Publications by authors named "Carles Lerin"

30 Publications

  • Page 1 of 1

Neonatal overfeeding during lactation rapidly and permanently misaligns the hepatic circadian rhythm and programmes adult NAFLD.

Mol Metab 2021 Jan 7;45:101162. Epub 2021 Jan 7.

Institut de Recerca Sant Joan de Déu (Saint John of God Children's Hospital Barcelona), Endocrinology, Esplugues, Barcelona, Spain. Electronic address:

Childhood obesity is a strong risk factor for adult obesity, type 2 diabetes, and cardiovascular disease. The mechanisms that link early adiposity with late-onset chronic diseases are poorly characterised. We developed a mouse model of early adiposity through litter size reduction. Mice reared in small litters (SLs) developed obesity, insulin resistance, and hepatic steatosis during adulthood. The liver played a major role in the development of the disease.

Objective: To gain insight into the molecular mechanisms that link early development and childhood obesity with adult hepatic steatosis and insulin resistance.

Methods: We analysed the hepatic transcriptome (Affymetrix) of control and SL mice to uncover potential pathways involved in the long-term programming of disease in our model.

Results: The circadian rhythm was the most significantly deregulated Gene Ontology term in the liver of adult SL mice. Several core clock genes, such as period 1-3 and cryptochrome 1-2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4-6 months of age. Defective circadian rhythm was restricted to the periphery since the expression of clock genes in the hypothalamus, the central pacemaker, was normal. The period-cryptochrome genes were primarily entrained by dietary signals. Hence, restricting food availability during the light cycle only uncoupled the central rhythm from the peripheral and completely normalised hepatic triglyceride content in adult SL mice. This effect was accompanied by better re-alignment of the hepatic period genes, suggesting that they might have played a causal role in mediating hepatic steatosis in the adult SL mice. Functional downregulation of Per2 in hepatocytes in vitro confirmed that the period genes regulated lipid-related genes in part through peroxisome proliferator-activated receptor alpha (Ppara).

Conclusions: The hepatic circadian rhythm matures during early development, from birth to postnatal day 30. Hence, nutritional challenges during early life may misalign the hepatic circadian rhythm and secondarily lead to metabolic derangements. Specific time-restricted feeding interventions improve metabolic health in the context of childhood obesity by partially re-aligning the peripheral circadian rhythm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2021.101162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851182PMC
January 2021

Effects of Subsp. (BPL1) Supplementation in Children and Adolescents with Prader-Willi Syndrome: A Randomized Crossover Trial.

Nutrients 2020 Oct 13;12(10). Epub 2020 Oct 13.

Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain.

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by a wide range of clinical manifestations, including obesity, hyperphagia, and behavioral problems. subsp. strain BPL1 has been shown to improve central adiposity in adults with simple obesity. To evaluate BPL1's effects in children with PWS, we performed a randomized crossover trial among 39 patients (mean age 10.4 years). Participants were randomized to placebo-BPL1 ( = 19) or BPL1-placebo ( = 20) sequences and underwent a 12-week period with placebo/BPL1 treatments, a 12-week washout period, and a 12-week period with the crossover treatment. Thirty-five subjects completed the study. The main outcome was changes in adiposity, measured by dual-energy X-ray absorptiometry. Secondary outcomes included lipid and glucose metabolism, hyperphagia, and mental health symptoms. Generalized linear modeling was applied to assess differences between treatments. While BPL1 did not modify total fat mass compared to placebo, BPL1 decreased abdominal adiposity in a subgroup of patients older than 4.5 years ( = 28). BPL1 improved fasting insulin concentration and insulin sensitivity. Furthermore, we observed modest improvements in some mental health symptoms. A follow-up trial with a longer treatment period is warranted to determine whether BPL1 supplementation can provide a long-term therapeutic approach for children with PWS (ClinicalTrials.gov NCT03548480).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12103123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650793PMC
October 2020

Size Does Matter: Litter Size Strongly Determines Adult Metabolism in Rodents.

Cell Metab 2020 Sep 18;32(3):334-340. Epub 2020 Aug 18.

Institut de Recerca Sant Joan de Déu, Endocrinology, c/ Santa Rosa 39-57, 4ª planta, Esplugues, 08950 Barcelona, Spain. Electronic address:

In this essay, we highlight how litter size in rodents is a strong determinant of neonatal growth and long-term metabolic health. Based on these effects, we strongly advise that scientific articles that utilize rodent models for obesity and metabolic research should include information on the litter sizes in the study to increase the data transparency of such reports.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.07.014DOI Listing
September 2020

Plasma Metabolome Alterations Associated with Extrauterine Growth Restriction.

