Association of placental nutrient sensing pathways with birth weight.

Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.

Identification of metabolic markers in patients with type 2 Diabetes by Ultrafast gas chromatography coupled to electronic nose. A pilot study.

Metabolomics is a potential tool for the discovery of new biomarkers in the early diagnosis of diseases. An ultra-fast gas chromatography system equipped to an electronic nose detector (FGC eNose) was used to identify the metabolomic profile of Volatile Organic Compounds (VOCs) in type 2 diabetes (T2D) urine from Mexican population. A cross-sectional, comparative, and clinical study with translational approach was performed. We recruited twenty T2D patients and twenty-one healthy subjects. Urine samples were taken and analyzed by FGC eNose. Eighty-eight compounds were identified through Kovats's indexes. A natural variation of 30% between the metabolites, expressed by study groups, was observed in Principal Component 1 and 2 with a significant difference (p < 0.001). The model, performed through a Canonical Analysis of Principal coordinated (CAP), allowed a correct classification of 84.6% between healthy and T2D patients, with a 15.4% error. The metabolites 2-propenal, 2-propanol, butane- 2,3-dione and 2-methylpropanal, were increased in patients with T2D, and they were strongly correlated with discrimination between clinically healthy people and T2D patients. This study identified metabolites in urine through FGC eNose that can be used as biomarkers in the identification of T2D patients. However, more studies are needed for its implementation in clinical practice.

Relationship of lactation, BMI, and rs12255372 TCF7L2 polymorphism on the conversion to type 2 diabetes mellitus in women with previous gestational diabetes.

Women with previous gestational diabetes mellitus (pGDM) have a high risk of developing postpartum type 2 diabetes mellitus (T2DM). This study aimed to analyze the relationship between lactation, BMI, and TCF7L2 polymorphisms in the conversion to T2DM in women with pGDM. One hundred and fifty-three women con pGDM were recruited from public hospitals of León Guanajuato México. Three groups: normal glucose tolerance (NGT), impaired glucose intolerance (IGT), and T2DM after the oral glucose tolerance test were formed. Metabolic and hormone variables were measured, and genotyping was made by PCR-RFLP. The questionnaire included data on lactation (yes/no), duration of lactation, and full lactation. After 35 (21-49) months from the last partum, 54% of women had an NGT, 30.7% IGT, and 15% T2DM. BMI and rs12255372 are associated with the risk of conversion to IGT and T2DM [OR = 1.07 (95% IC 1.0-1.14, p = .041; OR =2.14, 95% IC 1.01-4.55, p = .04 respectively), while the lactation shows a strong protective effects OR = 0.15 (95% IC 0.062-0.39, p = .00007), and an apparent interaction with rs12255372T decreasing the risk in carriers (OR =2.15; 95% IC 0.97-4.7, p = .05). BMI is an independent risk factor of IGT/T2DM development. The lactation shows a strong protective effect and a possible interaction with rs12255372 polymorphism.

Flow mediated vasodilation compared with carotid intima media thickness in the evaluation of early cardiovascular damage in menopausal women and the influence of biological and psychosocial factors.

BACKGROUND: Women after menopause increase risk for cardiovascular disease and several factors may be related. The purpose was to study biological and psychosocial factors associated with early cardiovascular damage in pre- and postmenopausal women, assessed with carotid intima-media thickness vs flow-mediated dilatation. METHODS: Women 45 to 57 years old were grouped in the pre- (n = 60), early (n = 58) and late post-menopause (n = 59). Anthropometric, metabolic and hormonal data were registered, as well as measures of depression, anxiety, submission, perceived stress, and sleep alterations. Heart Rate Variability was recorded to obtain the information regarding sympathovagal balance. Carotid intima-media thickness and flow-mediated dilatation were assessed by ultrasound. Two-way ANOVA and multiple regression model were used. RESULTS: At late postmenopause, the carotid intima-media was thicker (p < 0.001) and flow-mediated dilatation decreased (p < 0.001). Carotid intima-media thickness was associated positively with age (p < 0.001), submission score (p = 0.029), follicle stimulating hormone levels (p < 0.001), and body mass index (p = 0.009). Flow-mediated dilatation was associated only with age (p < 0.001). Regarding heart rate variability, the time domain pNN50 measurement was higher in premenopausal women (p = 0.001), Low Frequency (LF) was higher in the two groups of postmenopausal (p = 0.001) and High Frequency (HF) higher in the early postmenopausal women (p = 0.042). CONCLUSIONS: Under our conditions carotid intima-media thickness had higher predictive value for early cardiovascular damage at menopause. The finding of the association of the submission score, indicates de influence of stress on vascular damage.

