Biology subjects

Ellero-Simatos, S.

Publications and source records attributed to Ellero-Simatos, S..

15 recordsLinked to original sources

bioRxiv2026

Dietary fructose promotes anxiety through impairment of microglia physiology

Excessive dietary fructose has been linked to metabolic and mood disorders but the underlying brain mechanisms remain unclear. In this study, we tested whether microglia, the brain resident immune cells, mediate fructose-induced anxiety. Adult C57BL/6J mice and mice knock-down for the fructose transporter Glut5 selectively in microglia (Slc2a5flox/flox:Tmem119-Cre-positive mice) were exposed to 25% fructose in drinking water for 8 weeks. We assessed metabolic parameters, anxiety- and depression-like behaviors using a battery of behavioral tests. We then performed RNA sequencing in several brain regions, including the hippocampus to characterize fructose-induced transcriptional changes. Microglial responsiveness to lipopolysaccharide (LPS) treatment was assessed in vitro and in vivo using immunohistochemistry (microglia morphology) and RT-qPCR (cytokine gene expression). Fructose feeding induced marked metabolic alterations and robust anxiety-like behavior in male mice, together with memory deficits, whereas females showed milder metabolic changes and memory impairment without clear emotional disturbances. RNA sequencing revealed that fructose alters microglial gene-expression profiles in the hippocampus. Microglial Glut5 knockdown prevented fructose-induced anxiety-like behavior in the novelty-suppressed feeding test, indicating that microglial fructose uptake is required for this effect. At the molecular level, physiological fructose exposure did not markedly increase microglial cytokine expression but blunted the cytokine response to lipopolysaccharide, consistent with a hypo-reactive microglial state. Overall, these findings identify microglia as a critical mediator of fructose-induced anxiety and suggest that chronic fructose exposure promotes a maladaptive microglial phenotype that disrupts brain circuit function, with potential implications for diet-related mental health risk.

neuroscience↗

bioRxiv2026

The constitutive androstane receptor protects against metabolic dysfunction-associated steatotic liver disease through sex specific interactions with the gut microbiota

Background: The gut-liver axis is involved in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), but the host molecular actors involved in such dialogue have not yet been fully characterized. Objective: We investigated the sex-dependent role of the Constitutive Androstane Receptor (CAR) as a hepatic sensor of microbial signals in MASLD pathophysiology. Design: Male and female Car+/+ and Car-/- mice were fed a western diet (WD) for 4, 14 or 35 weeks. We performed plasma biochemistry, liver histology, bile acid and cholesterol quantification, untargeted multi-omics approach combining liver RNA-sequencing and 16S rRNA sequencing, together with co-housing, fecal microbiota transplantation and analysis of publicly available transcriptomics data in human cohorts. Results: Short-term WD revealed CAR-dependent protection against steatosis, together with perturbations in the transcriptional signatures of multiple transcription factors involved in hepatocyte identity in males. After 14 weeks, CAR deletion increased WD-induced liver damage, inflammation and fibrosis, and disrupted bile acid, cholesterol and gut microbiota homeostasis, in males only. Co-housing and fecal microbiota transplantations revealed that a Car+/+ gut microbiota protected against WD-induced liver damage, while a Car-/- microbiota was reshaped by a Car+/+ host. No CAR-dependent phenotype was observed in females. Finally, in human cohorts, hepatic CAR expression decreased in advanced clinical stages of MASLD. Conclusion: CAR is a sex-dependent protective nuclear receptor against MASLD progression, acting both as a transcriptional regulator of hepatocyte identity and as a mediator of the host-microbiota crosstalk.

physiology↗

bioRxiv2026

Environmentally relevant bisphenol mixtures modify heart-brain physiology, cerebrovascular structures, and transcriptomic profiles in zebrafish larvae