Nutrients 2020 Apr 23;12(4). Epub 2020 Apr 23.

Centro deMetabolómica y Bioanálisis, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain.

Very preterm infants (VPI, born at or before 32 weeks of gestation) are at risk of adverse health outcomes, from which they might be partially protected with appropriate postnatal nutrition and growth. Metabolic processes or biochemical markers associated to extrauterine growth restriction (EUGR) have not been identified. We applied untargeted metabolomics to plasma samples of VPI with adequate weight for gestational age at birth and with different growth trajectories (29 well-grown, 22 EUGR) at the time of hospital discharge. A multivariate analysis showed significantly higher levels of amino-acids in well-grown patients. Other metabolites were also identified as statistically significant in the comparison between groups. Relevant differences (with corrections for multiple comparison) were found in levels of glycerophospholipids, sphingolipids and other lipids. Levels of many of the biochemical species decreased progressively as the level of growth restriction increased in severity. In conclusion, an untargeted metabolomic approach uncovered previously unknown differences in the levels of a range of plasma metabolites between well grown and EUGR infants at the time of discharge. Our findings open speculation about pathways involved in growth failure in preterm infants and the long-term relevance of this metabolic differences, as well as helping in the definition of potential biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12041188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230608PMC
April 2020

Specific Dietary Components and Gut Microbiota Composition are Associated with Obesity in Children and Adolescents with Prader-Willi Syndrome.

Nutrients 2020 Apr 11;12(4). Epub 2020 Apr 11.

Institut de Recerca Sant Joan de Déu, 08950 Barcelona, Spain.

Prader-Willi syndrome is a rare genetic disorder associated with impaired body composition, hyperphagia, and excessive weight gain. Strict dietary restrictions from an early age is crucial to prevent or delay the early onset of obesity, which is the main driver of comorbidities in these patients. The aim of this study was to identify dietary and gut microbiota components closely linked to weight status of these patients. We studied a cohort of children and adolescents with genetic diagnosis of Prader-Willi syndrome ( = 31), in which we determined adiposity by Dual-energy X-ray absorptiometry (DXA) and dietary composition with 4-day food records. Furthermore, we obtained fecal samples to assess microbiota composition by 16S sequencing. Multivariate regression models showed that body mass index standard deviation score (BMI-SDS) and body fat mass were directly associated with saturated fat intake and meat consumption, and inversely associated with fruit consumption. Furthermore, the gut microbiome from normal weight patients was characterized by higher phylogenetic diversity compared to those overweight or obese, with differential abundance of several genera, including , , and . Notably, abundance was inversely correlated to adiposity, lipid and glucose homeostasis parameters, and meat intake. Our results suggest that limiting meat and increasing fruit intake might be beneficial for body weight management in children and adolescents with Prader-Willi syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12041063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230364PMC
April 2020

Use of Infrared Thermography to Estimate Brown Fat Activation After a Cooling Protocol in Patients with Severe Obesity That Underwent Bariatric Surgery.

Obes Surg 2020 06;30(6):2375-2381

Germans Trias i Pujol Research Institute, Barcelona, Spain.

Background: In contrast to the energy-storing role of white adipose tissue (WAT), brown adipose tissue (BAT) acts as the main site of non-shivering thermogenesis in mammals and has been reported to play a role in protection against obesity and associated metabolic alterations in rodents. Infrared thermography (IRT) has been proposed as a novel non-invasive, safe, and quick method to estimate BAT thermogenic activation in humans. The aim of this study is to determine whether the IRT could be a potential new tool to estimate BAT thermogenic activation in patients with severe obesity in response to bariatric surgery.

Methods: Supraclavicular BAT thermogenic activation was evaluated using IRT in a cohort of 31 patients (50 ± 10 years old, BMI = 44.5 ± 7.8; 15 undergoing laparoscopy sleeve gastrectomy and 16 Roux-en-Y gastric bypass) at baseline and 6 months after a bariatric surgery. Clinical parameters were determined at these same time points.

Results: Supraclavicular BAT-related activity was detected in our patients by IRT after a cooling stimulus. The BAT thermogenic activation was higher at 6 months after laparoscopy sleeve gastrectomy (0.06 ± 0.1 vs 0.32 ± 0.1), while patients undergoing to a roux-en-Y gastric bypass did not change their thermogenic response using the same cooling stimulus (0.09 ± 0.1 vs 0.08 ± 0.1).