Association of Nesfatin-1, Acylated Ghrelin and Cortisol with Scores of Compulsion, Food Addiction, and Binge Eating in Adults with Normal Weight and with Obesity.

BACKGROUND/AIMS: The alterations of eating behavior are insufficiently recognized in the clinical attention of adults with obesity. The objective of this study was to examine the characteristics of overeating behavior and its association with depression, perceived stress, acylated ghrelin, nestafin-1, and cortisol. METHODS: This cross-sectional comparative study included 80 participants with obesity and 50 with normal weight. The volunteers completed questionnaires to evaluate symptoms of food addiction (FA), obsessive compulsive, binge eating (BE), depression, and perceived stress. We measured glucose, lipids, acylated ghrelin, nesfatin-1, and insulin in a fasting blood sample as well as urine cortisol. We compared groups with students t test, and analysis of variance, and tested associations by logistic and multiple regression. RESULTS: By multiple regression, the BE total score was positively associated with the FA (p < 0.0001) and depression total score (p < 0.0001). By logistic regression, the positive score of FA was associated with ghrelin (p < 0.02). The perceived stress total score was associated negatively with cortisol (p < 0.0006). CONCLUSION: The BE and FA are strongly associated in agreement with the concept that both conditions have overlapping features. Depressive symptoms are associated with symptoms of disordered eating -behavior. FA positive score was associated with ghrelin. BE total score was associated with nesfatin-1.

Leptin and its Receptors in Human Placenta of Small, Adequate, and Large for Gestational Age Newborns.

Alterations in birth weight impact postnatal outcome and adult metabolic health. Therefore, fetal growth regulation is crucial for preventing chronic metabolic diseases. Leptin has been suggested to play an important role in placental and fetal growth, albeit its specific mechanisms of action have not been elucidated. The aim of this study was to analyze leptin concentrations in placenta, cord blood, and maternal blood of SGA, AGA, and LGA (small, adequate and large for gestational age, respectively) newborns, as well as placental leptin receptor (LEPRa and LEPRb) protein expression. We performed a cross-sectional comparative study in 3 groups of healthy mothers and their term newborns at delivery (SGA, AGA, and LGA, n=20 per group). Placental, maternal blood, and cord blood leptin content were measured by ELISA. Placental LEPRa and LEPRb protein expression were determined by Western Blot. Maternal leptin concentrations correlated positively with maternal weight before and at the end of gestation, without differences between groups. Cord leptin is higher in LGA and lower in SGA, whereas placental leptin is higher in SGA. Placental leptin was inversely correlated with placental weight, independently from maternal weight and gestational age. Both LEPRa and LEPRb expression are lower in SGA, while LEPRa positively correlated with placental weight and birthweight. The current findings indicate that placental leptin and its receptors are differentially expressed in SGA, AGA, and LGA newborns. We suggest that placental leptin and LEPR protein expression may influence placental growth and thus, birth weight.

Metabolic, hormonal characteristics and genetic variants of TCF7L2 associated with development of gestational diabetes mellitus in Mexican women.