Environmental exposure involves pollutant mixtures. Building on evidence that individual bisphenols alter zebrafish larval physiology and transcriptomic profiles at ng/L concentrations, we assessed the effects of specific mixtures of BPS, BPF, and BPAF without (M1) or with (M2) BPA. Experimentally, M1 and M2 induced 4.16% and 6.54% mortality in zebrafish larvae, despite the concentration addition model predicting no toxicity. Both mixtures reduced swimming-locomotor activities. These behaviors were accompanied by organ-level functional defects, as in vivo optical mapping revealed bradycardia and increased high-frequency (30-80 Hz) brain oscillations for both mixtures, while M2 additionally altered low-frequency (0.2-4 Hz) brain activity. The neurophysiological changes were accompanied by neurovascular remodeling, with in vivo two-photon microscopy revealing decreased vascular length and branching. Finally, transcriptomic analysis revealed common M1- and M2-induced alterations linked to pathways of vascular function, neuronal communication, and metabolism. M2 altered additional pathways of cardiac and neuronal signaling, consistent with the reported organ-physiology effects. We discuss the environmental relevance of mixture exposures and assess whether BPA intensifies mixture-induced responses.

pharmacology and toxicology↗

bioRxiv2026

PPARα-dependent effects in the liver and jejunum of mice in response to pemafibrate

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that plays a central role in metabolic adaptation by regulating gene expression programs involved in lipid utilization and energy homeostasis. Although the hepatic functions of PPAR and its target genes are well characterized, less is known about its transcriptional activity in extrahepatic tissues. Pemafibrate (K-877), a selective PPAR modulator (SPPARM), is a high-affinity PPAR ligand with improved potency and selectivity compared with conventional fibrates. Here, we investigated pemafibrate-induced tissue-specific transcriptional responses comparing wild type and whole-body PPAR-deficient littermate mice. Twelve-week-old male PPAR+/+ and PPAR-/- mice were treated daily with pemafibrate (0.1 mg/kg) or vehicle by oral gavage for 14 days. We performed genome-wide transcriptomic analyses in the liver, jejunum, kidney, soleus muscle, and BAT. Pemafibrate-induced transcriptional changes were entirely dependent on PPAR, as no differentially expressed genes were detected in PPAR-/- mice. The magnitude and nature of the response were tissue-specific, with the strongest transcriptional effects observed in the liver and jejunum, whereas the kidney, soleus muscle, and BAT showed limited responses. In the liver, pemafibrate primarily induced the expression of genes involved in fatty acid metabolism, mitochondrial function, and energy production. In the jejunum, pemafibrate activated lipid metabolic programs together with tissue-specific pathways related to cellular homeostasis. Collectively, our findings show that pemafibrate is a highly selective PPAR activator with a preferential transcriptional activity in the liver and intestine after oral administration. This study provides a resource for defining tissue-specific PPAR-responsive gene networks and expands our understanding of PPAR functions beyond the liver.

pharmacology and toxicology↗

bioRxiv2026

Diet modulates metabolic and hepatic responses to chronic pesticide mixture exposure in mice

Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed mice and exacerbated western diet-induced glucose intolerance, fasting hyperglycemia, and insulin resistance without affecting body weight or liver steatosis. These findings reveal that dietary context influences the metabolic consequences of pesticide mixtures, highlighting the need to consider nutritional status when evaluating environmental contaminant risks. Our results suggest that pesticide mixtures at reference doses may contribute to metabolic dysregulation, particularly under obesogenic dietary conditions. Highlights- Four common pesticides in mixture disrupt metabolism in liver cells - Dietary exposure to this pesticide mixture alters hepatic gene expression in mice - The pesticide mixture exacerbates WD-induced disruptions in glucose homeostasis - Pesticides and diet interact in producing the metabolic effects of a pesticide mixture

pharmacology and toxicology↗

bioRxiv2025

Soluble and insoluble dietary fibres differentially affect liver steatosis and gut microbiota in western-diet fed mice

ScopeMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic liver disease. An imbalance diet, rich in lipids and sugars and low in fibre, is a key contributing factor. However, there is limited knowledge about how soluble and fermentable dietary fibres, compared to insoluble and non-fermentable fibres, differently affect liver metabolism through their interactions with the intestinal microbiota. Methods and resultsMale mice housed at thermoneutrality were fed a Western Diet (WD) supplemented with fermentable inulin or non-fermentable cellulose for 18 weeks. Inulin supplementation mitigated WD-induced obesity, glucose intolerance, dyslipidemia and protected against WD-induced hepatic steatosis compared to cellulose. Hepatic gene expression changes induced by WD were attenuated with inulin. Additionally, inulin preserved gut microbiota composition and metabolism, indicating greater resilience against diet-induced perturbations. ConclusionThese findings suggest that soluble dietary fibres like inulin confer superior metabolic and hepatic benefits over insoluble fibres by modulating the gut microbiota-liver axis, highlighting their potential role in MASLD management.