Conclusions: Our study postulates the IRT as a potential tool to evaluate BAT thermogenic activation in patients with obesity before and after a bariatric surgery. Further studies are needed to evaluate differences between LSG technique and RYGB on BAT activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11695-020-04502-7DOI Listing
June 2020

Differential association between S100A4 levels and insulin resistance in prepubertal children and adult subjects with clinically severe obesity.

Obes Sci Pract 2020 Feb 2;6(1):99-106. Epub 2019 Dec 2.

Department of Endocrinology and Nutrition Germans Trias i Pujol Research Institute Barcelona Spain.

Objectives: S100A4 has been recently identified as an adipokine associated with insulin resistance (IR) in adult subjects with obesity. However, no data about its levels in children with obesity and only a few approaches regarding its potential mechanism of action have been reported. To obtain a deeper understanding of the role of S100A4 in obesity, (a) S100A4 levels were measured in prepubertal children and adult subjects with and without obesity and studied the relationship with IR and (b) the effects of S100A4 in cultured human adipocytes and vascular smooth muscle cells (VSMCs) were determined.

Methods: Sixty-five children (50 with obesity, age 9.0 ±1.1 years and 15 normal weight, age 8.4 ±0.8 years) and fifty-nine adults (43 with severe obesity, age 46 ±11 years and 16 normal weight, age 45 ±9 years) were included. Blood from children and adults and adipose tissue samples from adults were obtained and analysed. Human adipocytes and VSMC were incubated with S100A4 to evaluate their response to this adipokine.

Results: Circulating S100A4 levels were increased in both children ( = .002) and adults ( < .001) with obesity compared with their normal-weight controls. In subjects with obesity, S100A4 levels were associated with homeostatic model assessment-insulin resistance (HOMA-IR) in adults ( = .42, = .008) but not in children ( = .12, = .356). Human adipocytes were not sensitive to S100A4, while incubation with this adipokine significantly reduced inflammatory markers in VSMC.

Conclusions: Our human data demonstrate that higher S100A4 levels are a marker of IR in adults with obesity but not in prepubertal children. Furthermore, the in vitro results suggest that S100A4 might exert an anti-inflammatory effect. Further studies will be necessary to determine whether S100A4 can be a therapeutic target for obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/osp4.381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042100PMC
February 2020

A Role for Oncostatin M in the Impairment of Glucose Homeostasis in Obesity.

J Clin Endocrinol Metab 2020 Mar;105(3)

Department of Endocrinology and Nutrition, Germans Trias i Pujol Research Institute, Barcelona, Spain.

Context: Oncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood.

Objective: The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice.

Design: 28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects.

Results: OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice.

Conclusions: OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgz090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112982PMC
March 2020

Elevated Levels of Circulating miR-92a Are Associated with Impaired Glucose Homeostasis in Patients with Obesity and Correlate with Metabolic Status After Bariatric Surgery.

Obes Surg 2020 01;30(1):174-179

Germans Trias i Pujol Research Institute, Campus Can Ruti, Carretera de Can Ruti, Camí de les Escoles s/n, Badalona, 08916, Barcelona, Spain.

Introduction: miRNAs are small non-coding RNAs, some of which are expressed in adipose tissues, are present in the circulation, and are regulated in obesity. Bariatric surgery (BS) has been proposed to lead to activation of brown adipose tissue, an effect that may be related to beneficial effects of BS on systemic metabolism. Here, we evaluated circulating levels of miR-92a and miR-99b, two miRNAs proposed as biomarkers of brown fat activity, in a cohort of patients with severe obesity before and after BS, and studied their potential relationship with BS-associated improvements in metabolic parameters.

Methods: Circulating levels of miR-92a and miR-99b were quantified in a cohort of 26 patients (age, 48 ± 10 years; BMI, 45 ± 7 kg/m) before and 6 months after BS. Clinical parameters were determined at different time points and correlations among them were studied.

Results: Basal levels of miR-92a were significantly increased in patients with obesity relative to lean controls. Serum miR-92a levels were strongly reduced at 6 months after BS, reaching levels similar to those in controls. Serum miR-99b levels were unchanged in relation to both the obese condition and BS. Elevated levels of miR-92a were directly correlated with worsened glucose homeostasis parameters and poor BS outcome.

Conclusions: Our findings show that miR-92a is elevated in conditions of obesity, and its reduction after BS correlates with metabolic improvement. Further studies would be necessary to establish miR-92a as serum biomarker and potential predictor of the BS success in improving the metabolic status of patients with obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11695-019-04104-yDOI Listing
January 2020

Maternal obesity and the human milk metabolome: associations with infant body composition and postnatal weight gain.

