Biology subjects

Tseng, Y.-H.

Publications and source records attributed to Tseng, Y.-H..

15 recordsLinked to original sources

bioRxiv2026

Cold acclimation reprograms hepatic lipid composition toward n-3 HUFAs to uncouple adipose-derived lipid flux from steatosis

While cold exposure drives lipid flux from adipose tissue to the liver, this enhanced inter-organ crosstalk does not result in sustained hepatic steatosis during prolonged acclimation, indicating that factors beyond lipid flux shape metabolic outcome. To interrogate this adaptation, we performed integrated lipidomic and metabolic profiling across tissues and circulating lipoproteins over the course of cold acclimation. We showed that cold acclimation induces systemic reprogramming of lipid quality in mice, characterized by enrichment of n-3 highly unsaturated fatty acids (HUFAs) as a consequence of upregulation of fatty acid desaturases (FADS1 and 2) in the liver and white adipose tissue, thus increasing hepatic n-3/n-6 ratio. Cold-induced increase in n-3 HUFAs cause the suppression of SCD1-mediated desaturation, thus yielding a depletion of monounsaturated fatty acids (MUFAs) in the liver, along with the suppression of lipogenic markers. Notably, this high-HUFA/low-MUFA lipid signature is present in both hepatic free fatty acid and triglyceride pools, indicating that lipid remodeling occurs upstream of triglyceride synthesis. Lipidomic analysis revealed that the remodeled triglycerides are incorporated into very-low-density and intermediate density lipoproteins (VLDL and IDL), thereby propagating hepatic lipid reprogramming to the circulation. Thus, by selectively increasing endogenous n-3 HUFA availability, cold adaptation suppresses hepatic DNL and MUFA-driven triglyceride assembly, buffering lipid accumulation despite sustained fatty acid influx and reshaping systemic lipid distribution with potential cardiometabolic impact.

biochemistry↗

bioRxiv2025

TypeAssembly: Copy number estimation and allele typing for haplotype assemblies

Accurately annotating complex genes in the human genome, particularly from haplotype assemblies, remains a significant challenge. To overcome this, we developed TypeAssembly, a local alignment-based framework for copy number estimation and allele typing. Operating in two modes, mode-FASTA and mode-VCF, TypeAssembly can define alleles by either sequence or variant information. We successfully applied it to annotate 41 genes in the MHC locus, 17 KIR genes, and, for the first time, 15 pharmacogenes across 466 haplotype assemblies. This study establishes TypeAssembly as a robust method for accurately annotating complex genomic regions and provides an evaluation of existing gene annotations and callers.

bioinformatics↗

bioRxiv2025

Single-Nucleus Analysis of Human White Adipose Tissue Reveals Adipocyte Subsets with Distinct Metabolic Profiles

Anatomic location of white adipose tissue is a determinant of cardiometabolic risk. To understand differences within/between adipose depots, we generated 65,668 single-nucleus transcriptomes from human subcutaneous or intraabdominal adipose tissue (SAT/IAT). Unsupervised analysis revealed 26 adipose-resident cell clusters including two subpopulations of mature adipocytes, characterized by high vs. low expression of adipocyte maturation genes (ADIPOMAThi vs. ADIPOMATlo). ADIPOMATlo adipocytes demonstrate a low-differentiation, pro-inflammatory, and pro-fibrotic transcriptome. IAT-resident ADIPOMATlo were more abundant in higher BMI donors, while SAT-resident ADIPOMATlo associated with impaired glycemia. TSHZ3 was identified as a candidate regulator of ADIPOMATlo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibited differentiation, with downregulation of early adipogenic regulators (e.g. CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduced SAT and IAT weight. Here, we show that adipocyte subsets with distinct transcriptomic signature reside in human WAT; altered TSHZ3-mediated transcriptional regulation may contribute to low-maturation subpopulation linked to metabolic disease.

