Biology subjects

Peleg, S.

Publications and source records attributed to Peleg, S..

9 recordsLinked to original sources

bioRxiv2026

A conserved transcriptomic model defines metabolic resilience and vulnerability in obesity

BackgroundObesity arises from a complex interplay of genetic and environmental factors, with alterations of transcriptional networks that integrate metabolic, immune, and regulatory pathways. Conventional measures such as body mass index (BMI) quantify body size but fail to capture the molecular heterogeneity underlying divergent metabolic outcomes. We therefore sought to construct a gene expression-based transcriptomic representation of obesity, using BMI as a practical training anchor, and to use this framework to delineate transcriptional programs associated with metabolically healthy and pathogenic obesity, with subsequent projection to mouse transcriptomic data for cross-species validation. MethodsTranscriptome data of human visceral adipose tissue (N= 1,298) were used to derive the transcriptomic BMI model, and genes contributing to the model were functionally annotated by gene set enrichment analysis. The human-trained model was subsequently applied to mouse selection lines (N = 18) with divergent obesity phenotypes. In the human cohort, post hoc stratification into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) groups was performed using a downstream classification framework incorporating observed BMI together with predicted BMI, to assess whether model-derived predicted BMI reflected obesity-related pathophysiologic status. ResultsModel-selected genes were involved in coordinated regulation of lipid metabolism, immune activation, and growth signaling, extending to mitochondrial and translational pathways. Cross-species analyses uncovered conserved metabolic polarization: DU6 mice exhibited lipid-anabolic and inflammatory remodeling, whereas DU6P mice displayed oxidative, mitochondrial, and GH-axis-enriched transcriptional states. In human cohorts, MHO individuals showed upregulation of mitochondrial energetics and protein synthesis, while MUO individuals were characterized by increased autophagy, lipid catabolism, and stress-adaptive signaling on the transcriptional level. Together, these findings define a conserved molecular continuum linking oxidative efficiency to metabolic health and inflammation to metabolic vulnerability. ConclusionsThis integrative transcriptomic framework bridges human and mouse adipose biology to uncover conserved mechanisms underlying obesity phenotypes. By contrasting mitochondrial and translational programs with inflammatory and catabolic pathways, it provides mechanistic insight into metabolic resilience and a foundation for precision approaches to obesity management.

systems biology↗

bioRxiv2025

Reserpine prolongs lifespan but compromises heat-stress resilience in Drosophila melanogaster

Pharmacological modulation of monoaminergic signaling, a process targeted by many therapeutic and recreational drugs via receptors, transporters, degradation enzymes, or reuptake mechanisms, is emerging as a promising aging intervention and as a strategy to treat various maladies. Monoamines (including dopamine, serotonin, and norepinephrine) are central to the regulation of mood, movement, sleep, memory, and systemic physiology. Here, we demonstrate that Reserpine, chronic inhibitor of the vesicular monoamine transporter (VMAT), robustly extends lifespan in Drosophila melanogaster in a dose-dependent manner. However, reserpine-treated flies also exhibit reduced locomotor activity and impaired survival under acute heat stress, indicating a context-dependent trade-off between lifespan extension and stress resilience. Transcriptomic profiling revealed that reserpine induces a transcriptionally repressed, low-energy state characterized by downregulation of metabolic, immune, and stress-response genes in treated aged animals. Notably, under heat stress, reserpine blunts the induction of canonical protective genes, including heat shock proteins and antioxidant genes, resulting in increased proteotoxic vulnerability. These findings highlight the potential trade-offs of monoaminergic modulation and support further investigation of VMAT inhibitors, monoamine modulators and other hypertension drugs as geroprotective agents.

cell biology↗

bioRxiv2025

Chameau (HBO1) regulates starvation in a temperature-dependent manner in Drosophila melanogaster

The body temperature of Drosophila melanogaster depends on the extrinsic temperature. Numerous studies in fruit flies have shown that environmental temperature has an effect on metabolism, lifespan and starvation resilience. We have previously shown that Chameau (Chm), a MYST-domain acetyltransferase, promotes aging but also increases starvation resilience. As starvation resilience is highly temperature dependent, we explored the effect of temperature on starvation resilience in fruit flies with reduced chm expression. Strikingly, we found that an increase of 2{degrees}C was sufficient to restore starvation resilience in chm mutants. The increase in temperature rescued the dampened expression of genes involved in insulin, hormone and starvation response as well as a reduced rate of weight loss and misregulation of trehalose, which we observed in chm mutants at 23{degrees}C. Our data show that whereas Chm has an important role in regulating starvation at 23{degrees}C and below, it becomes obsolete at higher temperatures. Our finding that a gene plays an important role only under specific environmental conditions has important implications in light of the recent global change of climate conditions.