Am J Clin Nutr 2019 07;110(1):111-120

Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

Background: Maternal obesity is a risk factor for childhood obesity; this is a major public health concern given that ∼40% of pregnant women are either overweight or obese. Whether differences in milk composition in lean compared with obese women contribute to childhood obesity is unclear.

Objectives: We aimed to analyze relationships between maternal obesity and human milk metabolites, infant body composition, and postnatal weight gain.

Methods: This was a prospective study in which mothers intending to breastfeed exclusively, and their newborn infants, were enrolled at delivery (n = 35 mother-infant pairs). We excluded mothers with diabetes, other medical conditions, or pregnancy complications. Participants were grouped by maternal prepregnancy BMI <25 (lean) or ≥25 kg/m2 (overweight/obese). We analyzed infant body composition by dual-energy X-ray absorptiometry and used untargeted liquid chromatography-gas chromatography-mass spectrometry to measure the milk content of 275 metabolites at 1 and 6 mo postpartum.

Results: At 1 mo postpartum, 10 metabolites differed between overweight/obese and lean groups with nominal P < 0.05, but none was altered with a false discovery rate <0.25. Many differentially abundant metabolites belonged to the same chemical class; e.g., 4/10 metabolites were nucleotide derivatives, and 3/10 were human milk oligosaccharides. Milk adenine correlated positively with both continuously distributed maternal BMI and with infant adiposity and fat accrual. Analysis of milk composition at 6 mo postpartum revealed 20 differentially abundant metabolites (P < 0.05) in overweight/obese compared with lean women, including 6 metabolites with a false discovery rate of <0.25. At both 1 and 6 mo, human milk abundance of 1,5-anhydroglucitol, which has not previously been described in milk, was positively associated with maternal BMI.

Conclusions: Maternal obesity is associated with changes in the human milk metabolome. While only a subset of metabolites correlated with both maternal and infant weight, these point to potential milk-dependent mechanisms for mother-child transmission of obesity. This trial was registered at www.clinicaltrials.gov as NCT02535637.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqy334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599743PMC
July 2019

Lifestyle Intervention Decreases Urine Trimethylamine N-Oxide Levels in Prepubertal Children with Obesity.

Obesity (Silver Spring) 2018 10 11;26(10):1603-1610. Epub 2018 Sep 11.

Endocrinology Department, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.

Objective: Early lifestyle interventions in children with obesity decrease risk of obesity and metabolic disorders during adulthood. This study aimed to identify metabolic signatures associated with lifestyle intervention in urine samples from prepubertal children with obesity.

Methods: Thirty-four prepubertal children with obesity were studied before and after a 6-month lifestyle intervention program, and anthropometric, metabolic, and nutritional variables were collected. A nuclear magnetic resonance approach was applied to obtain the metabolomic profile from urine samples. Partial least squares-discriminant analysis (PLS-DA) was used to achieve group classification and variable importance on projection (VIP) for biomarker selection.

Results: The intervention reduced caloric intake by 10% (P < 0.05) and BMI standard deviation score by 0.47 SD (P < 0.001). PLS-DA identified trimethylamine N-oxide (TMAO, VIP = 2.21) as the metabolite with the highest discrimination properties between groups. Urine TMAO levels were reduced after the intervention (P < 0.05). TMAO is a biomarker of cardiovascular disease risk and is a product of gut microbiota-dependent metabolism of certain dietary compounds, including choline. Notably, changes in TMAO levels after the intervention did not correlate to differences in choline intake but were inversely associated with fiber intake (P < 0.05).

Conclusions: These results indicate that lifestyle intervention decreases TMAO levels in children with obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.22271DOI Listing
October 2018

Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.

FASEB J 2018 May 29:fj201700717RR. Epub 2018 May 29.

Endocrinology Department, Institut de Recerca Sant Joan de Déu, Esplugues, Barcelona, Spain.

Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long-lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long-term programming of metabolic disease. We used a well-characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up-regulation of monoacylglycerol O-acyltransferase ( Mogat) 1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long-lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late-onset insulin resistance and fatty liver disease.-Ramon-Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez-Wienese, R., Vilà, M., Palacios-Marin, I., Fernández-Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez-Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201700717RRDOI Listing
May 2018

Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.

Mol Metab 2016 Oct 6;5(10):926-936. Epub 2016 Aug 6.

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Objective: Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear.

Methods: To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis.

Results: Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding.

