Desacylghrelin modulates GHS-R1 receptor expression and cell differentiation in placental BeWo cells.

BACKGROUND: and purpose: Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor (GHS-R1). Ghrelin, and GHS-R1, may have a role in placental growth and function, and its unacylated form desacylghrelin (DAG) could be involved in fetal growth. Nevertheless, the effects of DAG on placental function, and the receptor involved in its actions, remain to be determined. We aimed to investigate the effect of DAG in placental BeWo cells viability, proliferation, differentiation, and GSH-R1 expression. METHODS: BeWo cells, a human trophoblast cell line, was cultured with 3 nM DAG during 12, 24, 48, and 72 h. Cell viability, proliferation, differentiation (assessed by human Chorionic Gonadotropin quantification), and GSH-R1 expression were analyzed. To evaluate the mechanism of DAG effect on GSH-R1, 30 nM receptor antagonist ([D-Lys3]-GHRP-6) was added alone or in combination with 3 nM DAG during 12 h and 24 h. RESULTS: DAG has no effect on cell proliferation or viability, but it has an inhibitory effect on cell differentiation. DAG had a stimulatory effect on GSH-R1 expression at 12 and 24 h (p = 0.029 and p = 0.025, respectively). On the contrary, culture with 48 h DAG inhibits GSH-R1 expression compared to the control (p = 0.005), while GSH-R1 antagonist inhibited the effect of DAG on GSH-R1 expression. DAG also reduces intracellular (p = 0.020) and secreted (p = 0.011) hCG concentration in BeWo cells. CONCLUSION: DAG increases GHS-R1 expression, potentially mediated through GHS-R1 itself. DAG may also inhibit placental BeWo cell differentiation, suggesting a possible role of DAG in placental and fetal physiology.

Correlation of the pediatric metabolic index with NAFLD or MAFLD diagnosis, and serum adipokine levels in children.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic fat deposition in the liver. However, a recent classification of this condition, which also integrates the presence of coexisting metabolic disorders, termed Metabolic dysfunction Associated Fatty Liver Disease (MAFLD), has been proposed. NAFLD is increasingly common in early childhood, partly due to the increase in metabolic disease in this age. Thus, studying hepatic steatosis in the metabolic context has become important in this population as well. However, NAFLD, and thus MAFLD, diagnosis in children is challenging by the lack of non-invasive diagnostic tools comparable to the gold standard of hepatic biopsy. Recent studies have reported that the Pediatric Metabolic Index (PMI) could be a marker of insulin resistance and abnormal liver enzymes, but its association with NAFLD, MAFLD, or altered adipokines in these conditions has not been reported. The aim of this study is to evaluate the correlation between PMI with the diagnosis of NAFLD or MAFLD, together with serum levels of leptin and adiponectin, in school-age children. METHODS: A cross sectional study was carried out in two hundred and twenty-three children without medical history of hypothyroidism, genetic, or chronic diseases. Anthropometry, liver ultrasound, and serum levels of lipids, leptin, and adiponectin were evaluated. The children were classified as having NAFLD or non-NAFLD, and a subgroup of MAFLD in the NAFLD group was analyzed. The PMI was calculated by the established formulas for age and gender. RESULTS: PMI correlated positively with the presence and severity of NAFLD (r = 0.62, p<0.001 and r = 0.79, p<0.001 respectively) and with the presence of MAFLD (r = 0.62; p<0.001). Also, this index correlated positively with serum leptin levels (r = 0.66; p<0.001) and negatively with serum adiponectin levels (r= -0.65; p<0.001). PMI showed to be a good predictor for diagnosing NAFLD in school-age children when performing a ROC curve analysis (AUROC=0.986, p< 0.0001). CONCLUSION: PMI could be a useful tool for the early diagnosis of NAFLD or MAFLD in children. However, future studies are necessary to establish validated cut-off points for each population.

Polymorphisms -374 T/A and -429 T/C of the Receptor for Advanced Glycation End-Products (RAGE) and Serum Levels of RAGE (sRAGE) Are Not Associated with Metabolic Syndrome.