BACKGROUND: Variation in TCF7L2 gene is associated with type 2 diabetes and with gestational diabetes mellitus in several populations, but there are no data in Mexican women with gestational diabetes mellitus. In this study, we examined metabolic and hormonal measurements as well as TCF7L2 genetic variants. METHODS: We selected 108 pregnant women with normal glucose tolerance and 90 with gestational diabetes mellitus according to 2010 American Diabetes Association criteria matched for gestational week. We collected data on blood pressure, body mass index (BMI) and concentrations of blood glucose, HbA1c , lipids profile, insulin and glucagon-like peptide-1 (GLP-1). The genotyping of rs7903146 and rs12255372 polymorphisms were made with polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Actual and pre-gestational BMI, fasting glucose and HbA1c were higher (p < 0.001), and high-density lipoprotein cholesterol was lower (p < 0.02) in gestational diabetes mellitus women than euglycemic women. No significant differences were found for lipids, insulin and homeostasis model assessment-insulin resistance. Gestational diabetes mellitus women had high GLP-1 levels (32 vs 24, p < 0.004) and decreased ß-cell function (266 vs 438, p < 0.001). The frequency of rs12255372 risk allele in gestational diabetes women was significantly higher than that in euglycemic women (χ² = 8.96; p < 0.003) and confers a risk for gestational diabetes mellitus (OR = 9.1, 95% CI 2.8-29, p < 0.0002; and OR = 4.3, 95% CI 1.6-11.4, p < 0.003 based on dominant and co-dominant model, respectively). The generalized linear model showed that low beta function, high pre-gestational BMI and rs12255372 risk allele are independently associated with gestational diabetes. CONCLUSIONS: The elevated GLP-1 levels in gestational diabetes women suggested some abnormality in insulin secretion. The low ß-cell function, high pre-gestational BMI and rs12255372 risk allele are risk factors independently associated with the development of gestational diabetes.

Metabolic and nutritional profile differences among Mexican, Mexican-American and Non-Hispanic White children.

OBJECTIVE: To compare somatometric variables, lipid profile, diet, and physical activity between Mexican children living in México (MEX), and Mexican-American (MXA) and Non-Hispanic White (NHW) children from the United States (US) to examine the possible influence of ethnicity and residency on these factors. MATERIAL AND METHODS: Six to twelve years old children data from a study from central México and the US National Health and Nutrition Examination Survey was compared. Data were categorized to examine the effect of residency (MEX vs. MXA and NHW) and ethnicity (MEX vs. MXA and NHW) on the variables of interest. RESULTS: Living in the US was associated with higher cholesterol levels in younger boys and older girls (p < 0.05), and high saturated fat intake in all groups (p < 0.0001). Living in México increased the likelihood of abnormal HDL (p < 0.001), systolic (p < 0.001), and diastolic blood pressure (p < 0.0001). Caucasian young girls were more likely to have high cholesterol intake (p < 0.02) than their Mexican counterparts. CONCLUSIONS: These findings suggest that residency is linked to impaired lipid profile and blood pressure in children, whereas ethnicity seems to have an impact on dietary choices.

Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children.

BACKGROUND: Recent genome wide association studies (GWAS) and previous positional linkage studies have identified more than 50 single nucleotide polymorphisms (SNPs) associated with obesity, mostly in Europeans. We aimed to assess the contribution of some of these SNPs to obesity risk and to the variation of related metabolic traits, in Mexican children. METHODS: The association of six European obesity-related SNPs in or near FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes with risk of obesity was tested in 1,463 school-aged Mexican children (N(cases) = 514; N(controls) = 949). We also assessed effects of these SNPs on the variation of body mass index (BMI), fasting serum insulin levels, fasting plasma glucose levels, total cholesterol and triglyceride levels, in a subset of 1,171 nonobese Mexican children. RESULTS: We found a significant effect of GNPDA2 rs10938397 on risk of obesity (odds ratio [OR] = 1.30; P = 1.34 × 10-3). Furthermore, we found nominal associations between obesity risk or BMI variation and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Importantly, the at-risk alleles of both MC4R rs17782313 and NPC1 rs1805081 showed significant effect on increased fasting glucose levels (ß = 0.36 mmol/L; P = 1.47 × 10(-3)) and decreased fasting serum insulin levels (ß = -0.10 µU/mL; P = 1.21 × 10(-3)), respectively. CONCLUSION: Our present results suggest that some obesity-associated SNPs previously reported in Europeans also associate with risk of obesity, or metabolic quantitative traits, in Mexican children. Importantly, we found new associations between MC4R and fasting glucose levels, and between NPC1 and fasting insulin levels.

Sensitivity and specificity of body mass index and main risk factors for cardiovascular disease in middle-income urban participants in Guanajuato, Mexico.

