Biology subjects

Patel, Y.

Publications and source records attributed to Patel, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Adenosylhomocysteinase drives epigenetic and metabolic reprogramming in ZFTA-RELA ependymoma

Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors predominantly driven by the recurrent ZFTA-RELA fusion, an oncogenic chromatin regulator that establishes an aberrant transcriptional program. Although metabolic pathways modulate epigenetic regulation by controlling the availability of metabolic cofactors, how ZFTA-RELA coordinates metabolic reprogramming with epigenetic regulation is not well understood. Here, we show that ZFTA-RELA-positive ependymomas exhibit enhanced methionine dependency, elevated adenosyl homocysteinase (AHCY) expression, and epigenetically control aspartate metabolism for tumor growth. Mechanistically, ZFTA-RELA upregulates AHCY, increasing cellular methylation potential which promotes H3K4me3-dependent expression of CAD, the first enzyme complex of de novo pyrimidine biosynthesis, while simultaneously enforcing H3K27me3 mediated repression of ASNS, which encodes asparagine synthetase. Through this coordinated epigenetic program, aspartate utilization is directed toward pyrimidine biosynthesis while endogenous asparagine production is limited. Restricting S-adenosylmethionine availability or genetically or pharmacologically inhibiting AHCY reverses these epigenetic states, leading to CAD downregulation, ASNS upregulation, impaired nucleotide synthesis, and suppression of tumor growth in vitro and in vivo. Similarly, EZH2 inhibition also restores ASNS expression and suppresses tumor proliferation. These findings suggest that ZFTA-RELA EPN maintain ASNS-low phenotype which conditionally make them dependent on extracellular asparagine. We further show that enhanced de novo pyrimidine synthesis not only supports nucleotide production but also provides UDP-sugars required for N-glycosylation and stabilization of the asparagine transporter SLC1A5, thereby promoting extracellular asparagine uptake and tumor proliferation. Collectively, our findings identify AHCY as a critical metabolic regulator of epigenetic and metabolic reprogramming that drives pyrimidine synthesis and establishes extracellular asparagine dependency, revealing actionable metabolic vulnerabilities in ZFTA-RELA-positive ST-EPNs.

cancer biology↗

bioRxiv2026

Exploration of Structural Optic Nerve Changes in Mouse Models of Retinal and Neuronal Degeneration with Optical Coherence Tomography

PurposeThe optic nerve head (ONH) is a central feature of the retina, affected in many human ocular pathologies, yet it has remained underexplored in most mouse models of disease. We hypothesize that the analysis of the ONH can yield valuable insight into the phenotype of retinal diseases and that pathological changes can be detected using state-of-the-art optical coherence tomography (OCT). MethodsFour mouse models - the 5xFAD, PS19 and APP/PS1 models of Alzheimers disease (AD) as well as the SOD1 knockout mouse model - were imaged using a polarization-sensitive OCT system to investigate potential disease related changes of the ONH. 5xFAD and SOD1 animals were investigated longitudinally to study disease progression. Additionally, aging effects in wild type mice were studied. ResultsTwo different analysis methods for the segmentation of the ONH were implemented and evaluated. Longitudinal changes to the ONH in 5xFAD animals were observed, specifically an increase of ONH volume from 3 to 5 months of age followed by a strong decrease until 9 months of age. Significant differences between transgenic (tg) and non-transgenic (ntg) animals, as well as sex dependent distinctions were found. Also, for the APP/PS1 model disease related differences between ntg and tg APP/PS1 were significant. ConclusionsWe demonstrated a simple segmentation of the ONH structure based on OCT intensity images and show its potential as a preclinical biomarker in amyloid mouse models of AD.

neuroscience↗

bioRxiv2026

Benchmarking generative scaffold design methods for peptide engineering in TCR-MHC complexes