RAGE is a multi-ligand transmembrane glycoprotein that promotes biological signals associated with inflammatory responses and degenerative diseases. sRAGE is a soluble variant, proposed as an inhibitor of RAGE activity. -374 T/A and -429 T/C polymorphisms of the advanced glycation end products receptor AGER gene are associated with the development of some diseases, such as type of cancer, cardiovascular disease, and micro and macrovascular disease in diabetes among others but their role in metabolic syndrome (MS) is still unknown. We studied 80 healthy men without MS, and 80 men with MS according to the harmonized criteria. -374 T/A and -429 T/C polymorphisms were genotyped by RT-PCR, and sRAGE was measured by ELISA. Allelic and genotypic frequencies did not differ between Non-MS and MS groups (-374 T/A p = 0.48, p = 0.57 and -429 T/C p = 0.36, p = 0.59). Significant differences were found in fasting glucose levels and diastolic blood pressure among the genotypes of the -374 T/A polymorphism in the Non-MS group (p < 0.01 and p = 0.008). Glucose levels were different between -429 T/C genotypes in the MS group (p = 0.02). sRAGE levels were similar in both groups, but in the Non-MS group showed a significant difference between individuals with only 1 or 2 components of the metabolic syndrome (p = 0.047). However, no associations of any SNP with MS were found (recessive model p = 0.48, dominant model p = 0.82 for -374 T/A; recessive model p = 0.48, dominant model p = 0.42 for -429 T/C). -374 T/A and -429 T/C polymorphisms are not associated with MS in Mexican population and have no influence on serum sRAGE levels.

Nutritional, pharmacological, and environmental programming of NAFLD in early life.

Nonalcoholic fatty liver disease (NAFLD) is the main liver disease worldwide, and its prevalence in children and adolescents has been increasing in the past years. It has been demonstrated that parental exposure to different conditions, both preconceptionally and during pregnancy, can lead to fetal programming of several metabolic diseases, including NAFLD. In this article, we review some of the maternal and paternal conditions that may be involved in early-life programing of adult NAFLD. First, we describe the maternal nutritional factors that have been suggested to increase the risk of NAFLD in the offspring, such as an obesogenic diet, overweight/obesity, and altered lipogenesis. Second, we review the association of certain vitamin supplementation and the use of some drugs during pregnancy, for instance, glucocorticoids, with a higher risk of NAFLD. Furthermore, we discuss the evidence showing that maternal-fetal pathologies, including gestational diabetes mellitus (GDM), insulin resistance (IR), and intrauterine growth restriction (IUGR), as well as the exposure to environmental contaminants, and the impact of microbiome changes, are important factors in early-life programming of NAFLD. Finally, we review how paternal preconceptional conditions, such as exercise and diet (particularly obesogenic diets), may impact fetal growth and liver function. Altogether, the presented evidence supports the hypothesis that both in utero exposure and parental conditions may influence fetal outcomes, including the development of NAFLD in early life and adulthood. The study of these conditions is crucial to better understand the diverse mechanisms involved in NAFLD, as well as for defining new preventive strategies for this disease.

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.

Association of diabetes-related variants in ADCY5 and CDKAL1 with neonatal insulin, C-peptide, and birth weight.

BACKGROUND AND PURPOSE: Neonates at the highest and lowest percentiles of birth weight present an increased risk of developing metabolic diseases in adult life. While environmental events in utero may play an important role in this association, some genetic variants are associated both with birth weight and type 2 diabetes mellitus (T2DM), suggesting a genetic link between intrauterine growth and metabolism in adult life. Variants rs11708067 in ADCY5 and rs7754840 in CDKAL1 are associated with low birth weight, risk of T2DM, and lower insulin secretion in adults. We aimed to investigate whether, besides birth weight, these polymorphisms were related to insulin secretion at birth. METHODS: A cohort of 218 healthy term newborns from uncomplicated pregnancies were evaluated for anthropometric and biochemical variables. Cord blood insulin and C-peptide were analyzed by ELISA. Genotyping of rs11708067 in ADCY5 and rs7754840 in CDKAL1 was performed. RESULTS: Newborns carrying the A allele of ADCY5 rs11708067 had lower cord blood insulin and C-peptide, even after adjusting by maternal glycemia, HbA1c, and pregestational BMI. Lower birth weight was found for AA-AG genotypes compared to GG, but no differences were seen in adjusted birth weight or z-score. Variant rs7754840 in CDKAL1 was not associated with birth weight, neonatal insulin, or C-peptide for any genotype or genetic model. CONCLUSIONS: The variant rs11708067 in ADCY5 is associated with lower neonatal insulin and C-peptide concentrations. Our results suggest that the genetic influence on insulin secretion may be evident from birth, even in healthy newborns, independently of maternal glycemia and BMI.