Introduction: Introduction: several studies have questioned body mass index (BMI) as an accurate diagnostic tool for obesity and therefore a predictor of cardiovascular risk. But BMI is widely used currently. Objective: we analyzed the sensitivity and specificity of BMI and compared cardiovascular risk factors in middle-income urban participants in Guanajuato, Mexico, at different ages. Design: an analytical and cross-sectional study was carried out in 385 apparently healthy subjects, stratified by age ranges (20 to 59 years old). A high global CVD risk was obtained with the Framingham risk score (Framingham Risk Score > 20 %). The odds ratio was used to assess the association between high global CVD risk and the dietetic and anthropometric variables. Sensitivity, specificity, and correlation statistical analyses were carried out between BMI and other anthropometric variables with high cardiovascular risk, and this was integrated to derive recommendations to improve risk factor detection (p < 0.05 and power of 80 %). Results: a high global CVD risk was found in 4 % of the sample. BMI ≥ 30 kg/m2 had a sensitivity of 77 % for the detection of high cardiovascular risk; waist circumference ≥ 90 cm (men) or ≥ 80 cm (women) and body fat percentage ≥ 2 5% (men) or ≥ 35 % (women) had a sensitivity of 100 %. BMI showed a significant association with high global CVD risk (OR = 6.1; 95 % CI, 1.6-22.6, p < 0.01), but was not able to predict high global CVD risk in at least 30 % of the cases. There was not significative difference by age group for waist circumference, body fat percentage, total cholesterol, and low-density lipoprotein. Regarding the comparison of dietary intake of the stratified population by age group, intake of cholesterol, added sugars, fiber, sodium were highest in the 20 years group. Conclusions: a higher intake of cholesterol, simple sugars, and sodium was observed in the 20-year-old age group. The use of BMI with waist circumference and percentage of body fat used together allow a better assessment of cardiovascular risk. We need to integrate this new recommendation to increase early detection of main risk factors for cardiovascular disease.

Introducción: Introducción: diversos estudios han cuestionado el índice de masa corporal (IMC) como herramienta diagnóstica certera de la obesidad y por tanto predictor de riesgo cardiovascular. Pero el IMC es ampliamente utilizado actualmente. Objetivo: se analizó la sensibilidad y especificidad del IMC y se compararon factores de riesgo cardiovascular en participantes de diferentes edades de zonas urbanas de ingresos medios en Guanajuato, México. Diseño: se realizó un estudio analítico y transversal en 385 participantes, aparentemente sanos, estratificados por rangos de edad (20 a 59 años). El riesgo de CVD global alto se obtuvo con la puntuación de riesgo de Framingham (puntuación de riesgo de Framingham > 20 %). Se calculó la odds ratio para evaluar la asociación entre el alto riesgo global de ECV y las variables dietéticas y antropométricas. Se realizó un análisis estadístico de sensibilidad, especificidad y correlación entre el IMC y otras variables antropométricas con el alto riesgo cardiovascular, y se integró para derivar recomendaciones para mejorar la detección de factores de riesgo (p < 0,05 y potencia del 80 %). Resultados: se encontró un alto riesgo global de ECV en el 4 % de la muestra. El IMC ≥ 30 kg/m2 tuvo una sensibilidad del 77 % para la detección del alto riesgo cardiovascular; la circunferencia de la cintura ≥ 90 cm (hombre) o ≥ 80 cm (mujer) y el porcentaje de grasa corporal ≥ 25 % (hombre) o ≥ 35 % (mujer) tuvo una sensibilidad del 100 %. El IMC mostró una asociación significativa con un alto riesgo global de ECV (OR = 6,1; IC 95 % 1,6-22,6; p < 0,01) pero no fue capaz de predecir un alto riesgo global de ECV en al menos el 30 % de los casos. No hubo diferencia significativa por grupo de edad para circunferencia de cintura, porcentaje de grasa corporal, colesterol total y lipoproteínas de baja densidad. Con respecto a la comparación de la ingesta dietética de la población estratificada por grupos de edad, la ingesta de colesterol, azúcares añadidos y sodio fue mayor en el grupo de 20 años. Conclusiones: se observó una mayor ingesta de colesterol, azúcares simples y sodio en el grupo de edad de 20 años. El uso del IMC con la circunferencia de la cintura y el porcentaje de grasa corporal utilizados conjuntamente permiten lograr una mejor evaluación del riesgo cardiovascular. Necesitamos contar con herramientas para aumentar la detección temprana de los principales factores de riesgo de enfermedad cardiovascular.

