Biology subjects

Fioramonti, X.

Publications and source records attributed to Fioramonti, X..

7 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

Low-molecular-weight Ulva lacinulata extract exhibiting anti-inflammatory and pro-autophagic activities in RAW 264.7 macrophages: a promising candidate for the development of active ingredients targeting low-grade inflammation

Marine macroalgae are valuable sources of bioactive compounds. In this study, we thus investigated the chemical composition and biological activity of an extract from the green seaweed Ulva lacinulata, composed of small bioactive compounds. Comprehensive compositional analyses and high-resolution mass spectrometry revealed its diverse molecular profile composed in particular of peptides/amino acid derivatives, saccharides, low-chain fatty diacids, oxylipins and minerals. Its anti-inflammatory activity was assessed after 6 h pre-treatment in LPS-stimulated cultured RAW 264.7 macrophages, showing that it significantly and dose-dependently reduced the expression and/or secretion of pro-inflammatory cytokines such as TNF- and IL-6, and targeted the NF-{kappa}B signaling cascade. It modulated the SIRT1-AMPK signaling axis and increased the LC3-II/LC3-I ratio, supporting the activation of a controlled autophagic response. This work highlighted the potential of this marine-derived extract as a safe and effective functional ingredient for the development of functional food and/or dietary supplements targeting chronic low-grade inflammation.

biochemistry↗

bioRxiv2025

Western diet reversibly alters the olfactory mucosa and impairs the response to appetitive food cues

Current feeding behaviors contribute to the epidemic levels of obesity and diabetes observed in Europe and worldwide. Together with other sensory modalities, olfaction is involved in the control of food intake. Olfactory cues can influence eating behaviors, yet the nutritional status and diet can also alter olfactory abilities. Patients with metabolic disorders present impaired olfactory sensitivity which could in turn worsen their eating behaviors. Here we examined the short-term impact of a Western diet enriched in fat and sugar (High-Fat High-Sugar, HFHS) on the anatomy and physiology of the olfactory epithelium of mice. After 8 weeks of diet, HFHS fed animals presented higher adiposity without overweight, were glucose intolerant without any change in basal blood glucose or plasma insulin. A buried food test indicated impaired olfactory capacities in the HFHS group. Whereas food related odours increased food intake in control chow fed animals, HFHS mice showed an altered response to olfactory appetitive food cues. HFHS fed mice presented olfactory sensory neurons (OSN) with shorter cilia. Finally, electro-olfactogram (EOG) recorded in response to different odorant molecules showed lower amplitudes in HFHS fed mice. HFHS diet withdrawal during one month at the end of the HFHS diet exposure improved metabolic parameters and restored both the OSN cilia length and EOGs. Our results show that diet enriched in fat and sugar can rapidly alter the physiology of the olfactory epithelium before the development of significant metabolic disorders. Anatomical changes of individual olfactory sensory neurons may participate to the reduced olfactory sensitivity.

neuroscience↗

bioRxiv2025

Nucleus raphe magnus serotonin neurons bidirectionally control spinal mechanical pain transmission

BackgroundNoxious stimuli are conveyed to and integrated in the dorsal horn of the spinal cord (DHSC) before being transmitted to supraspinal centers, where pain perception is generated. Descending pathways from the brainstem dynamically modulate this integration, either facilitating or inhibiting nociceptive information based on physiological, emotional, genetic and environmental factors. Serotonergic neurons in the nucleus raphe magnus (NRM), activating different spinal 5-HT receptors, exert bidirectional control, both facilitatory and inhibitory, but the underlying mechanisms of this control remain unclear. MethodsWe investigated in adult mice, the NRM serotonergic modulation of nociception using imaging, behavioral, pharmacological, electrophysiological, chemogenetic and optogenetic approaches. ResultsWe have demonstrated that the action of serotonergic neurons in the NRM on spinal nociceptive transmission depends on their activation pattern, which targets different spinal 5-HT receptors likely associated with different spinal microcircuits. Serotonergic neurons of the NRM exert a tonic analgesic effect mediated by 5-HT2c receptor. Low increase in 5-HT activity leads to an increased analgesia through spinal inhibitory interneurons expressing 5-HT2c and 5-HT2A receptors. Finally, prolonged stimulation of serotonergic neurons led to hyperalgesia mediated by 5-HT3 receptor. Comparison of 5-HT receptors in spinal tissue from mice and human shows that 5-HT2c receptor has a very high expression level, comparable between both species. ConclusionsThese results propose a model of bidirectional action of serotonin neurons on nociceptive transmission depending on their level of activity and show that 5-HT2c receptor is the main mediator of serotonin-induced analgesia.

neuroscience↗

bioRxiv2025

Fructose malabsorption induces dysbiosis and increases anxiety in Human and animal models

Background & AimsExcessive fructose intake is a growing public health concern, yet many individuals have a lower absorption capacity than the average intake, leading to widespread chronic fructose malabsorption. This results in intestinal fructose spillover, disrupting gut microbiota and triggering peripheral inflammation, which, along with neuroinflammation, plays a key role in mood disorders. This study investigates the connection between fructose malabsorption and mood disorders by examining gut microbiota changes in a human cohort and exploring their links with neuroinflammation in a GLUT5-KO mouse model. MethodsIn a human cohort, fructose malabsorption was assessed using a breath hydrogen test, while plasma lipopolysaccharide (LPS) levels and anxiety traits (measured using the State-Trait Anxiety Inventory, STAI) were analyzed. Gut microbiota composition was characterized through 16S rRNA sequencing, and dietary fructose intake was recorded. In the preclinical study, Glut5-KO mice, which lack intestinal fructose transport, were fed a 5% fructose diet for four weeks. Behavioral assays assessed anxiety- and depressive-like behaviors, while gut microbiota composition and microglia-associated gene expression were analyzed. ResultsAmong the recruited healthy volunteers, 60% exhibited fructose malabsorption, along with elevated plasma LPS levels, increased anxiety traits on the STAI, and distinct gut microbiota alterations, partially linked to fructose intake patterns. The average daily fructose intake was 30 g per individual, with significant variability in dietary sources. In the preclinical model, Glut5-KO mice on a 5% fructose diet displayed increased anxiety- and depressive-like behaviors, pronounced gut microbiota shifts, and altered expression of microglia-associated genes. ConclusionsThese findings highlight the complex interplay between dietary fructose, gut microbiota, and neuroinflammation in shaping mental health. Chronic fructose malabsorption may contribute to mood disorders through gut dysbiosis and microglia-dependent neuroinflammation, warranting further investigation into dietary interventions. HIGHLIGHTSO_LIFructose malabsorption is associated with anxiety traits in healthy volunteers. C_LIO_LIFructose malabsorption enhances anxiety-like behaviors in malabsorptive Glut5-KO mice. C_LIO_LIFructose malabsorption is associated with gut microbiota dysbiosis in human and preclinical mouse model of fructose malabsorption in association with fructose intake C_LIO_LIFructose malabsorption increases neuroinflammation and alters microglia functions in malabsorptive Glut5-KO mice. C_LI

microbiology↗

bioRxiv2023

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1{beta} and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.

neuroscience↗

bioRxiv2023

A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We demonstrate that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an 2-adrenergic receptor agonist, highlighting the functional implication of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. These findings identify a novel top-down neural mechanism engaged by OB GLP-1 signaling to control insulin secretion via the SNS.

physiology↗