Biology subjects

Liu, T.

Publications and source records attributed to Liu, T..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Three-dimensional chromatin mapping of sensory neurons reveals that cohesin-dependent genomic domains are required for axonal regeneration

The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression programme at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C and RNA-seq. We find that cohesin is required for the full induction of the regenerative transcriptional program, by organising 3D genomic domains required for the activation of regenerative genes. Importantly, loss of cohesin results in disruption of chromatin architecture at regenerative genes and severely impaired nerve regeneration. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent chromatin interactions in neuronal regeneration.

neuroscience↗

bioRxiv2024

Genome-wide mapping of native co-localized G4s and R-loops in living cells

The non-B DNA structures can act as dynamic functional genomic elements regulating gene expression. Among them, G4s and R-loops are two of the best studied. The interplay between R-loops and G4s are emerging in regulating DNA repair, replication and transcription. A comprehensive picture of native co-localized G4s and R-loops in living cells is currently lacking. Here, we describe the development of HepG4-seq and an optimized HBD-seq methods, which robustly capture native G4s and R-loops, respectively, in living cells. We successfully employed these methods to establish comprehensive maps of native co-localized G4s and R-loops in human HEK293 cells and mouse embryonic stem cells (mESCs). We discovered that co-localized G4s and R-loops are dynamically altered in a cell type-dependent manner and are largely localized at active promoters and enhancers of transcriptional active genes. We further demonstrated the helicase Dhx9 as a direct and major regulator that modulates the formation and resolution of co-localized G4s and R-loops. Depletion of Dhx9 impaired the self-renewal and differentiation capacities of mESCs by altering the transcription of co-localized G4s and R-loops - associated genes. Taken together, our work established that the endogenous co-localized G4s and R-loops are prevalently persisted in the regulatory regions of active genes and are involved in the transcriptional regulation of their linked genes, opening the door for exploring broader roles of co-localized G4s and R-loops in development and disease.

genomics↗

bioRxiv2024

CosGeneGate Selects Multi-functional and Credible Biomarkers for Single-cell Analysis

Selecting representative genes or marker genes to distinguish cell types is an important task in single-cell sequencing analysis. Although many methods have been proposed to select marker genes, the genes selected may have redundancy and/or do not show cell-type-specific expression patterns to distinguish cell types. Here we present a novel model, named CosGeneGate, to select marker genes for more effective marker selections. CosGeneGate is inspired by combining the advantages of selecting marker genes based on both cell-type classification accuracy and marker gene specific expression patterns. We demonstrate the better performance of the marker genes selected by CosGeneGate for various downstream analyses than the existing methods with both public datasets and newly sequenced datasets. The non-redundant marker genes identified by CosGeneGate for major cell types and tissues in human can be found at the website as follows: https://github.com/VivLon/CosGeneGate/blob/main/marker gene list.xlsx.

bioinformatics↗

bioRxiv2024

Genetic regulation of lncRNA expression in the whole human brain

Long non-coding RNAs (lncRNAs) play a key role in the human brain, and genetic variants regulate their expression. Herein, the expression quantitative trait loci (eQTL) of lncRNAs encompassing ten brain regions from 134 individuals was analyzed, and novel variants influencing lncRNA expression (eSNPs) and the respective affected lncRNAs (elncRNAs) were identified. The eSNPs are proximate to their corresponding elncRNAs, enriched in the non-coding genome, and have a high minor allele frequency. The elncRNAs exhibit a high-level and complex pattern of expression. The genetic regulation is more tissue-specific for lncRNAs than for protein-coding genes, with notable differences between cerebrum and cerebellum. However, it shows relatively similar patterns across the cortex regions. Furthermore, we observed a significant enrichment of eSNPs among variants associated with neurological disorders, especially insomnia, and identified insomnia-related lncRNAs involved in immune response functions. Moreover, the present study offers an improved tool for lncRNA quantification, a novel approach for lncRNA function analysis, and a database of lncRNA expression regulation in the human brain. These findings and resources will advance the research on non-coding gene expression regulation in neuroscience.