Conclusions: Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034611PMC
http://dx.doi.org/10.1016/j.molmet.2016.08.001DOI Listing
October 2016

eRah: A Computational Tool Integrating Spectral Deconvolution and Alignment with Quantification and Identification of Metabolites in GC/MS-Based Metabolomics.

Anal Chem 2016 10 14;88(19):9821-9829. Epub 2016 Sep 14.

Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili , 43003 Tarragona, Catalonia, Spain.

Gas chromatography coupled to mass spectrometry (GC/MS) has been a long-standing approach used for identifying small molecules due to the highly reproducible ionization process of electron impact ionization (EI). However, the use of GC-EI MS in untargeted metabolomics produces large and complex data sets characterized by coeluting compounds and extensive fragmentation of molecular ions caused by the hard electron ionization. In order to identify and extract quantitative information on metabolites across multiple biological samples, integrated computational workflows for data processing are needed. Here we introduce eRah, a free computational tool written in the open language R composed of five core functions: (i) noise filtering and baseline removal of GC/MS chromatograms, (ii) an innovative compound deconvolution process using multivariate analysis techniques based on compound match by local covariance (CMLC) and orthogonal signal deconvolution (OSD), (iii) alignment of mass spectra across samples, (iv) missing compound recovery, and (v) identification of metabolites by spectral library matching using publicly available mass spectra. eRah outputs a table with compound names, matching scores and the integrated area of compounds for each sample. The automated capabilities of eRah are demonstrated by the analysis of GC-time-of-flight (TOF) MS data from plasma samples of adolescents with hyperinsulinaemic androgen excess and healthy controls. The quantitative results of eRah are compared to centWave, the peak-picking algorithm implemented in the widely used XCMS package, MetAlign, and ChromaTOF software. Significantly dysregulated metabolites are further validated using pure standards and targeted analysis by GC-triple quadrupole (QqQ) MS, LC-QqQ, and NMR. eRah is freely available at http://CRAN.R-project.org/package=erah .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.6b02927DOI Listing
October 2016

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

Diabetes 2016 04 8;65(4):902-12. Epub 2016 Feb 8.

Endocrinology Section, Hospital Sant Joan de Déu, Barcelona, Spain

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db15-1094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806659PMC
April 2016

Transcriptional Profiling of Hypoxic Neural Stem Cells Identifies Calcineurin-NFATc4 Signaling as a Major Regulator of Neural Stem Cell Biology.

Stem Cell Reports 2015 Aug 30;5(2):157-65. Epub 2015 Jul 30.

Clinical and Experimental Neurosciences, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain. Electronic address:

Neural stem cells (NSCs) reside in a hypoxic microenvironment within the brain. However, the crucial transcription factors (TFs) that regulate NSC biology under physiologic hypoxia are poorly understood. Here we have performed gene set enrichment analysis (GSEA) of microarray datasets from hypoxic versus normoxic NSCs with the aim of identifying pathways and TFs that are activated under oxygen concentrations mimicking normal brain tissue microenvironment. Integration of TF target (TFT) and pathway enrichment analysis identified the calcium-regulated TF NFATc4 as a major candidate to regulate hypoxic NSC functions. Nfatc4 expression was coordinately upregulated by top hypoxia-activated TFs, while NFATc4 target genes were enriched in hypoxic NSCs. Loss-of-function analyses further revealed that the calcineurin-NFATc4 signaling axis acts as a major regulator of NSC self-renewal and proliferation in vitro and in vivo by promoting the expression of TFs, including Id2, that contribute to the maintenance of the NSC state.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2015.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618660PMC
August 2015

Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes.

Mol Metab 2015 Mar 2;4(3):151-63. Epub 2015 Jan 2.

Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA.

Objective: Dysregulated muscle metabolism is a cardinal feature of human insulin resistance (IR) and associated diseases, including type 2 diabetes (T2D). However, specific reactions contributing to abnormal energetics and metabolic inflexibility in IR are unknown.

Methods: We utilize flux balance computational modeling to develop the first systems-level analysis of IR metabolism in fasted and fed states, and varying nutrient conditions. We systematically perturb the metabolic network to identify reactions that reproduce key features of IR-linked metabolism.

