Biology subjects

Bellucci, A.

Publications and source records attributed to Bellucci, A..

5 recordsLinked to original sources

bioRxiv2026

Tirzepatide and Intermittent Cold Exposure Independently Improve Glucose Homeostasis in DIO Mice Housed at Thermoneutrality

Obesity is considered a risk factor for metabolic diseases, including type 2 diabetes, and results from an imbalance between energy intake and energy expenditure. While pharmacological approaches such as tirzepatide, a dual GIP/GLP-1 receptor agonist, effectively reduce food intake and body weight, strategies that enhance energy expenditure (EE) may provide complementary metabolic benefits. Intermittent cold exposure (ICE) is one such approach that enhances EE and improves glucose homeostasis independent of weight loss. However, the combined effects of these interventions remain unexplored. In this study, we investigated the individual and combined effects of tirzepatide and ICE on body composition, energy metabolism, and glucose homeostasis in diet-induced obese (DIO) male and female mice housed at thermoneutrality. After 8 weeks of 45% high-fat diet feeding, mice received tirzepatide (10 nmol/kg) or vehicle and were exposed to ICE (4{degrees}C, 1 h/day, 5 days/week) or remained at thermoneutrality for 3 weeks. Energy expenditure and substrate utilization were assessed using indirect calorimetry at thermoneutrality and during an acute 1 h cold challenge. Tirzepatide reduced body weight, food intake, and adiposity in both sexes, with a greater reduction in lean mass in males. ICE did not affect body weight but improved glucose homeostasis. At thermoneutrality, tirzepatide did not alter total EE but lowered respiratory exchange ratio (RER), indicating a shift toward lipid utilization. In contrast, ICE increased energy expenditure and fat oxidation, with no additive effects observed when combined with tirzepatide. Together, these findings highlight that targeting both energy intake and expenditure represents complementary, but not necessarily additive approaches to improving metabolic health.

physiology↗

bioRxiv2025

Alpha-synuclein aggregation and dopaminergic neuron death in a new mouse model of Parkinson disease expressing human full-length and C-terminally truncated 1-120 alpha-synuclein.

Parkinsons disease (PD) is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites made of aggregated alpha-synuclein (aSyn). Several studies have shown that Lewy bodies contain C-terminally truncated aSyn which is more prone to fibrillation and enhances the aggregation of human full-length aSyn in vitro. Nevertheless, in vivo studies addressing whether and how human C-terminally truncated aSyn may exacerbate the pathological aggregation and toxicity of human full-length aSyn are currently lacking. In the present study we aimed to determine whether the co-expression of human full-length and 1-120 truncated aSyn would enhance human full-length aSyn aggregation and toxicity. To this end we generated and characterized two novel alpha- synuclein mouse models. Specifically, we first produced a mouse line expressing full-length human aSyn under its own promoter (BACo mice) in the absence of endogenous mouse aSyn. Then, the BACo mice were crossed with the previously described MI2 mice, which express human 1-120 truncated aSyn under the control of the tyrosine hydroxylase (TH) promoter on a mouse aSyn null backgroundin order to obtain the MI2BACo mice, which express both human 1-120 truncated and full-length aSyn in a mouse aSyn null background. We found that aSyn aggregation was present and increased with age in both mouse lines but was significantly higher in the MI2BACo mice. These mice exhibited progressive nigrostriatal accumulation of aSyn aggregates which were often composed of full-length and 1-120haSyn, the latter being specifically recognized by using a novel antibody raised against the 1-120haSyn. In addition, we observed that the presence of both truncated and full-length aSyn in MI2BACo mice led to a faster and more pronounced aSyn aggregation which associated with more severe dopaminergic striatal fiber degeneration and nigral neuron loss. Collectively, our results indicate that the expression of human C-terminally truncated aSyn exacerbates human full-length aSyn pathology and support that the novel MI2BACo transgenic mouse line represents an innovative experimental model to study the biological basis of PD and test novel therapeutic approaches.