De novo peptide design at T cell receptor-peptide-major histocompatibility complex (TCR-pMHC) interfaces is a central challenge in computational immunology, with direct implications for vaccine development, cancer immunotherapy, and autoimmune disease. Despite rapid advances in generative protein modeling, there is currently no systematic benchmark evaluating these methods in the highly constrained and immunologically relevant setting of peptide-MHC presentation and TCR recognition. Here, we present two complementary contributions. First, we introduce a multi-stage computational pipeline for peptide design in predefined TCR-pMHC contexts, integrating generative modeling with sequence optimization and structure-based filtering. Second, we establish a benchmark for evaluating generative peptide design methods in TCR-pMHC complexes. Using a curated dataset of high-quality crystal structures deposited after the AlphaFold3 training cutoff, we assess state-of-the-art generative approaches for peptide backbone generation, sequence design, and the enrichment of near-native solutions. We explicitly examine whether different backbone generation strategies respect the geometric constraints of the MHC binding groove and recover native-like peptide conformations. Our results reveal substantial method-dependent differences: some generative strategies fail systematically in the groove-bound peptide setting, whereas others generate physically plausible backbones with varying accuracy and conformational diversity. We further show that enforcing anchor constraints strongly influences peptide conformations at non-anchor positions, highlighting a trade-off between structural accuracy and conformational sampling. To enable fair and reproducible comparison, we introduce a standardized, multi-stage scoring protocol that integrates MHC binding prediction, physics-based energy evaluation, and independent structure prediction confidence metrics to enrich near-native designs from large candidate pools. Together, this work establishes the first comprehensive pipeline and benchmark for generative peptide design at TCR-pMHC interfaces and provides practical guidelines for developing peptide design workflows and evaluating generative models in immunologically constrained protein design settings.

bioinformatics↗

bioRxiv2025

The Bacillus subtilis class A penicillin-binding protein 4 (PBP4) requires an accessory protein RpdA

Peptidoglycan (PG) synthesis is essential to maintain cell integrity during bacterial growth and division. In Bacillus subtilis, PG synthesis involves class A PBPs that act independently and class B PBPs that function in complexes for cell elongation (the elongasome) and division (the divisome). Here, we identify RpdA (formerly YufK) as a specific regulator of PBP4. Inactivation of either vegetative class A PBP (PBP1 or PBP4) by the {beta}-lactam antibiotic cefuroxime (CEF) is toxic and their loss confers CEF resistance. Similarly, loss of RpdA increases CEF resistance and genetic epistasis studies reveal that RpdA functions in a pathway with PBP4. In the absence of RpdA, PBP4 is no longer membrane localized. Analysis of a predicted RpdA-PBP4 protein complex suggests that RpdA has a second function in addition to serving as a membrane scaffold. Induction of RpdA reduces sensitivity to an undecaprenyl-phosphate binding antibiotic, consistent with a role in recycling of this important lipid carrier. We conclude that RpdA is a PBP4 accessory protein critical for its localization and activity.

microbiology↗

bioRxiv2025

RNA polymerase-mediated regulation of intrinsic antibiotic resistance and bacterial cell division

Rifampin is a frontline antibiotic that inhibits the RNA polymerase of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Unlike most antibiotics, rifampin has an unusual ability to shorten the duration of treatment needed to cure TB that is not simply explained by its antimicrobial potency. We sought specific secondary effects of rifampins inhibition of Mtb RNA polymerase that may mediate this activity. We discovered that rifampin elicited a cell division arrest that was mediated through its inhibition of RNA polymerase. This arrest resulted in a downstream inhibition of the MtrAB two-component regulatory system, a mediator of intrinsic antibiotic resistance in Mtb. This inhibition is broadly conserved in other bacteria and represents a novel form of antimicrobial activity, termed adjunctive sensitization, that can mediate synergy and may contribute to rifampins unusual treatment shortening activity.

microbiology↗

bioRxiv2025

Longitudinal investigation of spatial memory and retinal parameters in a 5xFAD model of Alzheimers disease reveals differences dependent on genotype and sex