Results: While reduced glucose uptake is a major hallmark of IR, model-based reductions in either extracellular glucose availability or uptake do not alter metabolic flexibility, and thus are not sufficient to fully recapitulate IR-linked metabolism. Moreover, experimentally-reduced flux through single reactions does not reproduce key features of IR-linked metabolism. However, dual knockdowns of pyruvate dehydrogenase (PDH), in combination with reduced lipid uptake or lipid/amino acid oxidation (ETFDH), does reduce ATP synthesis, TCA cycle flux, and metabolic flexibility. Experimental validation demonstrates robust impact of dual knockdowns in PDH/ETFDH on cellular energetics and TCA cycle flux in cultured myocytes. Parallel analysis of transcriptomic and metabolomics data in humans with IR and T2D demonstrates downregulation of PDH subunits and upregulation of its inhibitory kinase PDK4, both of which would be predicted to decrease PDH flux, concordant with the model.

Conclusions: Our results indicate that complex interactions between multiple biochemical reactions contribute to metabolic perturbations observed in human IR, and that the PDH complex plays a key role in these metabolic phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2014.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338313PMC
March 2015

Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus.

PLoS One 2012 11;7(7):e40600. Epub 2012 Jul 11.

Department of Endocrinology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain.

The beneficial effects of exercise in patients with type 1 diabetes (T1D) are not fully proven, given that it may occasionally induce acute metabolic disturbances. Indeed, the metabolic disturbances associated with sustained exercise may lead to worsening control unless great care is taken to adjust carbohydrate intake and insulin dosage. In this work, pre- and post-exercise metabolites were analyzed using a (1)H-NMR and GC-MS untargeted metabolomics approach assayed in serum. We studied ten men with T1D and eleven controls matched for age, body mass index, body fat composition, and cardiorespiratory capacity, participated in the study. The participants performed 30 minutes of exercise on a cycle-ergometer at 80% VO(2)max. In response to exercise, both groups had increased concentrations of gluconeogenic precursors (alanine and lactate) and tricarboxylic acid cycle intermediates (citrate, malate, fumarate and succinate). The T1D group, however, showed attenuation in the response of these metabolites to exercise. Conversely to T1D, the control group also presented increases in α-ketoglutarate, alpha-ketoisocaproic acid, and lipolysis products (glycerol and oleic and linoleic acids), as well as a reduction in branched chain amino acids (valine and leucine) determinations. The T1D patients presented a blunted metabolic response to acute exercise as compared to controls. This attenuated response may interfere in the healthy performance or fitness of T1D patients, something that further studies should elucidate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040600PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394718PMC
January 2013

Response to Brosch et al.

Cell Metab 2012 Mar;15(3):267-269

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.

We would like to respond to Brosch et al. regarding our manuscript "Expression of the Splicing Factor Gene Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis" (Pihlajamäki et al., 2011b). Brosch performed RT-PCR in liver samples from 13 lean and 34 obese individuals, finding no differences in or expression. We wish to address points raised by Brosch, including experimental strategy and analysis of human expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2012.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425348PMC
March 2012

PGC-1α induces mitochondrial and myokine transcriptional programs and lipid droplet and glycogen accumulation in cultured human skeletal muscle cells.

PLoS One 2012 17;7(1):e29985. Epub 2012 Jan 17.

CIBER de Diabetes y Enfermedades Metabólicas, Barcelona, Spain.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a chief activator of mitochondrial and metabolic programs and protects against atrophy in skeletal muscle (skm). Here we tested whether PGC-1α overexpression could restructure the transcriptome and metabolism of primary cultured human skm cells, which display a phenotype that resembles the atrophic phenotype. An oligonucleotide microarray analysis was used to reveal the effects of PGC-1α on the whole transcriptome. Fifty-three different genes showed altered expression in response to PGC-1α: 42 upregulated and 11 downregulated. The main gene ontologies (GO) associated with the upregulated genes were mitochondrial components and processes and this was linked with an increase in COX activity, an indicator of mitochondrial content. Furthermore, PGC-1α enhanced mitochondrial oxidation of palmitate and lactate to CO(2), but not glucose oxidation. The other most significantly associated GOs for the upregulated genes were chemotaxis and cytokine activity, and several cytokines, including IL-8/CXCL8, CXCL6, CCL5 and CCL8, were within the most highly induced genes. Indeed, PGC-1α highly increased IL-8 cell protein content. The most upregulated gene was PVALB, which is related to calcium signaling. Potential metabolic regulators of fatty acid and glucose storage were among mainly regulated genes. The mRNA and protein level of FITM1/FIT1, which enhances the formation of lipid droplets, was raised by PGC-1α, while in oleate-incubated cells PGC-1α increased the number of smaller lipid droplets and modestly triglyceride levels, compared to controls. CALM1, the calcium-modulated δ subunit of phosphorylase kinase, was downregulated by PGC-1α, while glycogen phosphorylase was inactivated and glycogen storage was increased by PGC-1α. In conclusion, of the metabolic transcriptome deficiencies of cultured skm cells, PGC-1α rescued the expression of genes encoding mitochondrial proteins and FITM1. Several myokine genes, including IL-8 and CCL5, which are known to be constitutively expressed in human skm cells, were induced by PGC-1α.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029985PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260188PMC
June 2012

Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis.