Placental Nutrient Transporters and Maternal Fatty Acids in SGA, AGA, and LGA Newborns From Mothers With and Without Obesity.

Adverse environmental factors in early life result in fetal metabolic programming and increased risk of adult diseases. Birth weight is an indirect marker of the intrauterine environment, modulated by nutrient availability and placental transport capacity. However, studies of placental transporters in idiopathic birth weight alterations and in maternal obesity in relation to neonatal metabolic outcomes are scarce. We aimed to analyze the placental nutrient transporter protein expression in small (SGA, n = 14), adequate (AGA, n = 18), and large (LGA n = 10) gestational age term for newborns from healthy or obese mothers (LGA-OB, n = 9) and their association with maternal fatty acids, metabolic status, placental triglycerides, and neonatal outcomes. The transporter expression was determined by Western blot. The fatty acid profile was evaluated by gas chromatography, and placental triglycerides were quantified by an enzymatic colorimetric method. GLUT1 was higher in LGA and lower in SGA and positively correlated with maternal HbA1c and placental weight (PW). SNAT2 was lower in SGA, while SNAT4 was lower in LGA-OB. FATP1 was lower in SGA and higher in LGA. SNAT4 correlated negatively and FATP1 correlated positively with the PW and birth anthropometry (BA). Placental triglycerides were higher in LGA and LGA-OB and correlated with pregestational BMI, maternal insulin, and BA. Maternal docosahexaenoic acid (DHA) was higher in SGA, specifically in male placentas, correlating negatively with maternal triglycerides, PW, cord glucose, and abdominal perimeter. Palmitic acid (PA) correlated positively with FATP4 and cord insulin, linoleic acid correlated negatively with PA and maternal cholesterol, and arachidonic acid correlated inversely with maternal TG and directly with FATP4. Our study highlights the importance of placental programming in birth weight both in healthy and obese pregnancies.

Coping strategies and adherence to treatment in patients with type 2 diabetes mellitus.

INTRODUCTION: Diverse psychosocial and cultural factors are related to adherence to treatment of type 2 Diabetes mellitus (DM2) such as social support, coping styles and the cost of medical attention. OBJECTIVE: To study the influence of diverse psychosocial factors on adherence to treatment in patients with DM2. MATERIAL AND METHODS: In a cross sectional design we studied adherence to diet and medication, and its relationship with CS for diabetes, belief in conventional medicine, social support, and the perception of the burden of treatment cost on family finances. RESULTS: We included 210 patients a mean age of 56.3 years, 9.4 years since diagnosis. Male DM patients had better adherence to medication (p<0.016) and social support (p<0.004), and higher rates for supportant CS (31.8 vs. 29.0; p<0.009). Adherence to diet was associated with belief in conventional medicine (p<0.035) and marginally related to fatalistic CS (p<0.05). After testing social security coverage as dummy variable, a marginal association was found (p<0.15). Adherence to medication was associated with supportant CS (p<0.02) and marginally with avoidant CS (p<0.05). CONCLUSIONS: Supportant CS was more frequent in men. Belief in conventional medicine, and supportant CS were associated with adherence to treatment. These factors should be considered for a more rational approach for the management of disease.

Sleep Extension Increases the Effect of Caloric Restriction Over Body Weight and Improves the Chronic Low-Grade Inflammation in Adolescents With Obesity.

PURPOSE: Diminution of sleep may be associated with obesity. However, evidence that extending sleep duration might favor weight loss is insufficient. The aim of this study was to compare the effect of dietary restriction with or without prescription of sleep extension on weight loss in adolescents with obesity. METHODS: A total of 52 adolescents with obesity (24 males and 28 females) received a diet with 500 calories restriction, randomly allocated to groups without (n = 27) and with sleep extension (n = 25) for 4 weeks. We collected data on anthropometry, caloric intake, and self-reported sleep diaries. Serum interleukin 6, tumor necrosis factor α, leptin, and insulin levels were quantified by enzyme-linked immunosorbent assay. Cortisol and 6-sulfatoxymelatonin excretions were measured in the first urine collection in the morning by liquid chromatography-mass spectrometry. Measurements were carried out at baseline and at the end of the intervention. RESULTS: After diet, weight decreased in both groups. Sleep extension, improved weight loss (p < .00001), and waist girth reduction (p = .00003), with diminution of insulin (p = .002) and interleukin 6 levels (p = .02). Caloric restriction was less effective in adolescent females. No differences in cortisol or 6-sulfatoxymelatonin excretion were found. CONCLUSIONS: A sleep extension favors weight loss in adolescents under caloric restriction and improves inflammation and metabolic conditions, thus supporting a possible additional benefit to diet in the treatment of obesity in adolescents.

