Biology subjects

Gastaldelli, A.

Publications and source records attributed to Gastaldelli, A..

8 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↗

bioRxiv2026

Beige/brown fat-mediated cardiac protection from high-fat diet is dependent on adipocyte beta3-adrenergic receptor

Cardiometabolic diseases associated with obesity are continuously increasing worldwide. Yet, current therapeutic strategies remain insufficient to improve patient outcomes. The beta3-adrenergic receptor ({beta}3AR) promotes lipolysis in adipose tissue (AT) and thermogenesis specifically in brown adipose tissue (BAT). In mice, BAT activation also improves systemic metabolism and limits cardiometabolic damage. While BAT is limited in humans (e.g., with ageing and obesity), {beta}3AR activation induces beige adipocytes within white adipose depots with similar thermogenic properties. To study the role of adipocyte {beta}3AR in the regulation of cardiac metabolism and remodeling, mice with/without adipocyte-specific {beta}3AR genetic deletion were fed a high-fat-sucrose (HF-S) diet and treated with the selective {beta}3AR agonist CL316,243 (CL). The metabolic and cardiac protection following {beta}3AR activation was abrogated upon {beta}3AR deletion in adipocytes, together with the beiging of the epididymal (visceral) AT, highlighting a critical role of adipose {beta}3AR signalling in mediating these benefits. Multi-omic analysis of AT and cardiac samples identified CL-induced secreted mediators of the crosstalk between AT and the heart. Therefore, adipocyte {beta}3AR is critical for the adipose-cardiac communication and supports the therapeutic potential of targeting {beta}3AR for the management of obesity-related cardiometabolic diseases.

systems biology↗

bioRxiv2025

CD300e Controls Macrophage Lipid Handling and Safeguards Adipose Tissue Function in Obesity

Previous studies in monozygotic twins discordant for body mass index (BMI) revealed that obese individuals exhibit elevated expression of the immune receptor CD300e in white adipose tissue (WAT). Notably, CD300e levels decreased following weight loss, implicating its involvement in adipose tissue remodeling and metabolic regulation. To elucidate the functional role of CD300e, we employed a Cd300e knockout (Cd300e-/-) mouse model subjected to a high-fat diet (HFD). Our findings demonstrate that CD300e deficiency exacerbates obesity-associated metabolic dysfunction, including increased weight gain, adipocyte hypertrophy, hepatic steatosis, and impaired glucose and insulin sensitivity. Adipose tissue macrophages (ATMs) lacking CD300e displayed reduced lipid and glucose uptake, alongside diminished mitochondrial respiration--a phenotype consistent with a broader metabolic impairment, as evidenced by proteomic profiling. These metabolic deficits were genotype-dependent and persisted after 16 weeks of HFD. Concurrently, adipocytes from Cd300e-/- mice exhibited enhanced lipogenesis and attenuated lipolysis. Remarkably, the impaired metabolic fitness exhibited by Cd300e-/- mouse macrophages was recapitulated in human cells upon gene silencing. Collectively, these results establish CD300e as essential for ATM metabolic activation, positioning it as a key regulator of adipose tissue homeostasis and a critical mediator of obesity-induced metabolic dysfunction. Given its pivotal role, CD300e emerges as a promising therapeutic target for modulating adipose tissue function and improving metabolic health in obesity.

immunology↗

bioRxiv2025

Succinate Modulation as a Novel Mechanism Underlying the Effects of Intermittent Fasting on Brain Function and Metabolism in Diet-Induced Obesity

Obesity significantly impacts the central nervous system (CNS), increasing risks of neuropsychiatric disorders and dementia. Intermittent fasting (IF) shows promise for improving peripheral and CNS health, but its mechanisms are unclear. Using a diet-induced obesity mouse model (10 weeks high fat diet (HFD), then 4 weeks intervention), we compared HFD, HFD-IF, ad libitum control chow (CC), and CC-IF groups. Switching to CC or IF reduced body weight, fat mass, and improved glucose tolerance. Notably, CC-IF uniquely enhanced exploration and reduced anxiety-like behavior. Transcriptomics revealed HFD-induced hippocampal neuroinflammation, while metabolomics identified a specific succinate signature in CC-IF mice: plasma concentration decreased while liver and brown adipose tissue (BAT) levels increased. Succinate supplementation mimicked CC-IF metabolic and behavioral benefits and reduced hippocampal inflammation. These findings suggest that regulating plasma succinate and its metabolism in liver and BAT may represent a novel mechanism underlying the metabolic, neuroinflammatory, and behavioral improvements induced by IF.