Cell Metab 2011 Aug;14(2):208-18

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.

Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2011.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167228PMC
August 2011

GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acetylation.

J Biol Chem 2009 Jul 2;284(30):19945-52. Epub 2009 Jun 2.

From the Department of Cancer Biology, Dana-Farber Cancer Institute, Harvad Medical School, Boston, Massachusetts 02115, USA.

Changes in expression levels of genes encoding for proteins that control metabolic pathways are essential to maintain nutrient and energy homeostasis in individual cells as well as in organisms. An important regulated step in this process is accomplished through covalent chemical modifications of proteins that form complexes with the chromatin of gene promoters. The peroxisome proliferators gamma co-activator 1 (PGC-1) family of transcriptional co-activators comprises important components of a number of these complexes and participates in a large array of glucose and lipid metabolic adaptations. Here, we show that PGC-1beta is acetylated on at least 10 lysine residues distributed along the length of the protein by the acetyl transferase general control of amino-acid synthesis (GCN5) and that this acetylation reaction is reversed by the deacetylase sirtuin 1 (SIRT1). GCN5 strongly interacts with PGC-1beta and represses its transcriptional activity associated with transcription factors such as ERRalpha, NRF-1, and HNF4alpha, however acetylation and transcriptional repression do not occur when a catalytically inactive GCN5 is co-expressed. Transcriptional repression coincides with PGC-1beta redistribution to nuclear foci where it co-localizes with GCN5. Furthermore, knockdown of GCN5 ablates PGC-1beta acetylation and increases transcriptional activity. In primary skeletal muscle cells, PGC-1beta induction of endogenous target genes, including MCAD and GLUT4, is largely repressed by GCN5. Functionally, this translates to a blunted response to PGC-1beta-induced insulin-mediated glucose transport. These results suggest that PGC-1beta acetylation by GCN5 might be an important step in the control of glucose and lipid pathways and its dysregulation could contribute to metabolic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M109.015164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740420PMC
July 2009

Effects of aging and calorie restriction on rat skeletal muscle glycogen synthase and glycogen phosphorylase.

Exp Gerontol 2009 Jun-Jul;44(6-7):426-33. Epub 2009 Mar 31.

CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Departament de Bioquímica i Biologia Molecular, IBUB, Facultat de Biologia, Universitat de Barcelona, Diagonal, 645, 08028 Barcelona, Spain.

Calorie restriction's (CR) effects on age-associated changes in glycogen-metabolizing enzymes were studied in rat soleus (SOL) and tibialis anterior (TA) muscles. Old (24 months) compared to young (6 months) rats maintained ad libitum on a standard diet had reduced glycogen synthase (GS) activity, lower muscle GS protein levels, increased phosphorylation of GS at site 3a with less activation in SOL. Age-associated impairments in GS protein and activation-phosphorylation were also shown in TA. There was an age-associated reduction in glycogen phosphorylase (GP) activity level in SOL, while brain/muscle isoforms (B/M) of GP protein levels were higher. GP activity and protein levels were preserved, but GP was inactivated in TA with age. Glycogen content was unchanged in both muscles. CR did not alter GS or GP activity/protein levels in young rats. CR hindered age-related decreases in GS activity/protein, unrelated to GS mRNA levels, and GS inactivation-phosphorylation; not on GP. In older rats, CR enhanced glycogen accumulation in SOL. Short-term fasting did not recapitulate CR effects in old rats. Thus, the predominant age-associated impairments on skeletal muscle GS and GP activities occur in the oxidative SOL muscle of rats, and CR can attenuate the loss of GS activity/activation and stimulate glycogen accumulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exger.2009.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127239PMC
November 2010

The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1{alpha}.

Proc Natl Acad Sci U S A 2008 Nov 28;105(44):17187-92. Epub 2008 Oct 28.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch, France.

Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3(-/-) mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1alpha. By controlling the expression of the only characterized PGC-1alpha acetyltransferase GCN5, SRC-3 induces PGC-1alpha acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1alpha activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1alpha activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1alpha as an effector to control mitochondrial function and energy homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0808207105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579399PMC
November 2008

Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways.

FEBS Lett 2008 Jan 26;582(1):46-53. Epub 2007 Nov 26.