Analysis of the percentages of monocyte subsets and ILC2s, their relationships with metabolic variables and response to hypocaloric restriction in obesity.

PURPOSE: Obesity results from excess energy intake over expenditure and is characterized by chronic low-grade inflammation involving circulating monocytes (Mo) and group 2 innate lymphoid cells (ILC2s) imbalance. We analyzed circulating Mo subsets and ILC2s percentages and ß2-adrenergic receptor (ß2AR) expression in lean and obese subjects, and the possible effect of hypocaloric restriction on these innate immune cells. METHODS: In 139 individuals aged 45 to 57 years, classified in 74 lean individuals (>18.9kg/m2 BMI <24.9kg/m2) and 65 with obesity (n = 65), we collected fasting blood samples to detect Mo subsets, ILC2s number, and ß2AR expression by flow cytometry. Lipids, insulin, leptin, and acylated-ghrelin concentrations were quantified. Resting energy expenditure (REE) was estimated by indirect calorimetry. These measurements were repeated in obese subjects after 7-weeks of hypocaloric restriction. RESULTS: Non-classical monocytes (NCM) and ß2AR expression on intermediate Mo (IM) were increased in obese individuals (p<0.001, in both cases), whereas the percent of ILC2s was decreased (p<0.0001). Stepwise regression analysis showed significantly negative associations of ILC2s with caloric intake, ß2AR expression on IM with REE, but a positive relationship between NCM and HOMA-IR. Caloric restriction allowed a significant diminution of NCM and the ß2AR expression on IM, as well as, an increase in the percent of classical Mo (CM), and ILC2s. ΔREE was related to ΔCD16+/CD16- ratio. CONCLUSIONS: These findings show that in obesity occur changes in NCM, ILC2s and ß2AR expression, which contribute to the low-grade inflammation linked to obesity and might revert with caloric restriction.

Associations of nicotidamide-N-methyltransferase, FTO, and IRX3 genetic variants with body mass index and resting energy expenditure in Mexican subjects.

The enzyme nicotidamide-N-methyltransferase (NNMT) regulates adipose tissue energy expenditure through increasing nicotinamide adenosine dinucleotide (NAD+) content. NNMT methylates nicotinamide to N1-methylnicotidamide (MNA-1) using S-adenosyl methionine. The rs694539 NNMT polymorphism is associated with non-alcoholic steatohepatitis, and rs1941404 is associated with hyperlipidemia. The rs1421085 FTO is related to poor eating behaviors, and rs3751723 IRX3 is associated with obesity. To investigate the association of rs694539 and rs1941404 NNMT, rs140285 FTO and rs3751723 IRX3 polymorphisms with MNA-1 concentrations, resting energy expenditure (REE) and BMI, we included clinically healthy Mexican subjects 30 to 50 years old, 100 subjects (35 men/65 women) with BMI > 30 kg/m2 and 100 subjects (32 men/68 women) with BMI < 25 kg/m2. Glucose, lipid profile, insulin, leptin, acylated ghrelin, and MNA-1 (LC-MS) were quantified. Resting energy expenditure (REE) was estimated using indirect calorimetry with a Fitmate instrument. Genotyping was performed using PCR-RFLP, and allelic discrimination was examined using TaqMan probes. MNA-1 concentrations and REE were significantly higher in obese subjects. Subjects with the rs694539AA NNMT genotype (recessive model) had lower weight, BMI, and REE. BMI showed an association with HDL-C, triglycerides, MNA-1, acetylated ghrelin, leptin, insulin concentrations, HOMA-IR, REE, and rs1421085. Subjects with the TC or CC genotypes of rs1421085 FTO showed 6 kg and 2 units of BMI more than did those with the TT wild type. The CG of the rs1421085 and rs3751723 haplotypes was associated with BMI. These findings showed that BMI was strongly associated with REE, rs1421085 FTO and the CG rs1421085 FTO and rs3751723 IRX3 haplotypes. We used the GMDR approach in obesity phenotype to show the interaction of four SNPs and metabolic variables.