cell biology↗

bioRxiv2025

Ultrafast and Ultralarge Distance-Based Phylogenetics Using DIPPER

MotivationDistance-based methods are commonly used to reconstruct phylogenies for a variety of applications, owing to their excellent speed, scalability, and theoretical guarantees. However, classical de novo algorithms are hindered by cubic time and quadratic memory complexity, which makes them impractical for emerging datasets containing millions of sequences. Recent placement-based alternatives provide better algorithmic scalability, but they also face practical scaling challenges due to their high cost to compute evolutionary distances and significant memory usage. Current tools also do not fully utilize the parallel processing capabilities of modern CPU and GPU architectures. ResultsWe present DIPPER, a novel distance-based phylogenetic tool for ultrafast and ultralarge phylogenetic reconstruction on GPUs, designed to maintain high accuracy and a small memory footprint. DIPPER introduces several novel innovations, including a divide-and-conquer strategy, a placement strategy, and an on-the-fly distance calculator that greatly improve the runtime and memory complexity. These allow DIPPER to achieve runtime and space complexity of O(N.log(N)) and O(N), respectively, with N taxa. With divide-and-conquer, DIPPER is also able to maintain a low memory footprint on the GPU, independent of the number of taxa. DIPPER consistently outperforms existing methods in speed, accuracy, and memory efficiency, and scales to tree sizes 1-2 orders of magnitude beyond the limits of existing tools. With the help of a single NVIDIA RTX A6000 GPU, DIPPER is able to reconstruct a phylogeny from 10 million unaligned sequences in under 7 hours, making it the only distance-based method to operate at this scale and efficiency. AvailabilityDIPPERs code is freely available under the MIT license at https://github.com/TurakhiaLab/DIPPER, and the documentation for DIPPER is available at https://turakhia.ucsd.edu/DIPPER. The test datasets and experimental results are available at https://zenodo.org/records/16803048.

bioinformatics↗

bioRxiv2025

Mitochondrial ATP-Sensitive K+ Channels (MitoKATP) Regulate Brown Adipocyte Differentiation and Metabolism

Brown adipose tissue (BAT) plays a central role in mammalian non-shivering thermogenesis, dissipating mitochondrial membrane potentials through the activity of uncoupling protein UCP1 to release heat. Inner membranes of mitochondria are known to be permeable to potassium ions (K+), which enter the matrix either through ATP-sensitive channels (MitoKATP) or leakage across the bilayer driven by inner membrane potentials. Mitochondrial K+ influx is associated with increased osmotic pressure, promoting water influx and increasing matrix volume. Since BAT mitochondria have lower inner membrane potentials due to uncoupling protein 1 (UCP1) activity, we hypothesized this could involve compensatory changes in MitoKATP activity, and thus tested MitoKATP involvement in brown adipocyte activities under basal and stimulated conditions. We find that cold exposure and adrenergic stimulation in mice modulate BAT MitoK levels, the channel portion of MitoKATP. Genetic ablation of the gene that codes for the pore-forming subunit of MitoKATP in human pre-adipocytes decreased cellular respiration and proliferation, compromising differentiation into mature adipocytes. In mouse cell lines, the absence of the protein limited cellular oxygen consumption in the precursor stage, but not in mature adipocytes. Interestingly, inhibition of MitoKATP in mature adipocytes increased adrenergic-stimulated oxygen consumption, indicating that shutdown of this pathway is important for full BAT thermogenesis. Similarly, MitoKATP inhibition increased oxygen consumption in BAT mitochondria isolated from mice treated with beta 3 adrenergic receptor agonist CL316,243. Overall, our results suggest that the activity of MitoKATP regulates differentiation and metabolism of brown adipocytes, impacting on thermogenesis. New and NoteworthyBrown fat cells are important to maintain healthy body weight by promoting mitochondrial uncoupling. Here, we demonstrate that mitochondrial ATP-sensitive potassium channels (MitoKATP) have important roles both in the differentiation of brown fat cells and in the activation of energy-dissipating uncoupling in this tissue.

physiology↗

bioRxiv2023

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro, which implicates this pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

