Biology subjects

Heurtaux, T.

Publications and source records attributed to Heurtaux, T..

5 recordsLinked to original sources

bioRxiv2026

Postprandial hypertriglyceridemia activates microglia to promote satiety via an ASC dependent signaling.

Reactive microglia are commonly considered neurotoxic and detrimental for brain functioning. Chronic consumption of a high-fat diet strongly activates microglia, disrupts the central control of energy metabolism, contributes to obesity, and promotes cognitive decline. In this study we report an unexpected beneficial function of microglia reaction at the time scale of a meal, whereby they promote satiety in a macronutrient-dependent manner. We show that murine microglia react to ingested dietary fat within three hours. Specifically, postprandial hypertriglyceridemia induced microglial hyper-ramification alongside with a transcriptional reprogramming promoting communication with neurons. This effect occurs in discrete brain areas, including the hypothalamus and the brainstem, which control hunger. Remarkably, microglia-specific genetic ablation of Apoptosis-associated Speck-like protein containing a CARD (named ASC), a master regulator of metabolism, immune function and cell shape, profoundly alters satiety following high-fat food consumption. These results reveal that microglia engage an immune signaling pathway to rapidly alert the neural circuits and activate an anorectic response that limits overconsumption of dietary fat. Unexpectedly, this regulatory process is sexually dimorphic, present in males only. Furthermore, we found that the postprandial microglial reaction is bypassed during obesity, providing a new therapeutic target to treat maladaptive eating disorders.

neuroscience↗

bioRxiv2026

Voluntary Exercise Differentially Affects High-Fat Induced Metabolic Phenotypes Across BXD Mouse Strains

Obesity and metabolic diseases such as diabetes reflect long-term interactions between diet, lifestyle, and genetics, variables that are hard to control in humans but can be systematically varied in mice, though behavioral variables like long-term exercise remain harder to model. Having previously phenotyped ~50 BXD strains, we identified BXD40, BXD43, and BXD100 as predisposed to voluntary wheel-running (~6 km/day at 24 weeks) with variable susceptibility to diet-induced obesity and diabetes. We followed these strains from 8-32 weeks on a 60% kcal/fat high-fat (HF) diet, with or without access to running wheels. Wheel usage declined from ~9 km/day in the first two weeks to a steady ~5 km/day thereafter yet still improved oral glucose tolerance by 35% over sedentary controls by 24 weeks. Despite equivalent body weight, runners ate 20% more relative to body weight, indicating the glucose benefit was independent of caloric intake. We next asked whether the gut microbiome contributes to this benefit. Long-term exercise produced only modest, cohort-dependent shifts in cecal microbial composition, though functional profiling revealed exercise-associated differences in carbohydrate- and glucose-metabolism pathways. Reciprocal bedding exchange between sedentary and running BXD43 cages reduced microbial differentiation in a taxon-specific manner and coincided with marked attenuation of the glucose phenotype, despite unchanged running behavior. Together, these findings validate BXD40, BXD43, and BXD100, alongside the canonical C57BL/6, as a model for studying diet, exercise, and genetics in metabolic disease, and implicate gut microbial taxa in shaping exercise's metabolic effects during HF feeding.

genetics↗

bioRxiv2024

Park7 deletion leads to age- and sex-specific transcriptome changes involving NRF2-CYP1B1 axis in mouse midbrain astrocytes

AbstractdispeLoss-of-function mutations in PARK7, encoding for DJ-1, can lead to early onset Parkinsons disease (PD). In mice, Park7 deletion leads to dopaminergic deficits during aging, and increased sensitivity to oxidative stress. However, the severity of the reported phenotypes varies. To understand the early molecular changes upon loss of DJ-1, we performed transcriptomic profiling of midbrain sections from young mice. Interestingly, while at 3 months the transcriptomes of both male and female mice were unchanged compared to their wildtype littermates, an extensive deregulation was observed specifically in 8-month-old males. The affected genes are involved in processes such as focal adhesion, extracellular matrix interaction, and epithelial-to-mesenchymal transition (EMT), and enriched for primary target genes of Nuclear factor erythroid 2-related factor 2 (NRF2). Consistently, the antioxidant response was altered specifically in the midbrain of male DJ-1 deficient mice. Many of the misregulated genes are known target genes of estrogen and retinoic acid signaling and show sex-specific expression in wildtype mice. Depletion of DJ-1 or NRF2 in male, but not female primary astrocytes recapitulated many of the in vivo changes, including downregulation of cytochrome P450 family 1 subfamily B member 1 (CYP1B1), an enzyme involved in estrogen and retinoic acid metabolism. Interestingly, knock-down of CYP1B1 led to gene expression changes in focal adhesion and EMT in primary male astrocytes. Finally, male iPSC-derived astrocytes with loss of function mutation in the PARK7 gene also showed changes in the EMT pathway and NRF2 target genes. Taken together, our data indicate that loss of Park7 leads to sex-specific gene expression changes specifically in males through astrocytic alterations in the NRF2-CYP1B1 axis. These findings suggest higher sensitivity of males to loss of DJ-1 and might help to better understand variation in the reported Park7-/-phenotypes.

molecular biology↗

bioRxiv2022

Dietary fibre deprivation and bacterial curli exposure shift gut microbiome and exacerbate Parkinson's disease-like pathologies in an alpha-synuclein-overexpressing mouse

The microbiome-gut-brain axis has been proposed as a pathogenic path in Parkinsons disease (PD). Dietary driven dysbiosis and reduced gut barrier function could facilitate the interaction of toxic external or internal factors with the enteric nervous system, where PD could start. Amyloid bacterial protein such as curli can act as seed to corrupt enteric -synuclein and lead to its aggregation. Misfolded -synuclein can propagate to and throughout the brain. Here, we aimed at understanding if fibre deprivation and amyloidogenic protein curli could, individually or together, exacerbate the phenotype in both enteric and central nervous systems of a transgenic mouse overexpressing wild-type human -synuclein. We analysed the gut microbiome, motor behaviour, gastrointestinal and brain pathologies in these mice. Our findings show that external interventions, akin to unhealthy life habits in humans, can exacerbate PD-like pathologies in mice. We believe that our results shed light on how lifestyle affects PD progression.

neuroscience↗

bioRxiv2020

Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson disease

A key process of neurodegeneration in Parkinson disease (PD) is the transneuronal spreading of alpha-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of alpha-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of alpha-synuclein induced by intracerebral injection of alpha-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for alpha-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without alpha-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that alpha-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric alpha-synuclein species, which induce unusual microglial reactivity, play a key role in this process. Our findings uncover new features of alpha-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of prion-like spreading of that protein.

neuroscience↗