Circulating microRNAs associated with prediabetes and geographic location in Latinos.

BACKGROUND: Globally, type 2 diabetes is highly prevalent in individuals of Latino ancestry. The reasons underlying this high prevalence are not well understood, but both genetic and lifestyle factors are contributors. Circulating microRNAs are readily detectable in blood and are promising biomarkers to characterize biological responses (i.e., changes in gene expression) to lifestyle factors. Prior studies identified relationships between circulating microRNAs and risk for type 2 diabetes, but Latinos have largely been under-represented in these study samples. AIMS/HYPOTHESIS: The aim of this study was to assess for differences in expression levels of three candidate microRNAs (miR-126, miR-146, miR-15) between individuals who had prediabetes compared to normal glycemic status and between individuals who self-identified with Latino ancestry in the United States (US) and native Mexicans living in or near Leon, Mexico. METHODS: This was a cross-sectional study that included 45 Mexicans and 21 Latino participants from the US. Prediabetes was defined as fasting glucose 100-125 mg/dL or 2-h post-glucose challenge between 140 and 199 mg/dL. Expression levels of microRNAs from plasma were measured by qPCR. Linear and logistic regression models were used to assess relationships between individual microRNAs and glycemic status or geographic site. RESULTS: None of the three microRNAs was associated with risk for type 2 diabetes. MiR-146a and miR-15 were significantly lower in the study sample from Mexico compared to the US. There was a significant interaction between miR-146a and BMI associated with fasting blood glucose. CONCLUSIONS/INTERPRETATION: This study did not replicate in Latinos prior observations from other racial groups of associations between miR-126, miR-146a, and miR-15 and risk for type 2 diabetes. Future studies should consider other microRNAs related to different biological pathways as possible biomarkers for type 2 diabetes in Latinos.

FGF21 and its Relationship with Inflammatory and Metabolic Parameters in HIV Patients after Antiretroviral Treatment.

BACKGROUND: Fibroblast Growth Factor 21 (FGF21) serum levels are associated with insulin resistance and metabolic syndrome in HIV patients. OBJECTIVE: To quantify FGF21 levels in HIV patients using antiretroviral therapy (ART) and to analyze a possible association between serum FGF21 levels and lipid profile, levels of proinflammatory cytokines, and atherogenic risk factors. MATERIALS AND METHODS: Twenty patients with HIV infection, who received ART in a scheme consisting of Tenofovir/Emtricitabine+Lopinavir/Ritonavir, were enrolled in this study. The serum levels of FGF21, inflammatory parameters (IL-6 and IL-1ß), glucose, cholesterol, triglycerides, and insulin were determined at baseline and after 36 weeks of treatment. The homeostatic model assessment for insulin resistance (HOMA-IR) and the atherogenic risk factor were also calculated. RESULTS: After 36 weeks, serum FGF21 levels decreased significantly (p=0.011), whereas IL-6 levels (r=0.821, p=0.0001) and the CD4+ T cell count (r=0.446, p=0.048), showed a positive correlation with the decrease in FGF21 levels. There was an increase in total cholesterol (r=-0.483, p=0.031), LDL (r=-0.496, p=0.026), VLDL (r=-0.320, p=0.045), and the atherogenic index factor (r=-0.539, p=0.014), these values showed a negative correlation with FGF21 levels. CONCLUSION: The decrease of serum FGF21 levels due to ART is associated with the alteration in lipid profile and an increased risk for cardiovascular diseases. These variations are predictors of inflammatory status in HIV patients using antiretroviral therapy.

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.

Early-life programming of adipose tissue.