bioinformatics↗

bioRxiv2024

Production and functional verification of 8-gene (GGTA1, CMAH, β4GalNT2, hCD46, hCD55, hCD59, hTBM, hCD39)-edited donor pigs for xenotransplantation

Gene-edited pig-to-human xenotransplantation continues to make breakthroughs and is expected to enter clinic to solve the global shortage of donor organs. However, which gene combination is suitable for which organ transplantation remains unclear. In this study, we utilized CRISPR/Cas9 gene editing technology, PiggyBac transposon system and somatic cell cloning to construct GTKO/CMAHKO/{beta}4GalNT2KO/hCD46/hCD55/hCD59/hCD39/hTBM 8 gene-edited cloned (GEC) donor pigs, and performed pig to non-human primate (NHP) transplantation to evaluate the effectiveness of these GEC pigs. The multiple vectors were co-transfected into fetal fibroblasts of Diannan miniature pig with O blood type, and 25 colonies were screened out, and one of them carried GGTA1, CMAH and {beta}4GalNT2 biallelic knockout and integration of hCD46, hCD55, hCD59, hTBM and hCD39 genes, which was used as a donor cell for cloning, and a 33-day-old viable fetus was obtained. The fetus was identified and confirmed for normal karyotype and the absence of three xenogeneic antigens -Gal, Neu5Gc and Sda, and expression of hCD46, hCD55, hCD59, hTBM and hCD39 genes, then the recloning was carried out and 28 cloned piglets were obtained by natural delivery. Molecular identification at DNA, mRNA and protein levels showed that 8 gene editing (GE) was successful in these GEC piglets. Moreover, antigen-antibody binding assay and complement-dependent cytotoxicity assay demonstrated that 8GE effectively reduced the immune incompatibility and kidney xenograft survived up to 15 and 17 days into two NHPs, respectively. During this period, the recipient serum antibodies IgA and IgM, complements C3 and C4, coagulation indicators PT, APTT, TT and FIB, as well as most electrolytes and liver function indicators remained relatively stable. The 24-hour urine output and serum creatinine remained normal at a period of post-transplantation. These results indicated that the 8GEC pigs effectively alleviated immune rejection and exerted life-supporting kidney function in the recipient.

genetics↗

bioRxiv2024

Structural insights into transcription regulation of the global virulence factor PhoP from Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), remaining as the leading cause of the worldwide threat Tuberculosis, relies heavily on its transcriptional reprogramming of diverse stress genes to swiftly adapt to adverse environments and ensure infections. The global virulence factor PhoP plays a pivotal role in coordinating transcription activation or repression of the essential phosphate-nitrogen metabolic remodeling genes. However, what defines PhoP to deferentially act as an activator or a repressor remains largely unexplored. Here, we determine one cryo-EM structure of Mtb RNAP-promoter open complex, three cryo-EM structures of PhoP-dependent transcription activation complexes (PhoP-TACs) consisting of Mtb RNA polymerase (RNAP), different number of PhoP molecules binding to different types of well-characterized consensus promoters, and one cryo-EM structure of Mtb PhoP-dependent transcription repression complex (PhoP-TRC) comprising of Mtb RNAP, PhoP, the nitrogen metabolism regulator GlnR and their co-regulated promoter. Structural comparisons reveal phosphorylation of PhoP is required for stabilization of PhoP-TACs, PhoP specifically recognizes promoters as novel tandem dimers and recruits RNAP through extensively interacting with its conserved {beta} flap and {sigma}AR4 domains. Strikingly, the distinct promoter spacer length and PhoP-GlnR interactions in PhoP-TRC constrain the upstream DNA into a distinct topology and retain PhoP in a novel dragging repression mode. Collectively, these data highlight the dual regulatory mechanisms of PhoP-dependent transcription regulation in governing stress adaptation. These findings provide structural basis for developing potential anti-tuberculosis drugs and/or interventions.

