Biology subjects

Thiroux, B.

Publications and source records attributed to Thiroux, B..

3 recordsLinked to original sources

bioRxiv2025

Sex-dependent effects of maternal high-fat diet during lactation in adult THY-Tau22 mice offspring

The perinatal environment has been suggested to participate to the development of tauopathies and Alzheimers disease but the molecular and cellular mechanisms involved remain contradictory and under-investigated. Here, we evaluated the effects of a maternal high-fat diet (HFD) during lactation on the development of tauopathy in the THY-Tau22 mouse strain, a model of progressive tau pathology associated with cognitive decline. During lactation, dams were fed either a chow diet (13.6% of fat) or a HFD (58% of fat). At weaning, offspring was fed a chow diet until sacrifice at 4 months of age (the onset of tau pathology) or 7 months of age (the onset of cognitive impairment). During lactation, maternal HFD increased body weight gain in offspring. At 3 months of age, maternal HFD led to a mild glucose intolerance only in male offspring. Moreover, it impaired spatial memory in both male and female 6-month-old offspring, with males being more impacted. These cognitive deficits were associated with increased phosphorylation of hippocampal tau protein-observed at 4 months in males and at 7 months in females, highlighting a sex-specific temporal shift. Additionally, maternal HFD modified adult hippocampal neurogenesis (AHN), leading to an increase of mature neuronal cells number in females and of dendritic arborization length in males. Synaptic analysis further revealed that maternal HFD led to synaptic loss only in males. Finally, multi-omics approaches showed that maternal HFD has long-term consequences on both transcriptome, proteome and regulome, this effect being also sex-dependent with mitochondrial pathways, ribosomal activity, cilium and the extracellular matrix predominantly impacted in males, while gliogenesis, myelination and synaptic plasticity were primarily affected in females. Regulome analysis suggested that this sex-dependent phenotype was more related to a temporal shift rather than distinct sex-specific alterations. Collectively, our data suggest that maternal malnutrition accelerates the development of tauopathy in THY-Tau22 offspring, with sex-dependent effects, males being impacted earlier than females. These findings highlight the critical role of the perinatal environment as a key window of opportunity for interventions aimed at preventing the development of neurodegenerative diseases.

neuroscience↗

bioRxiv2023

High-throughput quantitative screening of glucose-stimulated insulin secretion and insulin content using automated MAL-DI-TOF mass spectrometry

Type 2 diabetes (T2D) is a metabolic disorder characterized by loss of pancreatic {beta}- cell function, decreased insulin secretion and increased insulin resistance, that affects more than 400 million people worldwide. Although several treatments are proposed to patients suffering from T2D, long-term control of glycemia remains a challenge. Therefore, identifying new potential drugs and targets that positively affect {beta}-cell function and insulin secretion remains crucial. Here, we developed an automated approach to allow the identification of new compounds or genes potentially involved in {beta}-cell function in a 384-well plate format, using the murine {beta}-cell model Min6. Using MALDI-TOF mass spectrometry, we have implemented a high-throughput screening (HTS) strategy based on the automation of a cellular assay allowing to detect insulin secretion in response to glucose, quantitative detection of insulin, in a miniaturized system. As a proof of concept, we screened siRNA targeting well-know {beta}-cell genes and 1600 chemical compounds and identified several molecules as potential regulators of insulin secretion and/or synthesis, demonstrating that our approach allows HTS of insulin secretion in vitro.

physiology↗

bioRxiv2022

The HDAC inhibitor trichostatin A impairs pancreatic β-cell function through an epigenome-wide reprogramming

ObjectiveThe pancreatic islets of Langerhans contain distinct cell subtypes including insulin-producing {beta} cells. Although their cell-specific gene expression pattern defines their identity, the underlying molecular network driving this transcriptional specificity is not fully understood. Among the numerous transcriptional regulators, histone deacetylases (HDAC) enzymes are potent chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone proteins. The precise molecular mechanisms underlying HDAC effects on cellular plasticity and {beta}-cell identity are currently unknown. MethodsThe pharmacological inhibition of HDAC activity by trichostatin A (TSA) was studied in the mouse Min6 and human EndocBH1 cell lines, as well as primary mouse sorted {beta} cells and human pancreatic islets. The molecular and functional effects of treating these complementary {beta}-cell models with TSA was explored at the epigenomic and transcriptomic level through next-generation sequencing of chromatin immunoprecipitation (ChIP) assays (ChIP-seq) and RNA sequencing (RNA-seq) experiments, respectively. ResultsWe showed that TSA alters insulin secretion associated with {beta}-cell specific transcriptome programming in both mouse and human {beta}-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative {beta}-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. ConclusionsTaken together, our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of {beta}-cell identity with unsuitable expression of genes associated with alternative cell fates.

genomics↗