Biology subjects

Bartolomucci, A.

Publications and source records attributed to Bartolomucci, A..

9 recordsLinked to original sources

bioRxiv2026

Identification of an Endothelial Senotype Predicted by Ion Channel Expression in Aged Murine Perigonadal Adipose Tissue

Adipose tissue plays a key role in metabolic health, contributing to systemic dysfunction upon obesity or aging. A major driving factor of adipose-driven dysfunction is the accumulation of senescent cells (SnCs), but identification and characterization of specific SnCs is limited. To identify age-dependent SnCs, we performed snRNA-Seq on young and old adipose using two independent analytical strategies. The first, a SenMayo-based approach and the second, dependent on SEAC guidelines and Pearson correlation identified senescent nuclei in endothelial clusters. Subsequent subclustering and cell-to-cell communication analyses identified endothelial capillary nuclei that overexpress macrophage migration inhibitory factor (Mif), which exemplifies the specific characteristics and microenvironment of SnCs. Finally, rank analysis identified ion channel transport genes as the most predictive of the SnCs. Overall, these results highlight new defining features of senescence in endothelial adipose tissue and provide novel age-dependent biomarkers.

cell biology↗

bioRxiv2026

Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis

Somatic mosaicism contributes to genomic variation, yet postzygotic structural variants remain under-characterized. We performed long- and short-read WGS from multiple individuals (n=47 normal tissues; n=168 samples) and identified mosaic structural variants in all individuals and germ layers, impacting a median 285.2 kb/genome. Nearly half of breakpoints were independently validated, with tissue distributions reflecting both early and late developmental origins. Most mosaic variants were repeat-mediated and 8.3% overlapped functional elements, an enrichment compared to germline variants. To extend these analyses in samples where long-read sequencing is infeasible, we measured repeat alterations from short-read sequencing, recapitulating mosaic tissue-specific differences. We characterized tumor- and tissue- specific variation in repeats across 15 cancer types and found tumor-related repeat variation to be similar in scale to that of normal mosaic variation. Tracking repeat changes in cell-free DNA provided a noninvasive approach for tumor monitoring. Our analyses revealed widespread repeat-driven structural variation in health and disease.

genomics↗

bioRxiv2026

Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation and obesity

Microglia, the resident macrophages of the central nervous system, are recognized for their heterogeneity and integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive, acquiring a prevailing lipid associated microglial phenotype (also known as LAM). Yet, how microgliosis is induced and regulated remains unclear. Here we report a key role for the Complement 3a Receptor (C3aR), on HFD-induced hypothalamic gliosis and weight gain in mice. HFD consumption leads to elevated microglial expression of C3aR, which parallels widespread accumulation of reactive microglia, selectively in the hypothalamus. Conditional microglial C3aR deletion protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male but not female mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation, and acquisition of a LAM molecular signature. In summary, we uncovered a previously unknown role for C3aR in the acquisition of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.

immunology↗

bioRxiv2025

The AhR is a Critical Regulator of the Pulmonary Response to Cannabis Smoke

Cannabis use is prevalent worldwide, with smoking being the most common method of consumption. When smoking cannabis, users are exposed to both harmful combustion products as well as cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD). THC and CBD have purported anti-inflammatory effects through activation of cannabinoid receptors; however, the minimal expression of these receptors in lung tissue suggests that respiratory effects of cannabis may be mediated through alternative pathways. One potential mediator of these effects is the aryl hydrocarbon receptor (AhR), a transcription factor involved in xenobiotic metabolism. Notably, the AhR is activated by both combustion products and cannabinoids. This receptor is also known to dampen lung inflammation induced by tobacco smoke or air pollution. Therefore, we hypothesized that AhR activation would reduce susceptibility to the harmful effects of inhaled cannabis smoke. To investigate this hypothesis, Ahr+/- and Ahr-/- mice were exposed to air or cannabis smoke using a controlled puff regimen over a three-day period. In the first study to characterize the effects of cannabis smoke on lung tissue and the pulmonary secretome, including extracellular vesicles and secreted proteins, we found that acute exposure induced neutrophilia, vascular leakage, and activation of tissue remodeling pathways, all of which were regulated by AhR. These findings highlight not only the detrimental effects of cannabis smoke on lung health but also the pivotal role of the AhR as a key regulator of the pulmonary response to cannabis smoke exposure.