Worldwide obesity is increasing at an alarming rate in children and adolescents, with the consequent emergence of co-morbidities. Moreover, the maternal environment during pregnancy plays an important role in obesity, contributing to transgenerational transmission of the same and metabolic dysfunction. White adipose tissue represents a prime target of metabolic programming induced by maternal milieu. In this article, we review adipose tissue physiology and development, as well as maternal influences during the perinatal period that may lead to obesity in early postnatal life and adulthood. First, we describe the adipose tissue cell composition, distribution and hormonal action, together with the evidence of hormonal factors participating in fetal/postnatal programming. Subsequently, we describe the critical periods of adipose tissue development and the relationship of gestational and early postnatal life with healthy fetal adipose tissue expansion. Furthermore, we discuss the evidence showing that adipose tissue is an important target for nutritional, hormonal and epigenetic signals to modulate fetal growth. Finally, we describe nutritional, hormonal, epigenetic and microbiome changes observed in maternal obesity, and whether their disruption alters fetal growth and adiposity. The presented evidence supports the developmental origins of health and disease concept, which proposes that the homeostatic system is affected during gestational and postnatal development, impeding the ability to regulate body weight after birth, thereby resulting in adult obesity. Consequently, we anticipate that promoting a healthy early-life programming of adipose tissue and increasing the knowledge of the mechanisms by which maternal factors affect the health of future generations may offer novel strategies for explaining and addressing worldwide health problems such as obesity.

Association of the 3'UTR polymorphism (rs11665896) in the FGF21 gene with metabolic status and nutrient intake in children with obesity.

Background Fibroblast growth factor 21 (FGF21) is considered an important regulator of lipid and glucose metabolism. However, the role of FGF21 in macronutrient intake and metabolic disease, particularly in pediatric population, still needs further clarification. This study aimed to evaluate the association of rs11665896 in the FGF21 gene with metabolic status and macronutrient intake in a cohort of Mexican children with obesity. Methods Eighty-four lean children and 113 children with obesity, from 8 to 11 years of age, were recruited. FGF21 rs11665896 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Somatometric evaluations, nutrient intake, glucose, lipids, insulin and FGF21 serum levels were measured in the obesity group. Results The T allele of rs11665896 in the FGF21 gene was associated with obesity (odds ratio [OR] = 1.99, 95% confidence interval [CI] = 1.14-3.46; p = 0.0151). Subjects with obesity carrying the TT genotype consumed less lipids and more carbohydrates compared to other genotypes. Circulating FGF21 levels correlated negatively with carbohydrate intake (r = -0.232, p = 0.022) and positively with body weight (r = 0.269, p = 0.007), waist (r = 0.242, p = 0.016) and hip girth (r = 0.204, p = 0.042). FGF21 levels were lower in carriers of at least one T allele. Conclusions Genetic variants in FGF21 could influence metabolic status, food preferences and qualitative changes in nutritional behavior in children.

Effects of dietary biotin supplementation on glucagon production, secretion, and action.

OBJECTIVE: Despite increasing evidence that pharmacologic concentrations of biotin modify glucose metabolism, to our knowledge there have not been any studies addressing the effects of biotin supplementation on glucagon production and secretion, considering glucagon is one of the major hormones in maintaining glucose homeostasis. The aim of this study was to investigate the effects of dietary biotin supplementation on glucagon expression, secretion, and action. METHODS: Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7 mg biotin/kg diet) for 8 wk postweaning. Glucagon gene mRNA expression was measured by the real-time polymerase chain reaction. Glucagon secretion was assessed in isolated islets and by glucagon concentration in plasma. Glucagon action was evaluated by glucagon tolerance tests, phosphoenolpyruvate carboxykinase (Pck1) mRNA expression, and glycogen degradation. RESULTS: Compared with the control group, glucagon mRNA and secretion were increased from the islets of the biotin-supplemented group. Fasting plasma glucagon levels were higher, but no differences between the groups were observed in nonfasting glucagon levels. Despite the elevated fasting glucagon levels, no differences were found in fasting blood glucose concentrations, fasting/fasting-refeeding glucagon tolerance tests, glycogen content and degradation, or mRNA expression of the hepatic gluconeogenic rate-limiting enzyme, Pck1. CONCLUSIONS: These results demonstrated that dietary biotin supplementation increased glucagon expression and secretion without affecting fasting blood glucose concentrations or glucagon tolerance and provided new insights into the effect of biotin supplementation on glucagon production and action.