microbiology↗

bioRxiv2024

Specialized Pericyte Subtypes in the Pulmonary Capillary

Pericytes (PCs) play crucial roles in capillary maturation, stability, and homeostasis. Impaired PC coverage and function are implicated in various diseases, including pulmonary arterial hypertension (PAH). Challenges investigating PC biology are largely due to the lack of a concise marker, resulting in difficulty distinguishing PCs from other mural cell populations, including smooth muscle cells (SMCs) and fibroblasts (FBs). Utilizing bioinformatic analysis and RNAscope, we identified HIG hypoxia-inducible domain family member 1B (Higd1b) as a unique and conserved gene marker for PCs and generated a novel knockin mouse line, Higd1b-CreERT2, which precisely labels PCs in the lung and heart. Human lung single-cell RNAseq suggested the presence of two HIGD1B+ PC subtypes with different functions. By lineage tracing pulmonary Higd1b+ cells exposed to hypoxia in vivo, we identified Type 1 PCs remained in the capillary network, while Type 2 PCs accumulated in the arterioles and coexpressed SMC markers and increased levels of Vimentin, associated with focal adhesion pathways. These results suggest that Type 1 PCs are specialized for supporting capillary EC homeostasis and quiescent, while Type 2 PCs are lineage active and located close to the border zone of the arterioles and capillaries, which may be motile and transition to SMC-like cells in hypoxia-induced pulmonary hypertension. The discovery of PC-type specialization in capillaries transforms our understanding of the structure, function and regulation of pulmonary capillary circulation and their contribution to vascular remodeling.

cell biology↗

bioRxiv2024

Encoding of interdependent features of head direction and angular head velocity in navigation

To comprehend the complex world around us, our brains are tasked with the remarkable job of integrating multiple features into a cohesive whole. While previous studies have primarily focused on the processing and integration of independent features, here we investigated the simultaneous encoding of the interdependent features, specifically head direction (HD) and its temporal derivative, angular head velocity (AHV), by first employing computational modeling on HD systems to explore emergent algorithms and then validated its biological plausibility with empirical data from mices HD systems. Our analysis revealed two distinct neuron populations: those with multiphasic tuning curves for HD compromised their HD encoding capacity to better capture AHV dynamics, while those with monophasic tuning curves primarily encoded HD. This pattern of functional dissociation was observed in both artificial HD systems and the cortical and subcortical regions upstream of biological HD systems, suggesting a general principle for encoding interdependent features. Further, exploration of the underlying mechanisms involved examining neural manifolds embedded within the representational space constructed by these neurons. We found that the manifold by neurons with multiphasic tuning curves was locally jagged and complex, which effectively expanded the dimensionality of the neural representation space and in turn facilitated a high-precision representation of AHV. Therefore, the encoding strategy for HD and AHV likely integrates characteristics of both dense and sparse coding schemes to achieve a balance between preserving specificity for individual features and maintaining their interdependency nature, marking a significant departure from the encoding of independent features and thus advocating future research delving into the encoding strategies of interdependent features.

neuroscience↗

bioRxiv2024

Force-Enhanced Sensitive Detection of New DNA-Interactive Agents from Microorganisms at the Single-Molecule Level

The discovery of microbial-derived DNA-interacting agents, which hold broad therapeutic potential, is inherently challenging due to the limited sensitivity and specificity of conventional methodologies. Our study introduces a pioneering application of single-molecule stretching assay (SMSA) in natural product chemistry to identify DNA-intercalating agents directly from microbial cultures or extracts. We demonstrate that mechanical force can enhance sensitivity by increasing both the binding affinity Ka and the quantity of ligands bound. The changes induced by intercalators in the counter length and overstretching transition of dsDNA yield a distinctive and highly specific signature indicative of DNA intercalative binding, thereby enabling straightforward detection of DNA intercalators even in trace amounts from microbial cultures. This methodology eliminates the need for extensive large-scale fermentation and purification processes, thus offering a more streamlined approach to DNA-intercalating natural product discovery. By applying SMSA to 17 microorganisms, we identified two DNA intercalator-producing strains: Streptomyces tanashiensis and Talaromyces funiculosus. Subsequently, three DNA intercalators, namely medermycin, kalafungin, and ligustrone B, were isolated and characterized. Among them, medermycin and kalafungin showed significant inhibitory effects against HCT-116 cancer cells, with IC50 values of 52 {+/-} 6 nM and 70 {+/-} 7 nM, respectively.