physiology↗

bioRxiv2025

Hepatocyte FGF21 is not required for fasting-induced metabolic responses but guides protein appetite after energy depletion

Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we studied mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes did not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncovered a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.

physiology↗

bioRxiv2024

Effect of thermoneutral housing on MASLD severity, hepatic gene expression, and BAT activation during beta3-adrenergic stimulation in mice

Metabolic dysfunction-associated steatotic liver disease (MASLD), and its more advanced stage metabolic dysfunction-associated steatohepatitis, is the most common chronic liver disease, constituting a major public health issue. No medication is approved for MASLD treatment, and relevant preclinical models are needed to define molecular mechanisms underlying MASLD pathogenesis, and evaluate therapeutic approaches. Here we demonstrated that compared to standard temperature housing, thermoneutral housing aggravated western diet (WD)-induced obesity, diabetes, and steatosis in male mice, which was associated with increased hepatic expression of inflammation- and fibrosis-related genes. Accordingly, compared to standard-housed mice, thermoneutral-housed WD-fed mice developed more severe hepatic inflammation and fibrosis. The liver is the central metabolic organ in whole-body metabolic homeostasis. We used thermoneutrally housed mice with WD-induced MASLD to examine the effect of MASLD during {beta}3- adrenergic stimulation, and found that diet-induced MASLD was associated with defective inter- organ metabolic cross-talk, leading to impaired brown adipose tissue activation. HighlightsO_LIThermoneutral housing promotes WD-induced obesity and MASLD in mice C_LIO_LIThermoneutral housing fosters WD-induced change in gene expression C_LIO_LIThermoneutral housing fosters hepatic inflammation and fibrosis C_LIO_LIMASLD is associated with defective BAT response to {beta}3-adrenergic stimulation C_LI

physiology↗

bioRxiv2024

Maternal diet alters offspring early life host-microbiota communication through goblet cells, resulting in long-lasting diseases susceptibility

A crucial early-life developmental phase regulates microbiome settling while establishing critical and long-lasting immune and metabolic processes. During this period, the influence of select components of maternal diet on offspring microbiota and health remains largely unknown. To investigate the potential transgenerational impact of maternal exposure to microbiota-disrupting factors, dams were subjected prior breeding to dietary emulsifiers, known to directly perturb the microbiota. Such maternal exposure induced early-life microbiota alterations in offspring which associated with long-lasting susceptibility to diet-induced obesity and intestinal inflammation. These detrimental effects were entirely prevented by early-life microbiota normalization through cross-fostering procedures. Mechanistically, maternal emulsifier exposure induces strong offsprings impairment in goblet cells-mediated host-microbiota communication which is central in driving the observed long-lasting deleterious effects. To conclude, this study underscores the central role played by maternal intake of microbiota-disrupting agents on the next generations microbiota, with long lasting consequences for intestinal and metabolic health.

microbiology↗

bioRxiv2024

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is dependent on PI3K. We used mice lacking p110, the catalytic subunit of PI3K, to investigate its role in the regulation of liver gene expression in health and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). The absence of hepatocyte PI3K signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3K signaling. In addition, though PI3K deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3K, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110 in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.

cell biology↗

bioRxiv2023

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism

Background and AimsThe constitutive androstane receptor (CAR) is a nuclear receptor able to recognize a large panel of xenobiotics leading to the modulation of the expression of its target genes involved in xenobiotic detoxication and energy metabolism. While CAR hepatic activity is thought to be higher in women than in men, its response to an acute pharmacological activation has never been investigated in both sexes. MethodsHepatic transcriptome, plasma and hepatic metabolome, have been analyzed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or with vehicle. ResultsWhile 90% of TCPOBOP-sensitive genes were modulated in a sex- independent way, the remaining 10% were almost exclusively impacted in female liver specifically. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation and extracellular matrix organization. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Data mining on human data confirmed that CAR activation may be involved in sexually-dimorphic drug-induced liver injury. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and associated with a decrease of hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a possible role in the control of TMAO homeostasis, CAR activation decreased platelet hyperresponsiveness in female mice supplemented with dietary choline. ConclusionsOur results demonstrate that more than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic response such as platelet aggregation. Also, CAR activation may be an important mechanism of sexually- dimorphic drug-induced liver injury.