bioinformatics↗

bioRxiv2023

m6A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis

Brown adipose tissue (BAT) has the capacity to regulate systemic metabolism through the secretion of signaling lipids. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. In this study, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14), modifies the BAT secretome to initiate inter-organ communication to improve systemic insulin sensitivity. Importantly, these phenotypes are independent of UCP1-mediated energy expenditure and thermogenesis. Using lipidomics, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KO-BAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a levels are inversely correlated with insulin sensitivity in humans. Furthermore, in vivo administration of PGE2 and PGF2a in high-fat diet-induced insulin-resistant obese mice recapitulates the phenotypes of METTL14 deficient animals. PGE2 or PGF2a improves insulin signaling by suppressing the expression of specific AKT phosphatases. Mechanistically, METTL14-mediated m6A installation promotes decay of transcripts encoding prostaglandin synthases and their regulators in human and mouse brown adipocytes in a YTHDF2/3-dependent manner. Taken together, these findings reveal a novel biological mechanism through which m6A-dependent regulation of BAT secretome regulates systemic insulin sensitivity in mice and humans. HighlightsO_LIMettl14KO-BAT improves systemic insulin sensitivity via inter-organ communication; C_LIO_LIPGE2 and PGF2a are BAT-secreted insulin sensitizers and browning inducers; C_LIO_LIPGE2 and PGF2a sensitize insulin responses through PGE2-EP-pAKT and PGF2a-FP-AKT axis; C_LIO_LIMETTL14-mediated m6A installation selectively destabilizes prostaglandin synthases and their regulator transcripts; C_LIO_LITargeting METTL14 in BAT has therapeutic potential to enhance systemic insulin sensitivity C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/542169v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@16b3393org.highwire.dtl.DTLVardef@1072ae3org.highwire.dtl.DTLVardef@190a6d7org.highwire.dtl.DTLVardef@1b98bce_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Comprehensive analysis of intercellular communication in thermogenic adipose niche

Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a strategy against obesity. BAT undergoes major remodeling in a cold environment. This remodeling results from changes in the number and function of brown adipocytes, expanding the network of blood vessels and sympathetic nerves, and changes in the makeup and function of immune cells. All these processes are essential for enhanced BAT thermogenesis to maintain euthermia in the cold. Such synergistic adaptation requires extensive crosstalk between the individual cells in tissues to coordinate their responses. To understand the mechanisms of intercellular communication in BAT, we applied the CellChat algorithm to single-cell transcriptomic data of mouse BAT. We constructed an integrative network of ligand-receptor interactome in BAT and identified the major signaling input and output of each cell type. By comparing the ligand-receptor interactions in BAT of mice housed at different environmental temperatures, we found that cold exposure enhances the intercellular interactions among the major cell types in BAT, including adipocytes, adipocyte progenitors, lymphatic and vascular endothelial cells, myelinated Schwann cells (MSC), nonmyelinated Schwann cells (NMSC), and immune cells. Furthermore, we identified the ligands and receptors that are regulated at the transcriptional level by temperature. These interactions are predicted to regulate the remodeling of extracellular matrix (ECM), inflammatory response, angiogenesis, and neurite growth. Together, our integrative analysis of intercellular communications in BAT and their dynamic regulation in response to housing temperatures establishes a holistic understanding of the mechanisms involved in BAT thermogenesis. The resources presented in this study provide a valuable platform for future investigations of BAT development and thermogenesis.

systems biology↗

bioRxiv2022

Reconstructing human Brown Fat developmental trajectory in vitro

Brown adipocytes represent a specialized type of mammalian adipocytes able to uncouple nutrient catabolism from ATP generation to dissipate energy as heat. They play an important role in mammals, allowing non-shivering thermogenesis to regulate body temperature in response to cold exposure. In humans, the brown fat tissue is composed of small discrete depots found mostly throughout the neck and trunk region. Increasing brown fat activity either with drug treatment or cell therapy is considered a potential approach for the treatment of metabolic syndrome and obesity. The recent development of in vitro differentiation strategies relying on human pluripotent stem cells (hPSCs) offers the possibility to produce unlimited amounts of brown adipocytes. A strategy efficiently applied to several tissues is to recapitulate step by step the development of the tissue of interest by exposing hPSCs to the signaling cues used during normal embryonic development. However, this strategy has proven difficult to implement for brown fat as the development of this tissue is poorly understood. Here, we first used single cell RNA sequencing to characterize the development of interscapular brown fat in mouse. Our analysis identified a previously unrecognized population of brown adipocytes precursors characterized by expression of the transcription factor GATA6. We show that this precursor population can be efficiently generated from paraxial mesoderm precursors differentiated in vitro from hPSCs by modulating the signaling pathways identified in our transcriptomic analysis. These precursors can in turn be efficiently converted into functional brown adipocytes which can respond to adrenergic stimuli by increasing their metabolism resulting in heat production.

developmental biology↗

bioRxiv2022

MEBOCOST: Metabolic Cell-Cell Communication Modeling by Single Cell Transcriptome