Ghrelin in small-for-gestational age (SGA) newborn babies: a cross-sectional study.

BACKGROUND: Small-for-gestational newborn babies may have long-term metabolic consequences. Among the main hormones possibly involved in foetal growth regulation are the IGFs, IGFBPs and the recently described ghrelin. OBJECTIVE: To examine the levels of desacyl-ghrelin, IGF-1, IGFBP-1 and IGFBP-3 in children Small-for-gestational age (SGA) and children adequate-for-gestational age (AGA). DESIGN: This was a cross-sectional and comparative study. SUBJECTS: We included 40 children SGA and 40 children AGA. MEASUREMENTS: Blood sample was taken a week after birth and measuring hormonal levels were done by ELISA. RESULTS: SGA babies had lower IGF-1, IGFBP-3 and leptin levels, but higher ghrelin and IGFBP-1 levels. Birth weight was associated independently with ghrelin and IGFBP-1 (negatively) and IGFBP-3 (positively). Ghrelin circulating levels were associated negative and independently with IGFBP-3 and triglycerides in the mother. CONCLUSIONS: We interpreted these findings to indicate that diminished body weight in newborns induce different adaptive signals, some of them mediated by IGF-1/IGFBP-3, ghrelin or by IGFBP-1. This regulation is congruent with the proposed role of ghrelin to adaptation to under-nutrition favouring lipid accumulation. CONCyTEG grant number 05-16-K117-028.

Effect of Restriction of Foods with High Fructose Corn Syrup Content on Metabolic Indices and Fatty Liver in Obese Children.

OBJECTIVE: We examined the effect of restriction of foods with high fructose content in obese school children. METHODS: In a clinical study, we selected 54 obese children 6 to 11 years old with high fructose consumption (>70 g/day) in order indicate dietary fructose restriction (<20 g/day) for 6 weeks. Anthropometry, liver ultrasound as well as glucose, insulin, lipids, leptin, IGFBP1, and RBP4 serum levels were collected. RESULTS: The group of children had 80% adherence and reported decreased fructose consumption (110 ± 38.6 to 11.4 ± 12.0 g/day) and also a significant decrease in caloric (2,384 ± 568 to 1,757 ± 387 kcal/day) and carbohydrate consumption (302 ± 80.4 to 203 ± 56.0 g/day). The severity of steatosis improved significantly after fructose restriction (p < 0.000001). However, no changes in BMI, systolic blood pressure, or diastolic blood pressure were found. Only triglyceride levels decreased (1.44 ± 0.43 to 1.31 ± 0.38 mmol/l), High-densitiy lipoprotein cholesterol showed a marginal increase (1.45 ± 0.19 to 1.56 ± 0.44 mmol/l). Insulin resistance and RBP4 did not change. CONCLUSIONS: In school children, the restriction of high fructose foods with a decrease of caloric and carbohydrate intake at 6 weeks did not induce weight loss; however, triglyceride levels and hepatic steatosis decreased. Differences with other studies in regard to weight loss may be explained by adaptive changes on metabolic expenditure.

Factors associated with estrogen receptors-alpha (ER-alpha) and -beta (ER-beta) and progesterone receptor abundance in obese and non obese pre- and post-menopausal women.

There is scarce information about the factors associated with estrogen receptors (ER) at menopause. In 113 volunteers pre- and post-menopausal healthy women, grouped as with and without obesity, estrogen receptors-alpha and -beta, and progesterone receptor (PR) were measured by immunohistochemistry in skin punch biopsies obtained from the external gluteal area. In pre-menopausal women, biopsies and a blood sample were performed between days 7 and 14 of the cycle. Serum hormone levels were measured by immunoradiometric assay or radioimmunoassay. After menopause, ER and PR amounts decreased significantly. At pre-menopause, obese women had lower PR levels than non obese (P<.006). In the post-menopausal group, obese women showed higher ER-alpha (P<.03) and ER-beta (P<.02) levels than the non obese group. In the analysis of factors associated with the amount of steroid receptors for the total group, log[ER-alpha], log[ER-beta], and log[PR] were associated with age (P<.002, <.005, and <.004, respectively). The log[ER-alpha] was also associated with log[FSH] (P<.0008); meanwhile, the log[PR] showed a marginal correlation with log[FSH]. In pre-menopausal women no factor associated with any of the three receptors was found. In post-menopausal women log[ER-alpha] was associated with log[estrone] and log[DHEAS] (P<.003 and <.02, respectively). log[PR] was associated with BMI (P<.002), years since menopause (P<.05), and log[DHEAS] (P<.003). We concluded that ER and PR diminish sharply at post-menopause. At this stage the amount of receptors depends on several factors such as BMI, years since menopause, and androgen precursors.