molecular biology↗

bioRxiv2024

Cell-free immuno-profiling on a genetically programmed biochip

Emerging cell-free synthetic biology approaches provide biosafe, cheap, and versatile genetic tools to advance therapeutic research and development. Combined with micro-fabrication technology, we developed a platform to quantitatively reconstitute interactions of cell-free synthesized antigens with antibodies and human receptors in miniaturized compartments on a silicon chip. Photolithographic surface patterning of protein traps and on chip expression from high density gene brushes generated a continuous surface density gradient of fluorescently labeled antigens. Antibodies binding to the antigen gradient generate a full binding curve in each single compartment for affinity determination. We used the SARS-CoV-2 antigens as a model to profile the specificity and affinity of monoclonal antibodies to > 30 viral epitopes synthesized simultaneously on one chip in a genotype-phenotype linked compartments. We further profiled polyclonal antibodies in minute volumes of human sera, revealing patient-specific epitope profiles that are difficult to detect by conventional approaches. Cell-free co-synthesis of the human ACE2 receptor with the viral Receptor-Binding-Domain yielded relative binding affinities to different SARS-CoV-2 variants. This rapid, quantitative, and on-chip genetically programmed approach allows to study complex protein-protein interactions independent of protein purification steps for human immuno-profiling with a fast response time for combating emerging pathogens.

bioengineering↗

bioRxiv2024

Sodium butyrate is incorporated into central metabolism in fly head while inducing oxygen consumption increase

Butyrate has been proposed as a drug therapy by acting as a KDAC inhibitor and elevating protein acetylation, in particular on histones. Nonetheless, recent studies suggest that tissues such as the gut can utilize butyrate as a metabolite. We have previously shown that the addition of butyrate induces a rapid increase of oxygen consumption in whole Drosophila melanogaster heads. Here we show that while head oxygen consumption is increased by the addition of butyrate, no apparent changes are observed on the proteome and acetylome. Instead, we show that butyrate is metabolized and incorporated into the tricarboxylic acid cycle (TCA) cycle. Collectivity our data supports the notion that the therapeutic benefits of acute butyrate treatment may be also mediated by improving metabolic rates, rather than solely targeting the epigenome or acetylome.

biochemistry↗

bioRxiv2023

Longevity interventions in Titan mice attenuate frailty and senescence accumulation

Wild-type murine models for aging research have lifespans of several years, which results in long experimental duration and late output. Here we explore the short-lived non-inbred Titan mouse as a mouse model to test longevity interventions. We show that Titan mice exhibit increased frailty and cellular senescence at an early age. Dietary intervention attenuates the frailty progression of Titan mice. Additionally, cyclic administration of the senolytic drug Navitoclax at early age increases the lifespan and reduces cellular senescence. Our data suggests that Titan mice can serve as a cost-effective and timely model for longevity interventions in mammals.

systems biology↗

bioRxiv2022

Disrupted RNA editing in beta cells mimics early stage type 1 diabetes

A major hypothesis for the etiology of type 1 diabetes (T1D) postulates initiation by viral infection, leading to double-stranded RNA (dsRNA)-mediated interferon response; however, a causal virus has not been identified. Here we use a mouse model, corroborated with human data, to demonstrate that endogenous dsRNA in beta-cells can lead to a diabetogenic immune response, thus identifying a virus-independent mechanism for T1D initiation. We found that disruption of the RNA editing enzyme ADAR in beta-cells triggers a massive interferon response, islet inflammation and beta-cell failure, with features bearing striking similarity to early-stage human T1D. Glycolysis via calcium enhances the interferon response, suggesting an actionable vicious cycle of inflammation and increased beta-cell workload. One sentence summaryAdar inactivation in beta-cells triggers a glucose-dependent interferon response causing insulitis and diabetes

cell biology↗

bioRxiv2022

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan

Despite longstanding scientific interest in the centrality of mitochondria to biological aging, directly controlling mitochondrial function to test causality has eluded researchers. We show that specifically boosting mitochondrial membrane potential through a light-activated proton pump reversed age-associated phenotypes and extended C. elegans lifespan. We show that harnessing the energy of light to experimentally increase mitochondrial membrane potential during adulthood alone is sufficient to slow the rate of aging.

physiology↗

bioRxiv2020

Titan Mice are Unique Short-Lived Mammalian Model of Metabolic Syndrome and Aging

Suitable animal models are essential for translational research, especially in the case of complex, multifactorial conditions, such as obesity. The outbred mouse line Titan (DU6) results from the worlds longest selection experiment for high body mass and was previously described as a model for metabolic healthy (benign) obesity. The present study deeper characterized the geno- and phenotypes of this outbred mouse line and tested its suitability as an interventional obesity model. In contrast to previous findings, our data suggests that Titan mice are metabolically unhealthy obese and short-lived. Line-specific patterns of genetic invariability are in accordance with observed phenotypic traits. Titan mice show modifications in the liver transcriptome, proteome and epigenome that are linked to metabolic (dys)regulations. However, dietary intervention partially reversed the metabolic phenotype in Titan mice and significantly extended their life expectancy. Therefore, the Titan mouse line is a valuable resource for translational and interventional obesity research.

biochemistry↗