We developed MEBOCOST, a computational algorithm for quantitatively inferring metabolite-mediated intercellular communications using single cell RNA-seq data. The algorithm identifies cell-cell communications in which metabolites, such as lipids, are secreted by sender cells and traveled to interact with sensor proteins of receiver cells. The sensor proteins on receiver cell might be cell surface receptors, transporters across the cell membrane, or nuclear receptors. MEBOCOST relies on a comprehensive database of metabolite-sensor partners, which we manually curated from the literatures and other public sources. MEBOCOST defines sender and receiver cells for an extracellular metabolite based on the expression levels of the enzymes and sensors, respectively, thus identifies metabolite-sensor communications between the cells. Applying MEBOCOST to mouse brown adipose tissue (BAT) successfully recaptured known metabolite-mediated cell communications and further identified new communications. Additionally, MEBOCOST identified a set of BAT intercellular metabolite-sensor communications that was regulated by cold exposure of the mice. MEBOCOST will be useful to numerous researchers to investigate metabolite-mediated cell-cell communications in many biological and disease models. The MEBOCOST software is freely available at https://github.com/zhengrongbin/MEBOCOST.

bioinformatics↗

bioRxiv2022

Mapping the temporal transcriptional landscape of human white and brown adipogenesis using single-nuclei RNA-seq

Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in humans. By single-nuclei RNA-sequencing (snRNA-seq) of over 20,000 differentiating white and brown preadipocytes, we constructed a high-resolution temporal transcriptional landscape of human white and brown adipogenesis. White and brown preadipocytes were isolated from a single individuals neck region, thereby eliminating inter-subject variability across two distinct lineages. These preadipocytes were also immortalized to allow for controlled, in vitro differentiation, allowing sampling of distinct cellular states across the spectrum of adipogenic progression. Pseudotemporal cellular ordering revealed the dynamics of ECM remodeling during early adipogenesis, and lipogenic/thermogenic response during late white/brown adipogenesis. Comparison with adipogenic regulation in murine models revealed several targets for potential adipogenic/thermogenic drivers in humans. Key adipogenic and lipogenic markers revealed in our analysis were applied to analyze publicly available scRNA-seq datasets; these confirmed unique cell maturation features in recently discovered murine preadipocytes, and revealed inhibition of adipogenic expansion in humans with obesity. Overall, our study presents a comprehensive molecular description of both white and brown adipogenesis in humans and provides an important resource for future studies of adipose tissue development and function in both health and metabolic disease state.

bioengineering↗

bioRxiv2022

CORK1, a LRR-Malectin Receptor Kinase for Cellooligomer Perception in Arabidopsis thaliana

Cell wall integrity (CWI) maintenance is central for plant cells. Mechanical or chemical distortions, pH changes, or breakdown products of cell wall polysaccharides activate plasma membrane-localized receptors and induce appropriate downstream responses. Microbial interactions alter or destroy the structure of the plant cell wall, connecting CWI maintenance to immune responses. Cellulose is the major polysaccharide in the primary and secondary cell wall. Its breakdown generates short-chain cellooligomers which induce Ca2+-dependent CWI responses. We have shown here that these responses require the malectin domain-containing CELLOOLIGOMER-RECEPTOR KINASE 1 (CORK1) in Arabidopsis. CORK1 is required for cellooligomer-induced cytoplasmic Ca2+ elevation, reactive oxygen species (ROS) production, mitogen associated protein kinase (MAPK) activation, cellulose synthase phosphorylation, and the regulation of CWI-related genes including those involved in biosynthesis of cell wall material, secondary metabolites and tryptophan. Phosphoproteome analyses identified early targets involved in signaling, cellulose synthesis, the endoplasmatic reticulum/Golgi secretory pathway, cell wall repair and immune responses. Two conserved phenylalanine residues in the malectin domain are crucial for CORK1 function. We propose that cellulose breakdown products bind to the malectin domain in CORK1, indicating its role as a novel receptor kinase for CWI maintenance.

plant biology↗

bioRxiv2022

The impact of multigenerational high-fat diet feeding on the gut microbiome and host metabolism

