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

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 1e3 and cryptochrome 1e2, were altered in two-week-old SL mice and remained altered throughout their life course until they reached 4e6 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

Genome-wide multi-trait analysis of irritable bowel syndrome and related mental conditions identifies 38 new independent variants

Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction frequently accompanied by mental conditions, including depression and anxiety. Despite showing substantial heritability and being partly determined by a genetic component, the genetic underpinnings explaining the high rates of comorbidity remain largely unclear and there are no conclusive data on the temporal relationship between them. Exploring the overlapping genetic architecture between IBS and mental conditions may help to identify novel genetic loci and biological mechanisms underlying IBS and causal relationships between them. We quantified the genetic overlap between IBS, neuroticism, depression and anxiety, conducted a multi-trait genome-wide association study (GWAS) considering these traits and investigated causal relationships between them by using the largest GWAS to date. IBS showed to be a highly polygenic disorder with extensive genetic sharing with mental conditions. Multi-trait analysis of IBS and neuroticism, depression and anxiety identified 42 genome-wide significant variants for IBS, of which 38 are novel. Fine-mapping risk loci highlighted 289 genes enriched in genes upregulated during early embryonic brain development and gene-sets related with psychiatric, digestive and autoimmune disorders. IBS-associated genes were enriched for target genes of anti-inflammatory and antirheumatic drugs, anesthetics and opioid dependence pharmacological treatment. Mendelian-randomization analysis accounting for correlated pleiotropy identified bidirectional causal effects between IBS and neuroticism and depression and causal effects of the genetic liability of IBS on anxiety. These findings provide evidence of the polygenic architecture of IBS, identify novel genome-wide significant variants for IBS and extend previous knowledge on the genetic overlap and relationship between gastrointestinal and mental disorders. The online version contains supplementary material available at 10.1186/s12967-023-04107-5

Dietary betaine supplementation increases Fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice

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

PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci

Role of early postnatal nutrition during lactation in offspring metabolic health programming