pharmacology and toxicology↗

bioRxiv2022

Obesity promotes Fumonisin B1 toxicity and induces hepatitis

Background and aimObesity is a major public health issue worldwide. Obesity is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. This toxin provokes severe mycotoxicosis in animals, which leads to hepatotoxicity and alterations in the immune response and intestinal barrier permeability. We investigated here whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. MethodsThe metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the last three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water. ResultsAs expected, HFD feeding induced significant body weight gain, glucose intolerance, and hepatic steatosis. FB1-exposed mice displayed a higher sphinganine/sphingosine ratio, a well-known FB1 biomarker of exposure, due to inhibition of ceramide synthases activity by FB1. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. ConclusionThese results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

pharmacology and toxicology↗

bioRxiv2021

The hepatocyte insulin receptor is required to program rhythmic gene expression and the liver clock

In mammalian cells, gene expression is rhythmic and sensitive to various environmental and physiological stimuli. A circadian clock system helps to anticipate and synchronize gene expression with daily stimuli including cyclic light and food intake, which control the central and peripheral clock programs, respectively. Food intake also regulates insulin secretion. How much insulin contributes to the effect of feeding on the entrainment of the clock and rhythmic gene expression remains to be investigated. An important component of insulin action is mediated by changes in insulin receptor (IR)-dependent gene expression. In the liver, insulin at high levels controls the transcription of hundreds of genes involved in glucose homeostasis to promote energy storage while repressing the expression of gluconeogenic genes. In type 2 diabetes mellitus (T2DM), selective hepatic insulin resistance impairs the inhibition of hepatic glucose production while promoting lipid synthesis. This pathogenic process promoting hyperlipidemia as well as non-alcoholic fatty liver diseases. While several lines of evidence link such metabolic diseases to defective control of circadian homeostasis, the hypothesis that IR directly synchronizes the clock has not been studied in vivo. Here, we used conditional hepatocyte-restricted gene deletion to evaluate the role of IR in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in adult mouse liver.

physiology↗

bioRxiv2021

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor (PPAR) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPAR has not been investigated. MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPAR. Finally, we tested the consequences of hepatocyte-specific PPAR deficiency during pharmacological induction of adipocyte lipolysis with a {beta}3-adrenergic receptor agonist. ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPAR target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPAR. Adipose tissue lipolysis induced by acute activation of the {beta}3-adrenergic receptor also triggered PPAR-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPAR activity. In addition, the absence of hepatocyte PPAR altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the {beta}3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPAR showed decreased tolerance to acute cold exposure. ConclusionsThese results underscore the central role of hepatocyte PPAR in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPAR activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.

physiology↗

bioRxiv2018

Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

ObjectivesPeroxisome proliferator activated receptor (PPAR) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Ppar in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPAR in a preclinical model of steatosis.\n\nMethods/ResultsWe have investigated the role of hepatocyte PPAR in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Ppar-/-) mice and in mice lacking Ppar in hepatocyte (Pparhep-/-). We provide evidence that Ppar deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPAR activity predominantly contributes to the metabolic response to HFD.\n\nConclusionTaken together, our data support hepatocyte PPAR as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPAR activity contributes to whole-body lipid homeostasis.\n\nHighlightsO_LIPpar deletion in hepatocytes promotes steatosis and inflammation in HFD-induced obesity\nC_LIO_LIHepatocyte-specific deletion of Ppar dissociates NAFLD from glucose intolerance in HFD-induced obesity obesity\nC_LIO_LIExtrahepatic PPAR activity contributes to the metabolic response to HFD-induced obesity\nC_LI

pathology↗