pharmacology and toxicology↗

bioRxiv2025

Ketone body driven lipid remodeling supports thermogenic adaptation to fasting

Metabolic adaptation to fasting may have conferred survival advantage to early humans and predicts weight gain caused by overnutrition in modern societies. Fasting suppresses brown adipose tissue (BAT) thermogenesis; however, it is unclear how BAT rewires cellular metabolism to balance between energy conservation and heat generation. Here, we report that BAT in mice under fasting and cold challenge consumed ketone bodies, specifically acetoacetate (AcAc). Ablating liver ketogenesis decreased, while enhancing hepatic AcAc output defended, body temperature in mice facing the dual challenge. Using stable isotope tracing in brown adipocytes in vitro combined with quantitative analysis of metabolic fluxes and lipidomics in BAT from genetic mouse models, we disentangled the two metabolic fates of AcAc - terminal oxidation in the mitochondria and lipid biosynthesis in the cytosol. Notably, AcAc-sourced carbon preferentially supported polyunsaturated fatty acid synthesis in BAT, linking to the positive impact of intermittent fasting on lipid profiles in both mice and humans. Therefore, ketone body utilization by thermogenic adipocytes contributes to metabolic resilience of mammals and can be targeted to optimize benefits of dietary regimens.

physiology↗

bioRxiv2023

Hepatic lipid-associated macrophages mediate the protective effects of bariatric surgery against NASH

For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Here we report that VSG ameliorates MASH progression in a weight loss- independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) increase their lysosomal activity and repress inflammation in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytotic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by hepatic LAMs, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.

physiology↗

bioRxiv2023

Targeted and selective knockout of the TLQP-21 neuropeptide unmasks its unique role in energy homeostasis

Pro-peptide precursors are processed into biologically active peptide hormones or neurotransmitters, each playing an essential role in physiology and disease. Genetic loss of function of a pro-peptide precursor results in the simultaneous ablation of all biologically-active peptides within that precursor, often leading to a composite phenotype that can be difficult to align with the loss of specific peptide components. Due to this biological constraint and technical limitations, mice carrying the selective ablation of individual peptides encoded by pro-peptide precursor genes, while leaving the other peptides unaffected, have remained largely unaddressed. Here, we developed and characterized a mouse model carrying the selective knockout of the TLQP-21 neuropeptide ({Delta}TLQP-21) encoded by the Vgf gene. To achieve this goal, we used a knowledge-based approach by mutating a codon in the Vgf sequence leading to the substitution of the C-terminal Arginine of TLQP-21, which is the pharmacophore as well as an essential cleavage site from its precursor, into Alanine (R21[->]A). We provide several independent validations of this mouse, including a novel in-gel digestion targeted mass spectrometry identification of the unnatural mutant sequence, exclusive to the mutant mouse. {Delta}TLQP-21 mice do not manifest gross behavioral and metabolic abnormalities and reproduce well, yet they have a unique metabolic phenotype characterized by a temperature-dependent resistance to diet-induced obesity and activation of the brown adipose tissue.

physiology↗

bioRxiv2023

Tumour Extracellular Vesicles Induce Neutrophil Extracellular Traps To Promote Lymph Node Metastasis

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastasis status. However, there is evidence suggesting that LN metastasis is facilitated by a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. We have previously reported that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition abolishes LN metastases in animal mode. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings are the first to reveal the role of EV induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities. Graphic AbstractIllustrative demonstration of the LNs premetastatic niche formation induced by EVs and NETs. Primary tumour constantly secretes EVs, which were actively uptaken by LECs. LECs subsequently secretes CXCL8 or CXCL2 upon EV reception. CXCL8 and CXCL2 are both neutrophil chemoattractants and potent NETs inducers. The following neutrophil recruitment and NETs formation lead to increased LN metastasis burden. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/532413v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@c0c371org.highwire.dtl.DTLVardef@15f6a92org.highwire.dtl.DTLVardef@14dbeedorg.highwire.dtl.DTLVardef@131d3eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

In humans, brown adipose tissue (BAT) undergoes progressive involution or atrophy with increasing age, as manifested by decreased prevalence and mass, transformation to white adipose tissue (WAT), and reduction in thermogenic activity. This involution process cannot be fully recapitulated in rodent models and thus underlying cellular mechanisms are poorly understood. Here, we show that the interscapular BAT (iBAT) in rabbits involutes rapidly in early life, similarly to that in humans. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied with the loss of brown adipogenic competence of their precursor cells. Through single-cell RNA sequencing, we surveyed the heterogenous populations of mesenchymal cells within the stromal vascular fraction of rabbit and human iBAT. An analogous FSTL1high population of brown adipocyte progenitors exists in both species while gradually disappear during iBAT involution in rabbits. In mice, FSTL1 is highly expressed by adipocyte progenitors in iBAT and genetic deletion of FSTL1 causes defective WNT signaling and iBAT atrophy in neonates. Our results underscore the BAT-intrinsic contribution from FSTL1high progenitors to age-related tissue involution and point to a potential therapeutic approach for obesity and its comorbidities. HIGHLIGHTSO_LIRabbit BAT irreversibly transforms to WAT before puberty. C_LIO_LIiBAT adipocyte progenitors reprogram transcriptome and lose brown adipogenic ability. C_LIO_LIComparable FSTL1high brown adipocyte progenitors exist in rabbit and human iBAT. C_LIO_LILoss of FSTL1 in brown adipocyte progenitors causes iBAT atrophy in mice. C_LI

physiology↗