Biology subjects

Maggi, A.

Publications and source records attributed to Maggi, A..

3 recordsLinked to original sources

bioRxiv2026

Hepatic estrogen receptor α is required for stage-specific coupling of liver metabolism and proliferation during pregnancy

Background and AimsPregnancy requires dynamic, stage-specific adaptations in maternal liver metabolism and growth to sustain fetal development while preserving systemic homeostasis. Estrogen signaling, which significantly increases during pregnancy, is primarily mediated in hepatocytes by estrogen receptor (ER). Although hepatic ER regulates female liver metabolism under non-pregnant conditions, its role in pregnancy-induced hepatic remodeling remains unclear. MethodsWe studied non-pregnant and pregnant control and liver-specific ER knockout (LERKO) mice across gestational stages using longitudinal physiological measurements, liver transcriptomics, targeted metabolomics, histological assessment of cell proliferation, and metabolic phenotyping. ResultsIn control mice, pregnancy elicited sequential hepatic remodeling characterized by early induction of cell-cycle programs, a mid-gestational peak in hepatocyte proliferation with transient suppression of selected metabolic pathways, and late reactivation of specific metabolic programs. Chronic hepatic ER deficiency alters this temporal pattern. LERKO livers showed premature activation of proliferative and anabolic transcriptional programs, changes in amino acid- and fatty acid-related metabolic pathways, and altered temporal regulation of AKT-mTORC1-related signaling. At mid-gestation, LERKO mice displayed reduced hepatocyte proliferation, altered expression of metabolic and insulin-related genes, blunted gestational glucose adaptation without overt evidence of systemic insulin resistance, and changes in the light/dark-phase metabolic patterns. ConclusionsThese findings suggest that hepatic ER is required for the appropriate stage-specific coupling of liver growth, metabolic remodeling, and insulin-responsive signaling during pregnancy. Its loss is associated with gestational hepatic maladaptation and systemic metabolic phenotypes, providing a framework for investigating estrogen-dependent mechanisms underlying pregnancy-associated metabolic and liver disorders. HighlightsHepatic ER is required for stage-specific liver remodeling during pregnancy. Loss of hepatic ER alters temporal coupling of liver growth and metabolism. LERKO mice show early changes in amino acid- and fatty acid-related pathways. Hepatic ER loss reduces proliferation and alters gestational glucose adaptation. Hepatic ER loss is associated with altered light/dark-phase metabolic organization. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/743939v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@53d7a5org.highwire.dtl.DTLVardef@7294e1org.highwire.dtl.DTLVardef@8c7660org.highwire.dtl.DTLVardef@1af9d02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

MyoRep: a novel reporter system to detect early muscle atrophy in vitro and in vivo

Muscle atrophy occurs during physiological (i.e., fasting, aging) and pathological (i.e., amyotrophic lateral sclerosis, cancer) conditions and anticipates death. Since not all patients will undergo muscle wasting, it would be highly useful to identify them soon to intervene early. We have studied the promoters/enhancers of a subset of atrophy-related genes or atrogenes upregulated in muscles of rodents during various kinds of atrophy (i.e., disuse, diabetes, cancer, fasting, uremia) for their ability to induce early atrophy. Comparing their upstream non-coding regions, using as backbone MuRF1 promoter (one of the earliest muscle-specific genes induced by wasting), we cloned various promoters upstream of a doubled reporter system (FLuciferase/tdTomato). Through in vitro and in vivo studies in mice subjected to denervation or cancer injection, we selected a sequence (i.e., MyoRep) able to predict atrophy upon cut of the sciatic nerve or cancer. In vivo imaging of MyoRep mice emit a bioluminescent signal earlier than muscle loss. Importantly, MyoRep was unable to sense atrophy during fasting or physiological variations following the circadian rhythms. Since MyoRep can discriminate muscle loss due to pathological conditions from physiological ones anticipating wasting, it represents an unprecedented tool to predict it early in various diseases with local or systemic atrophy.

genetics↗

bioRxiv2021

Inhibition of microglial GBA hampers the microglia-mediated anti-oxidant and protective response in neurons

Homozygotic mutations in the GBA gene cause Gauchers disease, moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinsons disease. In homozygosis, these mutations impair the activity of {beta}-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gauchers disease. In the brain, most of the pathological effects caused by GBA mutations have been attributed to the {beta}-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Here, we applied the bioluminescence imaging technology, immunohistochemical and gene expression analysis to investigate the consequences of microglial {beta}-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia co-cultures and in cell lines. Our data demonstrate the existence of a novel mechanism by which microglia sustain the antioxidant/detoxifying response mediated by the nuclear factor erythroid 2-related factor 2 in neurons. The central role played by microglia in this neuronal response in vivo was proven by pharmacological depletion of the lineage in the brain, while co-cultures experiments provided insight on the nature of this cell-to-cell communication showing that this mechanism requires a direct microglia-to-neuron contact supported by functional actin structures. Pharmacological inhibition of microglial {beta}-glucocerebrosidase was proven to induce morphological changes, turn on an anti-inflammatory/repairing pathway and hinder the microglia ability to activate the anti-oxidant/detoxifying response, thus increasing the neuronal susceptibility to neurotoxins. Altogether, our data suggest that microglial {beta}-glucocerebrosidase inhibition impairs microglia-to-neuron communication increasing the sensitivity of neurons to oxidative or toxic insults, thus providing a possible mechanism for the increased risk of neurodegeneration observed in carriers of GBA mutations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/427380v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@15c2c3corg.highwire.dtl.DTLVardef@5c4e34org.highwire.dtl.DTLVardef@12718dorg.highwire.dtl.DTLVardef@dcfeca_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefMicroglia, through actin-dependent structures, contact neurons and induce a detoxification response by increasing the NFE2L2 signalling pathway. Inhibition of GCase activity by CBE treatment produces a morpho-functional change in microglia cells hampering the neuroprotective microglia-neuron communication thus inducing a phenotype in dopaminergic neurons characterized by increased susceptibility to oxidative stress or toxic insults.

neuroscience↗