11 beta-hydroxysteroid dehydrogenase 2 promoter methylation is associated with placental protein expression in small for gestational age newborns.

Small for gestational age infants have greater risk of developing metabolic diseases in adult life. It has been suggested that low birth weight may result from glucocorticoid excess in utero, a key mechanism in fetal programming. The placental enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11ß-HSD2, HSD11B2 gene) acts as a barrier protecting the fetus from maternal corticosteroid deleterious effects. Low placental 11ß-HSD2 transcription and activity have been associated with low birth weight, yet the mechanism regulating its protein expression is not fully understood. In the present study we aimed to analyze 11ß-HSD2 protein expression in placentas of adequate and small for gestational age (AGA and SGA, respectively) newborns from healthy mothers, and to explore whether 11ß-HSD2 protein expression could be modulated by DNA methylation. 11ß-HSD2 protein levels were measured by western blot in placental biopsies from term AGA and SGA infants (n=10 per group). DNA methylation was profiled both globally and in the HSD11B2 promoter by liquid chromatography with UV detection and methylation-specific melting curve analysis, respectively. We found lower placental 11ß-HSD2 protein expression and higher HSD11B2 promoter methylation in SGA compared to AGA. Promoter methylation was inversely correlated with both protein expression and, importantly, birth weight. No changes in global placental methylation were found. In conclusion, lower 11ß-HSD2 protein expression is associated with higher HSD11B2 promoter methylation, correlating with birth weight in healthy pregnancy. Our data support the role of 11ß-HSD2 in determining birth weight, providing evidence of its regulation by epigenetic mechanisms, which may affect postnatal metabolic disease risk.

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.

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.

Pharmacological concentrations of biotin reduce serum triglycerides and the expression of lipogenic genes.

Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. Several studies have shown that pharmacological concentrations of biotin reduce hypertriglyceridemia. The molecular mechanisms by which pharmacological concentrations of biotin affect lipid metabolism are largely unknown. The present study analyzed the effects of pharmacological doses of biotin on triglyceridemia, insulin sensitivity and on mRNA expression of various lipogenic genes. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-control or a biotin-supplemented diet (1.76 or 97.7mg of free biotin/kg diet, respectively) over a period of eight weeks. Serum triglyceride concentrations, insulin and glucose tolerance and mRNA abundance of various lipogenic genes were investigated. The biotin-supplemented group showed 35% less serum triglycerides than control mice. In the liver, we found a significant (P<0.05) reduction of mRNA levels of SREBP1-c, glucose transporter-2, phosphofructokinase-1, pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase, while glucose-6-phosphate dehydrogenase expression increased. No changes in glucokinase, stearoyl-CoA desaturase-1, FoxO1 or PPAR-gamma expression were observed. In adipose tissue, we found a decreased expression of SREBP1c, glucose-6-phosphate deshydrogenase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1, phosphofructokinase-1 and PPAR-gamma, but no changes in FoxO1 expression. Moreover, the group fed a biotin-supplemented diet showed a significant decrease in adipose tissue weight. No differences in insulin sensitivity or serum insulin concentrations were observed between groups. Our results indicate that pharmacological concentrations of biotin decrease serum tryglyceride concentrations and lipogenic gene expression in liver and adipose tissues.

[Transcription factors in the adult beta cell]. / Factores transcripcionales en la célula 3 adulta.

Insulin secretion by the pancreatic beta cell is critical to maintain glucose homeostasis. This secretion is impaired in type 1 diabetes, by beta cell autoimmune destruction, in type 2 diabetes, by multifactorial failures still not well determined, and in monogenic diabetes (MODY), by mutations in specific genes. During the last few years, several beta cell-specific transcription factors that regulate insulin synthesis and secretion in response to glucose have been discovered. Knockout mice studies for these genes and MODY diabetes demonstrate their importance for normal development and function of the beta cell. These factors are regulated not only in their expression by other genes, but also in their activity by other proteins and by post-translational modifications, therefore participating in physiologically important signaling pathways of the beta cell. The study of transcription factors is crucial for understanding the normal function of the beta cell, essential knowledge in developing new strategies for fighting diabetes.