neuroscience↗

bioRxiv2024

MAPK15 Protects Against The Development Of Metabolic Dysfunction-Associated Steatotic Liver Disease

Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. As liver injury progresses to metabolic dysfunction-associated steatohepatitis (MASH), MASLD can predispose individuals to cirrhosis and hepatocellular carcinoma. Here, we characterized the first knockout mouse model for mitogen-activated protein kinase 15 (MAPK15) and revealed its critical role in controlling lipid homeostasis in the liver. Indeed, Mapk15-/- mice exhibited a MASLD-like phenotype, and hepatocellular models allowed us to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a MASH-like phenotype. Ultimately, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, compared to unaffected individuals, ultimately supporting a protective role for MAPK15 against this disease. Overall, our data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintain physiological intracellular levels of lipids in this tissue.

cell biology↗

bioRxiv2022

Adipose tissue dysfunction and visceral fat are associated to hepatic insulin resistance and severity of NASH even in lean individuals

Background & AimsNonalcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue (AT) dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance (IR) and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (that is mainly subcutaneous fat, SC-AT), it is still unclear the impact of visceral fat (VF). Thus, we investigated how VF vs. SC-AT were related to NAFLD in lean, overweight, and obese individuals compared to lean controls. MethodsThirty-four non-diabetic NAFLD with liver biopsy and eight lean control individuals (CT) were enrolled in this study. We measured fat distribution (VF, SC-AT and IHTG) by magnetic resonance imaging (MRI), adiponectin concentration, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition by mass spectrometry (MS), lipolysis and IR by tracer infusion. ResultsIHTG was positively associated with lipolysis, adipose tissue IR, TG concentrations, and increased ratio of saturated/unsaturated fatty acids. VF was higher in NAFLD (including lean individuals) compared to controls, was increased with fibrosis stage and was associated with IR in liver, muscle and adipose tissue, increased lipolysis, and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD. ConclusionsThese findings propose VF as an early indicator of NAFLD independently of BMI, which may allow for evidence-based prevention and intervention strategies.

physiology↗

bioRxiv2021

Assessment of exposure to Di (2-ethylhexyl) phthalate (DEHP) metabolites and Bisphenol A (BPA) and its importance for the prevention of cardiometabolic diseases

Exposomics analyses have highlighted the importance of biomonitoring of human exposure to pollutants, even non-persistent, for the prevention of non-communicable diseases like obesity, diabetes, non-alcoholic fatty liver disease, atherosclerosis and cardiovascular diseases. Phthalates and bisphenol A (BPA) are endocrine disrupting chemicals (EDCs) widely used in industry and in a large range of daily life products that increase the risk of endocrine and cardiometabolic diseases especially if the exposure starts during childhood. Thus, it is important the biomonitoring of exposure to these compounds not only in adulthood but also in childhood. This was the goal of the LIFE-PERSUADED project that measured the exposure to phthalates (DEHP metabolites, MEHP, MEHHP, MEOHP) and BPA in Italian mother-children couples of different ages. In this paper we describe the method that was set up for the LIFE PERSUADED project and validated during in the proficiency test (ICI/EQUAS) showing that accurate determination of urinary phthalates and BPA can be achieved starting from small sample size (0.5ml) using two MS techniques applied in cascade on the same deconjugated matrix.

pharmacology and toxicology↗

bioRxiv2020

TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models

Background and aimsThe I148M PNPLA3, the rs641738 in MBOAT7/TMC4 locus and the E167K TM6SF2 polymorphisms represent the main predisposing factors to non-alcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for the I148M PNPLA3. Therefore, we aimed to:1) investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients;2) create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. MethodsNAFLD patients (n=1380) of whom 121 had HCC were stratified with a semi-quantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2 and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through CRISPR/Cas9. ResultsIn NAFLD patients, the additive weight of these mutations was associated with liver disease severity and increased risk to develop HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of micro-vesicular LDs, whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed micro/macro pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum (ER) and mitochondria ultrastructures thus increasing ER/oxidative stress. Mitochondrial number raised in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift towards anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. ConclusionsThe co-presence of the 3 at-risk variants impacts on NAFLD course, in both patients and experimental models affecting LDs accumulation, mitochondrial functionality and metabolic reprogramming towards HCC.

genetics↗