cancer cells and mediates gemcitabine-induced cytotoxicity.

Short Allele of Serotonin Transporter Gene Promoter Is a Risk Factor for Obesity in Adolescents

Obesity and hypertension are increasing medical problems in adolescents. Serotonin transporter (5‐HTT) is involved in mood and eating disturbances. Encoded by the gene SLC6A4, the promoter shows functional insertion/deletion alleles: long (L) and short (S). Because individuals who are carriers for the short version are known to be at risk for higher levels of anxiety, we hypothesized that this variant may be associated with overweight. Data and blood samples were collected from 172 adolescents out of a cross‐sectional, population‐based study of 934 high school students. To replicate the findings, we also included 119 outpatients from the Nutrition and Diabetes Section of the Childrens County Hospital. We found that the S allele was associated with overweight (BMI > 85th percentile), being a risk factor for overweight independently of sex, age, and hypertension [odds ratio (OR): 1.85; 95% confidence interval (CI): 1.13, 3.05; p < 0.02]. Additionally, in the outpatient study, compared with the homozygous LL subjects, S allele carriers showed a higher BMI z‐score (1.47 ± 1.09 vs. 0.51 ± 1.4; p < 0.002) and were more frequent in overweight children. In conclusion, the S allele of the SLC6A4 promoter variant is associated with overweight being an independent genetic risk factor for obesity.

A Decreased Mitochondrial DNA Content Is Related to Insulin Resistance in Adolescents

The aim of this study was to investigate whether mitochondrial DNA (mtDNA) content is associated with insulin resistance (IR) in a sample of adolescents with features of metabolic syndrome. We further studied the link between polymorphisms in three genes involved in mitochondrial biogenesis and the presence of deleted mtDNA and mtDNA content. Data and blood samples were collected from 175 adolescents out of a cross‐sectional, population‐based study of 934 high school students. On the basis of the median value of homeostasis model assessment of IR (HOMA‐IR) of the whole sample (2.2), the population was divided into two groups: noninsulin resistance (NIR) and IR. mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using a real‐time quantitative PCR method. Genotyping for peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) (pro12Ala), PPAR‐ γ coactivator‐1α (PGC‐1α) (Gly482Ser), and Tfam (rs1937 and rs12247015) polymorphisms was performed by PCR‐based restriction fragment length polymorphism. Long‐extension PCR was performed to amplify the whole mitochondrial genome. The mtDNA/nDNA ratio was significantly lower in the IR group (median: 9.08, range: 68.94) in comparison with the NIR group (12.24, 71.92) (P < 0.03). Besides, the mtDNA/nDNA ratio was inversely correlated with HOMA (R: −0.18, P < 0.02), glucose (R: −0.21, P < 0.008), and uric acid (R: −0.18, P < 0.03). Genotypes for the PPAR‐ γ, PGC‐1α, and Tfam variants were not associated with the mtDNA/nDNA ratio. Long‐extension PCR did not show significant levels of mtDNA deletions. In conclusion, our findings indicate that reduced mtDNA content in peripheral leukocytes is associated with IR. This result seems not to be related with the previously mentioned variants in genes involved in the regulation of mitochondrial biogenesis.