Although human genetics partially explain the heritability of obesity and type 2 diabetes (T2D), the human gut microbiome also plays a significant role. While changes in human genetics at the population level occur only after many generations, the gut microbiome evolves over a shorter time span. The gut microbiome is also vertically transmitted across generations, therefore, changes in one generation can be passed on to subsequent generations. However, it is unknown whether the gut microbiome influences natural selection of its host under obesogenic pressure. Here, we show that C57BL/6 mice fed a high-fat diet (60% fat, HFD) over four generations develop resistance to obesity and the metabolic syndrome (MetS). Unexpectedly, the mice were increasingly leaner as well as more glucose tolerant and insulin sensitive across generations. This phenomenon was attributed to the most obese mice not yielding progenies, whereas the leanest mice successfully reproduced, and their offspring were also resistant to obesity. In other words, a population bottleneck was observed. Because all the mice were nearly genetically identical inbred C57BL/6J mice, the large variation in body weight gain in response to HFD feeding was likely independent of genetics. We explored whether microbial factors enriched in obesity-resistant mice promote healthier host metabolic phenotypes under HFD feeding, thereby contributing to the heterogeneity in body weight gain and providing an adaptive advantage to the host. Pearson correlation analysis revealed that body weight gain was positively correlated with Lactococcus lactis, as well as negatively correlated with Lactobacillus johnsonii and pathways for coenzyme A biosynthesis, amino acid biosynthesis (lysine, isoleucine, valine), and nucleotide biosynthesis (adenosine, guanosine). Overall, we observed multigenerational adaptation in the gut microbiome correlated with improved metabolism, yet further studies are needed to validate that these adaptations drive metabolic health.

microbiology↗

bioRxiv2021

Characterization of transcript enrichment and detection bias in single-nuclei RNA-seq for mapping of distinct human adipocyte lineages

Single-cell RNA-sequencing (scRNA-seq) enables molecular characterization of complex biological tissues at high resolution. The requirement of single-cell extraction, however, makes it challenging for profiling tissues such as adipose tissue where collection of intact single adipocytes is complicated by their fragile nature. For such tissues, single-nuclei extraction is often much more efficient and therefore single-nuclei RNA-sequencing (snRNA-seq) presents an alternative to scRNA-seq. However, nuclear transcripts represent only a fraction of the transcriptome in a single cell, with snRNA-seq marked with inherent transcript enrichment and detection biases. Therefore, snRNA-seq may be inadequate for mapping important transcriptional signatures in adipose tissue. In this study, we compare the transcriptomic landscape of single nuclei isolated from preadipocytes and mature adipocytes across human white and brown adipocyte lineages, with whole-cell transcriptome. We demonstrate that snRNA-seq is capable of identifying the broad cell types present in scRNA-seq at all states of adipogenesis. However, we also explore how and why the nuclear transcriptome is biased and limited, and how it can be advantageous. We robustly characterize the enrichment of nuclear-localized transcripts and adipogenic regulatory lncRNAs in snRNA-seq, while also providing a detailed understanding for the preferential detection of long genes upon using this technique. To remove such technical detection biases, we propose a normalization strategy for a more accurate comparison of nuclear and cellular data. Finally, we demonstrate successful integration of scRNA-seq and snRNA-seq datasets with existing bioinformatic tools. Overall, our results illustrate the applicability of snRNA-seq for characterization of cellular diversity in the adipose tissue.

bioengineering↗

bioRxiv2020

Vascular smooth muscle-derived TRPV1-expressing progenitors are a new source of cold-induced thermogenic adipocytes

Brown adipose tissue (BAT) functions in energy expenditure in part due its role in thermoregulation. The prominent capacity of BAT to enhance fuel utilization and energy expenditure makes it an attractive target for treating obesity and metabolic disorders. Prolonged cold exposure induces de novo recruitment of brown adipocytes and activates their thermogenic activity. However, the exact source of cold-induced brown adipocytes is not completely understood. In this study, we sought to investigate the cellular origin of cold-induced brown adipocytes using single-cell RNA sequencing. We identified two distinct types of adipocyte progenitors that contribute to de novo recruitment of brown adipocytes in response to cold challenge. One is the previously known Pdgfra-expressing mesenchymal progenitors and the other is a vascular smooth muscle-derived adipocyte progenitor (VSM-APC) population, which expresses the temperature-sensitive ion channel transient receptor potential cation channel subfamily V member 1 (Trpv1). Using flow cytometry and lineage tracing, we demonstrated that the Trpv1pos VSM-APCs were indeed distinct from the Pdgfrapos progenitors and could contribute to brown adipocytes with greater thermogenic potential. Together, these findings illustrate a landscape of thermogenic adipose niche at the single cell resolution and identify a new cellular origin for the development of brown adipocytes.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