SignificanceThe retinal phenotype of Alzheimers disease (AD) is poorly understood. The connection between spatial memory and retinal phenotype is poorly investigated. Additionally, the influence of sex on the disease in mouse models is not sufficiently clear and requires further investigation. AimTo investigate the retina and spatial memory of 5xFAD mouse models of AD by measuring retinal and behavioral parameters. ApproachA custom-built optical coherence tomography (OCT) system is used to image the retina of both eyes of 32 transgenic 5xFAD mice and 32 non-transgenic littermates over the course of 6 months (3-9 months of age) to investigate retinal parameters. The Morris Water Maze (MWM) test was performed to examine correlations between the retinal and spatial memory phenotype of the mouse model. ResultsData were acquired in the form of OCT reflectivity images and OCT angiograms as well as video recordings of the MWM test. Layer thickness and vascular density were calculated from the resulting data. Behavioral data was extracted from the videos acquired from the MWM. Total retinal and inner retinal layer thickness increased slightly over the measurement period, while outer retinal layer and retinal nerve fiber layer thickness showed no significant change. The correlation analysis between MWM and layer thickness data revelated a positive correlation between inner nuclear layer thickness and MWM test day parameters. ConclusionsOCT and MWM data revealed sex-based differences in the retinal phenotype of the 5xFAD mouse model, with changes in retinal thickness in different stages of the study and dissimilar correlations between retinal and spatial memory phenotype.

neuroscience↗

bioRxiv2025

Alleviation of Drought Stress and Plant Growth Promotion in Mungbean through Rhizospheric Actinobacteria

Drought is a major cause for decreasing in crop yield and agricultural productivity around the Globe. The application of drought tolerance Actinobacteria to agroecosystem improves the growth and protect from water scarcity and they can be better alternative for natural farming and sustainable agriculture for aride and semi-aride regions. Herein, we isolated ten morphologically different actinobacteria from the rhizospheric soil of Datura and Khejri plants which are surviving in the nature without any special treatment provided. All the isolated bacteria were screened in-vitro for their drought tolerance capability for different time intervals against polyethylene glycol 8000 (PEG8000) with 5%, 10% and 10% concentration to media which produce moisture stress in which medium bacteria were growing. Among them best five bacterial isolates were selected and named RADM1 to RADM5 for further experimentation. Physiological characterizations were done through their ability to grow in different temperature, pH ranges and NaCl concentration supplemented with the 5% PEG8000. Morphology of the bacteria was Grams positive and mycelium producing same as typical Actinobacterial species and for biochemical diversity stains were able to IMVIC test and carbohydrate utilization through IMVIC test. Enzymatic observations of isolates were resulted positive for nitrate reduction, catalase production and negative for starch hydrolysis. PCR amplification and 16S rRNA gene sequencing in BlastN found maximum similarity of three species with Streptomyces clavuligerus and two species with Rhodococcus erythropolis and submitted to NCBI gene bank database with accession number PQ114139 (RADM1), PQ120343 (RADM2), PQ114109 (RADM3), PQ120390 (RADM4), PQ039766 (RADM5). In pot trial of mungbean, all the isolates showed better performance in bacterial treatments with an average increase in physiological parameters like, seedlings shoot length (52.70% and 9.62%), root length (35.63% and 17.25%), fresh weight (42.8% and 13.76%) dry weight (45.25% and 21.24%) in compared to uninoculated induced drought and watered treatments. Stress features of seedlings revealed significant increase in proline and chlorophyll contents whereas decrease in MDA contents than the untreated plants which indicates actinobacteria reduced water scarcity and damage of plant membrane. IMPORTANCERhizosphere of plant contains diversity of microbes with different abilities to support the plant growth. The role of plant growth promoting bacteria in soil presented and their association with plant can be the one reason for survive of the plant against the abiotic stress conditions like drought, salinity, temperature or pH. The actinobacteria found in the rhizosphere have evolved multiple strategies to assist plants in managing the adverse effects of drought. These strategies may include alterations in phytohormones, which play a vital role in enabling plants to withstand environmental stresses, modifications to root structures, accumulation of osmolytes, enhancements in the plants antioxidant defense mechanisms, synthesis of exopolysaccharides, and the identification of particular genes that support plant growth and improve drought resilience. These actinobacteria as bioinoculant can be the better alternative for the chemical fertilizers use and protect from the water scarcity.

microbiology↗

bioRxiv2024

A robust benchmark for detecting low-frequency variants in the HG002 Genome In A Bottle NIST reference material.