Dana-Farber Cancer Institute, Harvard Medical School, One Jimmy Fund Way, Smith-936C, Boston, MA 02115, USA.

Energy homeostasis in mammals is achieved through tight regulation of tissue-specific metabolic pathways that become dysregulated in metabolic diseases including diabetes and obesity. At the molecular level, main nutrient and hormonal signaling pathways impinge on expression of genes encoding for metabolic enzymes. Among the major components of this transcriptional circuitry are the PGC-1 alpha transcriptional complexes. An important regulatory mechanism of this complex is through acetylation and SIRT1-mediated lysine de-acetylation under low nutrient conditions. Activation of SIRT1 can mimic several metabolic aspects of calorie restriction that target selective nutrient utilization and mitochondrial oxidative function to regulate energy balance. Thus, understanding the PGC-1 alpha and SIRT1 pathways might have important implications for comprehending metabolic and age-associated diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.febslet.2007.11.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275806PMC
January 2008

Expression and glycogenic effect of glycogen-targeting protein phosphatase 1 regulatory subunit GL in cultured human muscle.

Biochem J 2007 Jul;405(1):107-13

Departament de Bioquímica i Biologia Molecular, Facultat de Biología, Universitat de Barcelona, 08028-Barcelona, Spain.

Glycogen-targeting PP1 (protein phosphatase 1) subunit G(L) (coded for by the PPP1R3B gene) is expressed in human, but not rodent, skeletal muscle. Its effects on muscle glycogen metabolism are unknown. We show that G(L) mRNA levels in primary cultured human myotubes are similar to those in freshly excised muscle, unlike subunits G(M) (gene PPP1R3A) or PTG (protein targeting to glycogen; gene PPP1R3C), which decrease strikingly. In cultured myotubes, expression of the genes coding for G(L), G(M) and PTG is not regulated by glucose or insulin. Overexpression of G(L) activates myotube GS (glycogen synthase), glycogenesis in glucose-replete and -depleted cells and glycogen accumulation. Compared with overexpressed G(M), G(L) has a more potent activating effect on glycogenesis, while marked enhancement of their combined action is only observed in glucose-replete cells. G(L) does not affect GP (glycogen phosphorylase) activity, while co-overexpression with muscle GP impairs G(L) activation of GS in glucose-replete cells. G(L) enhances long-term glycogenesis additively to glucose depletion and insulin, although G(L) does not change the phosphorylation of GSK3 (GS kinase 3) on Ser9 or its upstream regulator kinase Akt/protein kinase B on Ser473, nor its response to insulin. In conclusion, in cultured human myotubes, the G(L) gene is expressed as in muscle tissue and is unresponsive to glucose or insulin, as are G(M) and PTG genes. G(L) activates GS regardless of glucose, does not regulate GP and stimulates glycogenesis in combination with insulin and glucose depletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BJ20061572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1925244PMC
July 2007

Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.

EMBO J 2007 Apr 8;26(7):1913-23. Epub 2007 Mar 8.

Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA.

In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.emboj.7601633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847661PMC
April 2007

Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha.

Cell 2006 Dec 16;127(6):1109-22. Epub 2006 Nov 16.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / ULP, 67404 Illkirch, France.

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2006.11.013DOI Listing
December 2006

Resveratrol improves health and survival of mice on a high-calorie diet.

Nature 2006 Nov 1;444(7117):337-42. Epub 2006 Nov 1.

Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature05354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990206PMC
November 2006

GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha.

Cell Metab 2006 Jun;3(6):429-38

Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Hormonal and nutrient regulation of hepatic gluconeogenesis mainly occurs through modulation of the transcriptional coactivator PGC-1alpha. The identity of endogenous proteins and their enzymatic activities that regulate the functions and form part of PGC-1alpha complex are unknown. Here, we show that PGC-1alpha is in a multiprotein complex containing the acetyltransferase GCN5. PGC-1alpha is directly acetylated by GCN5 resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci. Adenoviral-mediated expression of GCN5 in cultured hepatocytes and in mouse liver largely represses activation of gluconeogenic enzymes and decreases hepatic glucose production. Thus, we have identified the endogenous PGC-1alpha protein complex and provided the molecular mechanism by which PGC-1alpha acetylation by GCN5 turns off the transcriptional and biological function of this metabolic coactivator. GCN5 might be a pharmacological target to regulate the activity of PGC-1alpha, providing a potential treatment for metabolic disorders in which hepatic glucose output is dysregulated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2006.04.013DOI Listing
June 2006