Effects of sleeve gastrectomy and rs9930506 FTO variants on angiopoietin/Tie-2 system in fat expansion and M1 macrophages recruitment in morbidly obese subjects.

Angiogenesis in inflammation are hallmarks for adipose tissue expansion in obesity. The role of angiopoietin/Tie-2 system in adipose tissue expansion and immune cell recruitment is unclear. We studied the effect of sleeve gastrectomy and the influence of FTO rs9930506 polymorphism on Tie-2, angiopoietin-1 and angiopoietin-2 expression in morbid obesity. Fifteen morbidly obese subjects (4 men and 11 women) aged 24-55 years were followed-up 3 and 6 months after sleeve gastrectomy. Serum sTie-2, angiopoietin-1, angiopoietin-2, and hypoxia-inducible factor-1α concentrations were determined by ELISA. Tie-2 and its ligands in visceral and subcutaneous adipose tissue were localized by immunohistochemistry. Tie-2 expression was measured by flow cytometry in circulating monocytes and infiltrated macrophages. Comparisons before and after sleeve gastrectomy were carried out using ANOVA for repeated measures. rs9930506FTO genotyping was performed by PCR-RFLP. Circulating sTie-2 and angiopoietin-2 were higher before sleeve gastrectomy. Tie-2 and angiopoietin-2 mRNA levels were higher in subcutaneous adipose tissue than visceral and both decreased after surgery. Monocytes and infiltrated macrophages showed a pro-inflammatory phenotype, with increased Tie-2 expression that decreased 3 and 6 months after sleeve gastrectomy. Baseline sTie-2 correlated inversely with adiponectin levels. At baseline the rs9930506FTO AG ó GG genotypes carriers had more 34 kg than genotype carriers of rs9930506 AA. Weight and body mass index decreased at 6 months. We found that angiopoietin/Tie-2 system is mainly expressed in subcutaneous adipose tissue, contributing to expandability, fat accumulation, and monocytes attachment in obesity. Bariatric surgery favorably modifies the pro-angiogenic profile, allowed a reduced angiogenic expression in the circulation and adipose tissue.

Association of cord blood des-acyl ghrelin with birth weight, and placental GHS-R1 receptor expression in SGA, AGA, and LGA newborns.

Although ghrelin in cord blood has been associated to birth weight, its role in fetal and postnatal growth has not been elucidated. The aim of this study was to analyze total ghrelin, acyl ghrelin (AG), and des-acyl ghrelin (DAG) in cord blood of newborns with idiopathic birth weight alterations, and to evaluate protein expression of placental GHS-R1, in order to investigate their correlation with birth weight and placental weight. We performed a cross-sectional comparative study in umbilical cord blood and placentas from healthy mothers of SGA, AGA, and LGA (small, adequate and large for gestational age) term newborns (n = 20 per group). Cord blood total ghrelin, AG, and DAG were measured by ELISA, and placental GHS-R1 expression was evaluated by Western blot. Cord blood DAG was higher in SGA compared to AGA newborns (902.1 ± 109.1 and 597.4 ± 58.2 pg/ml, respectively, p = 0.01) while LGA and AGA showed similar values (627.2 ± 76.4 pg/ml for LGA, p = 0.80). DAG negatively correlated with birthweight (r = -0.31, p = 0.02) and placental weight (r = -0.33, p = 0.02). No differences in AG or total ghrelin were found. GHS-R1 protein in placenta was not differentially expressed among SGA, AGA, and LGA. Our results suggest a role of DAG in intrauterine growth. Further studies are needed in order to elucidate the mechanisms by which DAG participates in fetal growth.