Somatic mosaicism is an important cause of disease, but mosaic and somatic variants are often challenging to detect because they exist in only a fraction of cells. To address the need for benchmarking subclonal variants in normal cell populations, we developed a benchmark containing mosaic variants in the Genome in a Bottle Consortium (GIAB) HG002 reference material DNA from a large batch of a normal lymphoblastoid cell line. First, we used a somatic variant caller with high coverage (300x) Illumina whole genome sequencing data from the Ashkenazi Jewish trio to detect variants in HG002 not detected in at least 5% of cells from the combined parental data. These candidate mosaic variants were subsequently evaluated using >100x BGI, Element, and PacBio HiFi data. High confidence candidate SNVs with variant allele fractions above 5% were included in the HG002 draft mosaic variant benchmark, with 13/85 occurring in medically relevant gene regions. We also delineated a 2.45 Gbp subset of the previously defined germline autosomal benchmark regions for HG002 in which no additional mosaic variants >2% exist, enabling robust assessment of false positives. The variant allele fraction of some mosaic variants is different between batches of cells, so using data from the homogeneous batch of reference material DNA is critical for benchmarking these variants. External validation of this mosaic benchmark showed it can be used to reliably identify both false negatives and false positives for a variety of technologies and detection algorithms, demonstrating its utility for optimization and validation. By adding our characterization of mosaic variants in this widely-used cell line, we support extensive benchmarking efforts using it in simulation, spike-in, and mixture studies.

bioinformatics↗

bioRxiv2024

StableLift: Optimized Germline and Somatic Variant Detection Across Genome Builds

Reference genomes are foundational to modern genomics. Our growing understanding of genome structure leads to continual improvements in reference genomes and new genome "builds" with incompatible coordinate systems. We quantified the impact of genome build on germline and somatic variant calling by analyzing tumour-normal whole-genome pairs against the two most widely used human genome builds. The average individual had a build-discordance of 3.8% for germline SNPs, 8.6% for germline SVs, 25.9% for somatic SNVs and 49.6% for somatic SVs. Build-discordant variants are not simply false-positives: 47% were verified by targeted resequencing. Build-discordant variants were associated with specific genomic and technical features in variant- and algorithm-specific patterns. We leveraged these patterns to create StableLift, an algorithm that predicts cross-build stability with AUROCs of 0.934 {+/-} 0.029. These results call for significant caution in cross-build analyses and for use of StableLift as a computationally efficient solution to mitigate inter-build artifacts.

genomics↗

bioRxiv2024

TRENDY: Gene Regulatory Network Inference Enhanced by Transformer

Gene regulatory networks (GRNs) play a crucial role in the control of cellular functions. Numerous methods have been developed to infer GRNs from gene expression data, including mechanism-based approaches, information-based approaches, and more recent deep learning techniques, the last of which often overlook the underlying gene expression mechanisms. In this work, we introduce TRENDY, a novel GRN inference method that integrates transformer models to enhance the mechanism-based WENDY approach. Through testing on both simulated and experimental datasets, TRENDY demonstrates superior performance compared to existing methods. Furthermore, we apply this transformer-based approach to three additional inference methods, showcasing its broad potential to enhance GRN inference.

genetics↗

bioRxiv2024

Metapipeline-DNA: A Comprehensive Germline & Somatic Genomics Nextflow Pipeline

SummaryThe price, quality and throughout of DNA sequencing continue to improve. Algorithmic innovations have allowed inference of a growing range of features from DNA sequencing data, quantifying nuclear, mitochondrial and evolutionary aspects of both germline and somatic genomes. To automate analyses of the full range of genomic characteristics, we created an extensible Nextflow meta-pipeline called metapipeline-DNA. Metapipeline-DNA analyzes targeted and whole-genome sequencing data from raw reads through pre-processing, feature detection by multiple algorithms, quality-control and data- visualization. Each step can be run independently and is supported robust software engineering including automated failure-recovery, robust testing and consistent verifications of inputs, outputs and parameters. Metapipeline-DNA is cloud-compatible and highly configurable, with options to subset and optimize each analysis. Metapipeline-DNA facilitates high-scale, comprehensive analysis of DNA sequencing data. AvailabilityMetapipeline-DNA is an open-source Nextflow pipeline under the GPLv2 license and is available at https://github.com/uclahs-cds/metapipeline-DNA.

