Biology subjects

Postic, C.

Publications and source records attributed to Postic, C..

9 recordsLinked to original sources

bioRxiv2025

Hepatocyte ERα orchestrates sex-specific liver adaptation to fasting and feeding states

Sex differences in hepatic physiology are thought to influence individual susceptibility to chronic liver diseases including Metabolic-Associated Steatotic Liver Disease (MALSD). Previous studies demonstrated the central contribution of estrogens which primarily influence liver biology through the activation of Estrogen Receptor alpha (ER). However, how ER signaling in hepatocyte modulates liver functions according to the nutritional status, a critical determinant of hepatic metabolism, remains to be characterized. The present study first reveals the nycthemeral expression profile of liver ER, which peaks during the feeding period (ZT16) in both male and female mice. ER expression is altered by reprogramming the hepatic circadian clock in response to inverted food intake, highlighting the influence of feeding on liver ER expression patterns. As ER is mainly expressed in hepatocytes both in human and mouse livers, the functional role of hepatocyte ER during fasting or feeding state was then delineated, using mice harboring ER hepatocyte-specific deletion (ERhep-/-) compared with their wild-type littermates (ERhep+/+). Transcriptomic analyses reveal significant sex differences in the adaptation of liver functions to this contrasted nutritional status, as well as the sex-specific regulatory effects of hepatocyte ER. In such physiological settings, hepatocyte ER deletion does not influence liver transcriptomic profiles in males but significantly alters gene expression in female livers, both fed and fasted conditions. Hepatocyte ER more specifically controls genes associated with inflammatory responses and fatty acid metabolic pathways in females, modulating the ChREBP and PPAR pathways in feeding or fasting states, respectively. Thus, hepatocyte ER is integral to liver metabolic adaptations to fasting and feeding in females but not in males, thus exhibiting both sex-specific and diet-dependent actions. Further characterizing sex differences in liver metabolic flexibility, these results provide new information to develop sex-based strategies for the prevention and management of MASLD.

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↗

bioRxiv2025

The gut insulin receptor acts as gatekeeper of intestinal barrier integrity

An impaired gut barrier has emerged as a potential driver of the low-grade inflammation that accompanies obesity and its complications. Among these, hyperglycemia per se has been proposed to sustain such increased intestinal permeability and subsequent translocation of bacterial endotoxins in the systemic circulation. Because reduced insulin signaling in the gut epithelium has also been reported upon obese conditions, we hypothesized that, beyond hyperglycemia, defective intestinal insulin signaling could directly compromise epithelial integrity. To mimic this diabesity feature, we induced deletion of the insulin receptor (IR) in the adult gut epithelium of IR{Delta}GUT mice. Remarkably, gut IR loss persistently maintained normal body weight and glucose homeostasis, thereby allowing the specific role of insulin action to be investigated. While IR{Delta}GUT mice exhibited increased intestinal paracellular permeability, mechanistic characterization of this gut leakiness revealed that IR{Delta}GUT mice displayed a rapid and drastic decline in Paneth cells anti-microbial defenses. This paralleled the onset of a cecal dysbiosis, as characterized by increased abundance of Pseudomonadota, and enhanced microbiota encroachment. Of note, IR{Delta}GUT mice exhibited intestinal stem cell (ISC) defects, as evidenced by reduced expression of ISC markers and ISC-mediated growth of intestinal organoids. Although expression of niche factors such as Wnt3a was diminished in Paneth cells isolated from IR{Delta}GUT mice, pharmacological activation of the canonical Wnt pathway failed to rescue the growth defects of IR-deleted gut organoids. The direct contribution of IR-downstream signaling to ISCs homeostasis was confirmed by the transcriptional reprogramming of FACS-sorted ISCs from IR{Delta}ISC mice. Finally, while gut IR loss did not worsen endotoxemia or impaired glycemic control upon HFD-feeding, IR{Delta}GUT displayed a higher susceptibility to chemically induced colitis and enteric infections (S. typhimurium, C. rodentium), underscoring intestinal insulin signaling as a key determinant of barrier integrity and epithelial homeostasis.

physiology↗

bioRxiv2021

Loss of intestinal ChREBP impairs absorption of dietary sugars and prevents glycemic excursion curves

Increased sugar consumption is a risk factor for features of the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease. The gut epithelium, which plays a central role in dietary sugar digestion, absorption and metabolism has emerged a key actor of metabolic disorders. While the transcription factor ChREBP (Carbohydrate response element binding protein) has been established as a key player of the adaptive reprograming of cellular metabolism in various tissues upon glucose or fructose challenge, its specific contribution to the regulation of blood glucose upon dietary sugar intake was not previously addressed. We demonstrate here that ChREBP is abundantly expressed in the proximal gut epithelium, where carbohydrate digestion and absorption primarily occur and in particular L cells, which produce the glucoincretin GLP-1. The inducible deletion of ChREBP specifically in the mouse gut epithelium (Ch{Delta}GUT mice) resulted in the reduction of early glycemic excursion upon oral glucose load. Surprisingly, despite being associated with reduced GLP-1 production, loss of gut ChREBP activity significantly dampened glucose transepithelial flux, and thereby delayed glucose distribution to peripheral tissues. Among the underlying mechanisms, we unveil that Ch{Delta}GUT mice show an impaired expression of key intestinal hexose (glucose, galactose, fructose) transporters and metabolic enzymes as well as brush border dissacharidases. In agreement, intestinal ChREBP deficiency was accompanied by a precocious intolerance to both high-lactose and high-sucrose diets concomitant with mild galactose and severe fructose malabsorption syndromes. Altogether, our study demonstrates that, by transcriptionally orchestrating local digestion and absorption of dietary sugars, ChREBP activity in the mouse gut epithelium controls glucose appearance rate into systemic circulation and prevents against intolerance to mono- and disaccharides.

physiology↗

bioRxiv2021

A Creb3-Like Transcription Factor Coordinates ER Function uponFood Intake to Regulate Lipid Metabolism

Ingestion of nutrients elicits essential physiological responses, including absorption, digestion, cessation of feeding and nutrient storage. The endoplasmic reticulum (ER) is central to this nutritional homeostasis, since it regulates intracellular organelle function, drives intercellular communication and promotes metabolite distribution. We identified the Drosophila Creb3L-family transcription factor, CrebA, as the key metabolic regulator of ER function, thereby affecting lipid metabolism and feeding behavior. In response to feeding, CrebA activity is rapidly and transiently activated. CrebA directly drives the expression of the ER protein sorting machinery. We demonstrate that CrebA levels regulate lipid metabolism through lipoprotein secretion into the hemolymph and suppress feeding behavior. Further, CrebA mouse homologs are also upregulated in the liver following feeding and drive the transcriptional activation of ER protein sorting machinery genes in mammals. Our results reveal an evolutionarily conserved transcription switch which is turned on in response to food ingestion and orchestrates a negative feedback loop that promotes satiety by regulating ER function and protein secretion.

cell biology↗

bioRxiv2021

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXR activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXR. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXR axis during NAFLD.

pathology↗

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↗