biophysics↗

bioRxiv2024

BAITSAO: Building A Foundation Model for Drug Synergy Analysis Powered by Language Models

Drug synergy prediction is a challenging and important task in the treatment of complex diseases including cancer. In this manuscript, we present a novel unified Model, known as BAITSAO, for tasks related to drug synergy prediction with a unified pipeline to handle different datasets. We construct the training datasets for BAITSAO based on the context-enriched embeddings from Large Language Models for the initial representation of drugs and cell lines. After demonstrating the relevance of these embeddings, we pre-train BAITSAO with a large-scale drug synergy database under a multi-task learning framework with rigorous selections of tasks. We demonstrate the superiority of the model architecture and the pre-trained strategies of BAITSAO over other methods through comprehensive benchmark analysis. Moreover, we investigate the sensitivity of BAITSAO and illustrate its unique functions including new drug discoveries, drug combinations-gene interaction, and multi-drug synergy predictions.

bioinformatics↗

bioRxiv2024

Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin

The antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for the development of vaccines capable of eliciting long-term protection. Prior efforts to understand the mechanisms that govern viral antigenic evolution mainly focus on HA in isolation, ignoring the fact that HA must act in concert with the viral neuraminidase (NA) during replication and spread. Numerous studies have demonstrated that the degree to which the receptor binding avidity of HA and receptor cleaving activity of NA are balanced with each other influences overall viral fitness. We recently showed that changes in NA activity can significantly alter the mutational fitness landscape of HA in the context of a lab-adapted virus strain. Here, we test whether natural variation in relative NA activity can influence the evolutionary potential of HA in the context of the seasonal H1N1 lineage (pdmH1N1) that has circulated in humans since the 2009 pandemic. We observed substantial variation in the relative activities of NA proteins encoded by a panel of H1N1 vaccine strains isolated between 2009 and 2019. We comprehensively assessed the effect of NA background on the HA mutational fitness landscape in the circulating pdmH1N1 lineage using deep mutational scanning and observed pronounced epistasis between NA and residues in or near the receptor binding site of HA. To determine whether NA variation could influence the antigenic evolution of HA, we performed neutralizing antibody selection experiments using a panel of monoclonal antibodies targeting different HA epitopes. We found that the specific antibody escape profiles of HA were highly contingent upon NA background. Overall, our results indicate that natural variation in NA activity plays a significant role in governing the evolutionary potential of HA in the currently circulating pdmH1N1 lineage.

microbiology↗

bioRxiv2024

Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behaviour, and understanding the relationships between these layers may be fundamental to advancing our understanding of how the brain works in health and disease. Recent neuroimaging research has shown that alterations in brain function that are associated with schizophrenia spectrum disorders (SSD) are already present in young adults at clinical high-risk for psychosis (CHR-P), yet the cellular and molecular determinants of these alterations are not well understood. Here, combining regional cerebral blood flow (rCBF) data with existing transcriptomic and neurotransmitter data, we show that cell-types involved in stress response and inflammation, as well as the dopamine, acetylcholine, GABAA and NMDA receptor systems, align as shared and distinct cellular and neurochemical signatures of rCBF phenotypes in people with SSD and those at CHR-P. Decoding the biological pathways involved in neuroimaging-based psychosis phenotypes may provide a basis for the development of novel interventions.

neuroscience↗

bioRxiv2024

Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity and tumor-specific looping-mediated biological pathways

Current knowledge in three-dimensional (3D) chromatin regulation in normal and disease states was mostly accumulated through Hi-C profiling in in vitro cell culture system. The limitations include failing to recapitulate disease-specific physiological properties and often lacking clinically relevant disease microenvironment. In this study, we conduct tissue-specific Hi-C profiling in a pilot cohort of 12 breast tissues comprising of two normal tissues (NTs) and ten ER+ breast tumor tissues (TTs) including five primary tumors (PTs), and five tamoxifen-treated recurrent tumors (RTs). We find largely preserved compartments, highly heterogeneous topological associated domains (TADs) and intensively variable chromatin loops among breast tumors, demonstrating 3D chromatin-regulated breast tumor heterogeneity. Further cross-examination identifies RT-specific looping-mediated biological pathways and suggests CA2, an enhancer-promoter looping (EPL)-mediated target gene within the bicarbonate transport metabolism pathway, might play a role in driving the tamoxifen resistance. Remarkably, the inhibition of CA2 not only impedes tumor growth both in vitro and in vivo, but also reverses chromatin looping. Our study thus yields significant mechanistic insights into the role and clinical relevance of 3D chromatin architecture in breast cancer endocrine resistance.