bioinformatics↗

bioRxiv2024

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

neuroscience↗

bioRxiv2024

moPepGen: Rapid and Comprehensive Proteoform Identification

Proteogenomics is limited by challenges of modeling the complexities of gene expression. We create moPepGen, a graph-based algorithm that comprehensively generates non-canonical peptides in linear time. moPepGen works with multiple technologies, in multiple species and on all types of genetic and transcriptomic data. In human cancer proteomes, it enumerates previously unobservable noncanonical peptides arising from germline and somatic genomic variants, noncoding open reading frames, RNA fusions and RNA circularization.

bioinformatics↗

bioRxiv2024

Quantifying the seed sensitivity of cancer subclonal reconstruction algorithms

BackgroundIntra-tumoural heterogeneity complicates cancer prognosis and impairs treatment success. One of the ways subclonal reconstruction (SRC) quantifies intra-tumoural heterogeneity is by estimating the number of subclones present in bulk DNA sequencing data. SRC algorithms are probabilistic and need to be initialized by a random seed. However, the seeds used in bioinformatics algorithms are rarely reported in the literature. Thus, the impact of the initializing seed on SRC solutions has not been studied. To address this gap, we generated a set of ten random seeds to systematically benchmark the seed sensitivity of three probabilistic SRC algorithms: PyClone-VI, DPClust, and PhyloWGS. ResultsWe characterized the seed sensitivity of three algorithms across fourteen whole-genome sequences of head and neck squamous cell carcinoma and nine SRC pipelines, each composed of a single nucleotide variant caller, a copy number aberration caller and an SRC algorithm. This led to a total of 1470 subclonal reconstructions, including 1260 single-region and 210 multi-region reconstructions. The number of subclones estimated per patient vary across SRC pipelines, but all three SRC algorithms show substantial seed sensitivity: subclone estimates vary across different seeds for the same set of input using the same SRC algorithm. No seed consistently estimated the mode number of subclones across all patients for any SRC algorithm. ConclusionsThese findings highlight the variability in quantifying intra-tumoural heterogeneity introduced by the seed sensitivity of probabilistic SRC algorithms. We recommend that authors, reviewers and editors adopt guidelines to both report and randomize seed choices. It may also be valuable to consider seed-sensitivity in the benchmarking of newly developed SRC algorithms. These findings may be of interest in other areas of bioinformatics where seeded probabilistic algorithms are used and suggest consideration of formal seed reporting standards to enhance reproducibility.

bioinformatics↗

bioRxiv2024

The Bacillus subtilis cell envelope stress-inducible ytpAB operon modulates membrane properties and contributes to bacitracin resistance

Antibiotics that inhibit peptidoglycan synthesis trigger the activation of both specific and general protective responses. {sigma}M responds to diverse antibiotics that inhibit cell wall synthesis. Here, we demonstrate that cell wall inhibiting drugs, such as bacitracin and cefuroxime, induce the {sigma}M-dependent ytpAB operon. YtpA is a predicted hydrolase previously proposed to generate the putative lysophospholipid antibiotic bacilysocin (lysophosphatidylglycerol), and YtpB is the branchpoint enzyme for the synthesis of membrane-localized C35 terpenoids. Using targeted lipidomics we reveal that YtpA is not required for the production of lysophosphatidylglycerol. Nevertheless, ytpA was critical for growth in a mutant strain defective for homeoviscous adaptation due to a lack of genes for the synthesis of branched chain fatty acids and the Des phospholipid desaturase. Consistently, overexpression of ytpA increased membrane fluidity as monitored by fluorescence anisotropy. The ytpA gene contributes to bacitracin resistance in mutants additionally lacking the bceAB or bcrC genes, which directly mediate bacitracin resistance. These epistatic interactions support a model in which {sigma}M-dependent induction of the ytpAB operon helps cells tolerate bacitracin stress, either by facilitating the flipping of the undecaprenyl-phosphate carrier lipid or by impacting the assembly or function of membrane-associated complexes proteins involved in cell wall homeostasis. ImportancePeptidoglycan synthesis inhibitors include some of our most important antibiotics. In Bacillus subtilis, peptidoglycan synthesis inhibitors induce the {sigma}M regulon, which is critical for intrinsic antibiotic resistance. The {sigma}M-dependent ytpAB operon encodes a predicted hydrolase (YtpA) and the enzyme that initiates the synthesis of C35 terpenoids (YtpB). Our results suggest that YtpA is critical in cells defective in homeoviscous adaptation. Further, we find that YtpA functions cooperatively with the BceAB and BcrC proteins in conferring intrinsic resistance to bacitracin, a peptide antibiotic that binds tightly to the UPP lipid carrier that sustains peptidoglycan synthesis.