[eng] Childhood obesity and overweight can often cause severe complications, including hypertension, dyslipidemia, insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease, amongst other disorders. Several studies have shown that early postnatal nutrition is of great importance in modulating newborn health outcomes. In this work, we have studied the role of nutrition during early stages of life in long-term metabolic health applying two different approaches: a) transgenerational transmission of impaired metabolic health induced by accelerated early weight gain caused by postnatal overnutrition and b) short and long-term metabolic effects on offspring of maternal diet supplementation with betaine. Rapid weight gain during early life has been associated with several components of the Metabolic Syndrome. Previously we developed a mouse model of neonatal overfeeding and rapid weight gain by litter size reduction. Neonatal overnutrition (ON) altered the metabolism of the exposed individuals (F0). Furthermore, offspring (F1) and grand-offspring (F2) of postnatal overfed male mice also developed metabolic complications during adulthood. In agreement, it has been shown that environmental exposure on males can affect health in subsequent generations. Here, we hypothesized that epigenetic modifications, including DNA methylation, histone modifications, and noncoding-RNA, might be involved in the inheritance of diabetes risk in our model. We analyzed sperm methylome of F0 and F1 generations, and in the liver of 8-day-old mice of F1 and F2 generations, observing significant changes in methylation of specific DNA regions. We found 912 probes differentially methylated when comparing control and ON mice throughout the three generations, between the two tissues. Our results suggest that methylation of the male germ line caused by nutritional challenges during early life may carry information that influence metabolism across multiple generations. We then analyzed gene expression by qPCR of these genes in the liver of 8-days-old mice finding differences in some genes. Breast milk composition is important in modulating growth and health of the infant. Amongst the many nutrients that breast milk contains one worth highlighting is glycine betaine (or betaine). In addition to decreasing levels of fat in the liver, previous data demonstrated that maternal supplementation with betaine during breastfeeding also improves glucose homeostasis and modulates offspring early-life gut microbiota composition. Gut microbiota in the newborn is defined at birth and during early nutrition. Breast milk also contains essential bacteria that can influence gut microbiota composition of the breastfed infant. Changes in the microbiome caused by antibiotic administration during early life were significantly correlated to higher adiposity and development of obesity during adulthood. We observed beneficial short and long-term metabolic effects of betaine on offspring and protection against adult diet-induced obesity. We have analyzed ilea and gut microbiota of mice supplemented with betaine, and with or without antibiotics at different stages of life. Analyzing the microbiome we found that microbial community composition was modulated by betaine supplementation in 2-week-old offspring. Antibiotic treatment annulled completely long-term betaine-induced effects on body weight. Moreover, glucose tolerance was no longer improved when combining antibiotics with betaine treatment.[cat] L'obesitat i el sobrepès infantil poden causar sovint complicacions greus en la salut, incloent hipertensió, dislipèmia, resistència a la insulina, diabetis tipus 2 i esteatosis hepàtica no alcohòlica, entre d’altres. Diversos estudis han demostrat que la nutrició post-natal precoç és de gran importància en la modulació de la salut del nounat. En aquesta tesis, hem estudiat el paper de la nutrició durant les primeres etapes de la vida en la salut metabòlica a llarg termini aplicant dos enfocaments diferents: a) efectes metabòlics de suplementar de la dieta materna durant la lactància amb betaïna sobre la descendència a curt i llarg termini i b) transmissió transgeneracional del fenotip d’intolerància a la glucosa induïda per un augment accelerat de pes en etapes primerenques de la vida, causat per l'excés de nutrició post-natal. La composició de la llet materna és important per modular el creixement i la salut metabòlica de l'infant. Entre els nutrients que conté la llet materna, cal destacar la glicina betaïna (o betaïna). A més de disminuir els nivells de greix en fetge, diverses publicacions demostren que suplementar la dieta materna amb betaïna durant la lactància també millora l'homeòstasi de la glucosa i modula la composició de la microbiota intestinal del nounat. Al suplementar amb betaïna l’aigua de femelles durant la lactància vam observar efectes beneficiosos en la descendència a nivell metabòlic a curt i llarg termini. També vam poder observar que la betaïna protegia contra l'obesitat induïda per una dieta rica en greixos en l’etapa adulta. Se sap que la llet materna també conté bacteris essencials que poden influir en la composició de microbiota intestinal del lactant. S'ha analitzat la microbiota de l’ili i cec de ratolins suplementats amb betaïna, i amb o sense antibiòtics en diferents etapes de la vida. Analitzant el microbioma trobem que la composició de la comunitat microbiana dels ratolins de dues setmanes de vida estava modulada per la suplementació de betaina. Els canvis en el microbioma causats per l'administració d'antibiòtics durant la lactància estan significativament correlacionats amb una major adipositat i risc de desenvolupar obesitat durant l'edat adulta. El tractament amb antibiòtics en els nostres ratolins va anul·lar els efectes induïts per betaïna a llarg termini sobre el pes corporal. A més, la tolerància a la glucosa no estava millorarada quan es combinaven els antibiòtics amb el tractament amb betaïna. L'augment ràpid de pes durant les primeres etapes de la vida s'ha associat a diversos components de la Síndrome Metabòlica en l’adult. Prèviament en aquest laboratori hem desenvolupat un model murí de sobrealimentació neonatal i augment de pes ràpid a partir d’una reducció de la mida de la ventrada. L'excés d'alimentació neonatal (ON) va alterar el metabolisme dels mascles exposats (F0). A més, els fills (F1) i els néts (F2) dels ratolins exposats a la sobrenutrició també van desenvolupar un metabolisme alterat durant l'edat adulta. En acord, s'ha demostrat que l'exposició ambiental sobre els mascles pot afectar la salut de generacions posteriors. Així, ens vam plantejar que les modificacions epigenètiques, incloses la metilació de l'ADN, les modificacions de l'histona i l'ARN no codificant, podrien estar implicades en l'herència del risc de diabetis en el nostre model. Es va analitzar el metilma d’esperma de les generacions F0 i F1, i el metiloma de fetges de ratolins de 8 dies d'edat de les generacions F1 i F2, observant canvis significatius en la metilació de regions específiques d'ADN. Al comparar els ratolins control amb ON de cada generació i teixit, vam trobar 912 sondes diferentment metiladas. Els nostres resultats suggereixen que la metilació de la línia germinal masculina provocada per reptes nutricionals durant etapes primerenques de la vida pot portar informació que influeixi en el metabolisme en les següents generacions

Transcriptomic risk scores for attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. We performed a transcriptome-wide association study (TWAS) using the latest genome-wide association study (GWAS) meta-analysis, in 38,691 individuals with ADHD and 186,843 controls, and 14 gene-expression reference panels across multiple brain tissues and whole blood. Based on TWAS results, we selected subsets of genes and constructed transcriptomic risk scores (TRSs) for the disorder in peripheral blood mononuclear cells of individuals with ADHD and controls. We found evidence of association between ADHD and TRSs constructed using expression profiles from multiple brain areas, with individuals with ADHD carrying a higher burden of TRSs than controls. TRSs were uncorrelated with the polygenic risk score (PRS) for ADHD and, in combination with PRS, improved significantly the proportion of variance explained over the PRS-only model. These results support the complementary predictive potential of genetic and transcriptomic profiles in blood and underscore the potential utility of gene expression for risk prediction and deeper insight in molecular mechanisms underlying ADHD

Self-aggregation of free base porphyrins in aqueous solution and in DMPC vesicles

Free base porphyrin (PPhe), derivatized with aminosulfonyl groups linked to the aromatic amino acid phenylalanine at the meso-positions, was mixed with DMPC vesicles. The resulting interaction was studied by absorption, steady-state and transient state fluorescence, at different pHs.http://www.sciencedirect.com/science/article/B6TFB-4R68NKV-2/1/aca6e255f297903981898ccea264a38

Dietary betaine supplementation increases Fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice

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

Dietary betaine supplementation increases Fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice

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