cancer biology↗

bioRxiv2024

Genetic polymorphisms of Leukocyte Immunoglobulin-Like Receptor B3 (LILRB3) gene in African American kidney transplant recipients are associated with post-transplant graft failure

BackgroundAfrican American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared to other racial and ethnic populations, highlighting the need to identify causative factors underlying this disparity. MethodWe analyzed RNA sequences of pretransplant whole blood from subjects followed in three kidney transplant cohorts to identify single nucleotide polymorphisms (SNPs) associated with death censored graft loss (DCGL). We employed a meta-analysis to uncover key transcriptional signatures and pathways associated with the identified SNPs and used single cell RNA to define cellular specificity. We characterized SNP functions using in vitro immunological and survival assays and tested for associations between the identified SNPs and other immune-related diseases using a [~]30,100 subject, electronic health record (EHR)-linked database. ResultsWe uncovered a cluster of four consecutive missense SNPs in the Leukocyte Immunoglobulin-Like Receptor B3 (LILRB3, a negative immune response regulator) gene that strongly associated with DCGL. This LILRB3-4SNPs cluster encodes missense mutations at amino acids 617-618 proximal to a SHP-1/2 phosphatase-binding ITIM motif. LILRB3-4SNPs is specifically enriched within subjects of AA ancestry (8.6% prevalence vs 2.3% in Hispanic and 0.1% in European populations), is not linked to APOL1 G1/G2 alleles, and exhibited a strong association with DCGL. Analysis of PBMC and transplant biopsies from recipients with LILRB3-4SNPs showed evidence of enhanced adaptive immune responsiveness and ferroptosis-associated death in monocytes. Overexpression of the variant allele in THP-1 cells (macrophage line) induced augmented inflammation and ferroptosis, which were attenuated by a ferroptosis inhibitor, verifying a causal link. The LILRB3-4SNPs also associated with multiple systemic and organ-specific immune-related diseases in AAs, consistent with conferring a broadly relevant immune function. Conclusionthe LILRB3-4SNPs represent a functionally important, distinct genetic risk factor for kidney transplant outcome and development/severity of other immune-related diseases in patients of AA ancestry. Pharmacological targeting of ferroptosis should be tested to prevent or treat these disease processes in AA recipients carrying LILRB3-4SNPs.

genetics↗

bioRxiv2024

The discovery of antimicrobial peptides from the gut microbiome of cockroach Blattella germanica using deep learning pipeline

Antimicrobial peptides (AMPs) are candidates for use against antibiotic-resistant microorganisms. However, due to high cytotoxicity and poor performance in biological contexts, most AMPs are unable to satisfy the requirements. The gut microbiomes of pathogenic species like Blattella germanica represent unexploited reservoirs of naturally evolved biocompatible AMPs. Here we developed a lightweight AI pipeline called AMPidentifer with two nine-layers Dense-Net blocks and one embedded new self-attention module to enable the discovery of biocompatible AMPs from microbiome. The core structure of AMPidentifer is simple, not requiring complexing code basis. On the independent test dataset, it showed robust performance and avoided high false-positive results. From the gut microbiome of B. germanica, new AMP candidates with potential low toxicities and antimicrobial activities were identified by AMPidentifer. The selected two AMPs demonstrated good antimicrobial effects in vitro and in vivo. The Cys residue was demonstrated to perform different action mechanisms in the antimicrobial activity of two AMPs, providing insights for future rational design. New efficient AMPs with low cytotoxicity identified by the new high-throughput AI pipeline from the gut microbiome of B. germanica successfully showed an important interdisciplinary strategy for discovering bio-safe AMPs from nature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/580024v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@143e033org.highwire.dtl.DTLVardef@134620dorg.highwire.dtl.DTLVardef@11809forg.highwire.dtl.DTLVardef@1134ef6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOThe Graphic AbstractC_FLOATNO C_FIG

microbiology↗

bioRxiv2024

Psilocybin induces dose-dependent changes in functional network organization in rat cortex