microbiology↗

bioRxiv2024

Tissue-specific RNA-seq defines genes governing male tail tip morphogenesis in C. elegans

Caenorhabditis elegans males undergo sex-specific tail tip morphogenesis (TTM) under the control of the transcription factor DMD-3. To find genes regulated by DMD-3, We performed RNA-seq of laser-dissected tail tips. We identified 564 genes differentially expressed (DE) in wild-type males vs. dmd-3(-) males and hermaphrodites. The transcription profile of dmd-3(-) tail tips is similar to that in hermaphrodites. For validation, we analyzed transcriptional reporters for 49 genes and found male-specific or male-biased expression for 26 genes. Only 11 DE genes overlapped with genes found in a previous RNAi screen for defective TTM. GO enrichment analysis of DE genes finds upregulation of genes within the UPR (unfolded protein response) pathway and downregulation of genes involved in cuticle maintenance. Of the DE genes, 40 are transcription factors, indicating that the gene network downstream of DMD-3 is complex and potentially modular. We propose modules of genes that act together in TTM and are coregulated by DMD-3, among them the chondroitin synthesis pathway and the hypertonic stress response.

developmental biology↗

bioRxiv2023

Development of a human glioblastoma model using humanized DRAG mice for immunotherapy

Glioblastoma (GBM) is the most common and lethal primary brain tumor with high mortality rates and a short median survival rate of about 15 months despite intensive multimodal treatment of maximal surgical resection, radiotherapy, and chemotherapy. Although immunotherapies have been successful in the treatment of various cancers, disappointing results from clinical trials for GBM immunotherapy represent our incomplete understanding. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. In this study, we developed a humanized DRAG (NOD.Rag1KO.IL2R{gamma}cKO) mouse model, in which the human hematopoietic stem cells (HSCs) were well-engrafted and subsequently differentiated into a full lineage of immune cells. Using this humanized DRAG mouse model, GBM patient-derived tumorsphere lines were successfully engrafted to form xenografted tumors, which can recapitulate the pathological features and the immune cell composition of human GBM. Importantly, the administration of anti-human PD-1 antibodies in these DRAG mice bearing a GBM patient-derived tumorsphere line resulted in decreasing the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR-CD15- and CD11b+CD14- CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mouse model as a useful model to test the efficacy of immune checkpoint inhibitors in GBM immunotherapy. Together, these results suggest that humanized DRAG mouse models are a reliable preclinical platform for brain cancer immunotherapy and beyond.

cancer biology↗

bioRxiv2022

Circadian reprogramming of adipose progenitor cells regulates intermittent fasting-mediated adipose tissue remodeling and metabolic improvement

White adipose tissue (WAT) fibrosis is a hallmark of dysfunctional WAT that is directly linked to metabolic abnormalities. Recent studies have highlighted the role of dysfunctional adipose progenitor cells (APCs) in WAT fibrosis and impaired adaptive tissue plasticity, leading to systemic insulin resistance. However, therapeutic options for WAT fibrosis are limited. Intermittent fasting (IF) is an effective dietary regimen for weight control and metabolic improvement through various mechanisms, including healthy remodeling of WAT. However, whether IF is effective in improving age-associated WAT fibrosis and metabolic homeostasis is unknown. Here, we show that IF confers therapeutic benefits in aged and obese mice through reduction of WAT fibrosis. Single-cell analyses revealed that IF significantly reduces pro-fibrotic signatures within APCs along with upregulation of the circadian pathways, suggesting that the circadian clock of APCs mediates IF-induced WAT remodeling. Importantly, mice lacking core circadian gene exhibited increased fibrotic signatures in WAT and diminished beneficial response to IF, further supporting the importance of circadian rhythm in IF-mediated metabolic benefits. Lastly, insulin resistance in humans also presented with dysregulated circadian rhythm signatures in APC populations. Collectively, our findings highlight the novel role of the APC circadian rhythm in plasticity of WAT and metabolic response to IF.

molecular biology↗