neuroscience↗

bioRxiv2025

Genomic prediction of agronomic traits in perennial ryegrass (Lolium perenne L.) and genotype x environment interactions at the limit of the species distribution

BackgroundIn breeding the aim is to identify and accumulate beneficial variants. However, detection of these variants may be challenging in the presence of extensive genotype x environment interactions (GxE), as variant effects will be conditional on environment. MethodsThe study assesses the performance of 264 diploid perennial ryegrass accessions in a multi-environment field trial. We investigate the extent of GxE, for yield (total dry matter) and persistence traits, i.e. winter kill and spring cover, under environmental conditions experienced in Nordic and Baltic regions at the limit of the species distribution. Two different approaches to modelling GxE were tested: reaction norm and envirotyping, and the models were validated under three different breeding scenarios. ResultsOur analysis documented the presence of significant GxE interaction for all traits investigated in the study. Validation showed improvements in prediction accuracy when accounting for GxE: up to 4% for yield when predicting in unobserved environments, and up to 22% and 9% for spring cover and winter kill, respectively when predicting unobserved germplasm. Genome-wide-association-studies (GWAS) were utilized to detect genetic variants with marginal effects (environment-independent effect) and conditional effects (environment-dependent effects). Results showed the presence of large-effect genetic variants with marginal effects, in addition to few QTL whose effects were adaptive under specific environmental conditions while neutral or deleterious under different environmental conditions. ConclusionThis study demonstrates the usefulness and limitations of genomic prediction models for predicting GxE in highly diverse samples, and describes the extent of GxE interactions at the limit of species distribution for perennial ryegrass. Finally, our study points toward adaptive variation, which may enhance persistence of perennial ryegrass populations in Nordic and Baltic growing conditions.

genetics↗

bioRxiv2025

Topical application of the cold-mimetic L-menthol decreases wheel running without affecting the beneficial effects of voluntary exercise in mice

Topical application of L-menthol, a pharmacological cold-mimetic and agonist of the cold-sensing receptor TRPM8 (Transient Receptor Potential Cation Channel Subfamily M Member 8), has been shown to stimulate brown adipose tissue (BAT) thermogenesis and reduce weight gain in both obese and lean male mice, without affecting energy intake. While these findings suggest that L-menthol could offer a novel approach to prevent weight gain, its potential to enhance the benefits of exercise on whole-body metabolic health remains unexplored. In this study, we investigated whether daily topical L-menthol application, combined with voluntary wheel running, could enhance exercise-induced improvements in metabolic health in male and female C57BL/6J mice housed at thermoneutrality (29{degrees}C). Our results demonstrated that although L-menthol treatment reduced voluntary wheel running distance there was still a main effect of exercise to reduce fat mass, weight gain and improve glucose tolerance. Indirect calorimetry revealed that L-menthol increased total energy expenditure, potentially explaining improvements in metabolic health despite reductions in voluntary wheel running. These findings suggest that although L-menthol does not enhance the effects of voluntary exercise, it remains a promising strategy for improving metabolic health. Key pointsO_LIL-menthol treatments led to a reduction in voluntary wheel running distance C_LIO_LIDespite the reduced voluntary exercise with L-menthol, wheel running led to significant reductions in fat mass as well as improved glucose tolerance C_LIO_LITreatment with L-menthol increased energy expenditure perhaps providing an explanation for exercise-induced improvements in indices of metabolic health despite reduction in wheel running C_LI

physiology↗

bioRxiv2021

DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson's disease.

Dopamine dyshomeostasis has been acknowledged to be among the determinants of nigrostriatal neuron degeneration in Parkinsons disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the aldehydic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein Synuclein (Syn), whose misfolding and aggregation represent a major trait of PD pathology, triggering Syn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits Syn neuronal accumulation and hampers Syn clearance at synapses and the soma. By combining cellular and in vivo models, we provided evidence that DOPAL-induced Syn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, specifically at neuronal projections. The resulting progressive decline of neuronal homeostasis leads to dopaminergic neuron loss and motor impairment, corroborating the Syn-DOPAL interplay as an early event in PD neurodegeneration.

neuroscience↗