Psilocybin produces an altered state of consciousness in humans and is associated with complex spatiotemporal changes in brain networks. Given the emphasis on rodent models for mechanistic studies, there is a need for characterization of the effect of psilocybin on brain-wide network dynamics. Previous rodent studies of psychedelics, using electroencephalogram, have primarily been done with sparse electrode arrays that offered limited spatial resolution precluding network level analysis, and have been restricted to lower gamma frequencies. Therefore, in the study, we used electroencephalographic recordings from 27 sites (electrodes) across rat cortex (n=6 male, 6 female) to characterize the effect of psilocybin (0.1 mg/kg, 1 mg/kg, and 10 mg/kg delivered over an hour) on network organization as inferred through changes in node degree (index of network density) and connection strength (weighted phase-lag index). The removal of aperiodic component from the electroencephalogram localized the primary oscillatory changes to theta (4-10 Hz), medium gamma (70-110 Hz), and high gamma (110-150 Hz) bands, which were used for the network analysis. Additionally, we determined the concurrent changes in theta-gamma phase-amplitude coupling. We report that psilocybin, in a dose-dependent manner, 1) disrupted theta-gamma coupling [p<0.05], 2) increased frontal high gamma connectivity [p<0.05] and posterior theta connectivity [p[≤]0.049], and 3) increased frontal high gamma [p<0.05] and posterior theta [p[≤]0.046] network density. The medium gamma frontoparietal connectivity showed a nonlinear relationship with psilocybin dose. Our results suggest that high-frequency network organization, decoupled from local theta-phase, may be an important signature of psilocybin-induced non-ordinary state of consciousness.

neuroscience↗

bioRxiv2024

Gentle rhodamines for live-cell fluorescence microscopy

Rhodamines have been continuously optimized in brightness, biocompatibility, and colors to fulfill the demands of modern bioimaging. However, the problem of phototoxicity caused by the excited fluorophore under long-term illumination has been largely neglected, hampering their use in time-lapse imaging. Here we introduce cyclooctatetraene (COT) conjugated rhodamines that span the visible spectrum and exhibit significantly reduced phototoxicity. We identified a general strategy for the generation of Gentle Rhodamines, which preserved their outstanding spectroscopic properties and cell permeability while showing an efficient reduction of singlet-oxygen formation and diminished cellular photodamage. Paradoxically, their photobleaching kinetics do not go hand in hand with reduced phototoxicity. By combining COT-conjugated spirocyclization motifs with targeting moieties, these gentle rhodamines compose a toolkit for time-lapse imaging of mitochondria, DNA, and actin and synergize with covalent and exchangeable HaloTag labeling of cellular proteins with less photodamage than their commonly used precursors. Taken together, the Gentle Rhodamines generally offer alleviated phototoxicity and allow advanced video recording applications, including voltage imaging.

cell biology↗

bioRxiv2024

Neurotensin-Neurotensin Receptor 2 signaling in adipocytes regulates food intake through ceramide metabolism

Neurotensin (NTS) is a secretory peptide produced by the lymphatic endothelial cells (LEC). Our previous study revealed that NTS suppressed the activity of brown adipose tissue via the interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in the white adipocytes upregulated food intake, while the local treatment of NTS suppressed the food intake. Mechanistic study revealed that the suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2 (CerS2), increased the abundance of its products ceramide C20-C24 and downregulated the production of GDF15 in the white adipose tissues, which was responsible for the elevation of food intake. With four populations of different age and ethnic background, we discovered a potential causal and positive correlation between ceramide C20-24 and food intake in human. Our study identified that NTS-NTSR2 signaling can perform the neurological regulation via controlling the production of ceramide in the white adipocytes.

physiology↗