Biology subjects

Kimura, T.

Publications and source records attributed to Kimura, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Transcriptomic signatures associated with mania-to-depression and depression-to-mania transitions in bipolar disorder: a case report using induced microglia-like (iMG) cells

IntroductionBipolar disorder (BD) is characterized by recurring episodes of mania and depression. Despite extensive research, the pathophysiology underlying these mood swings remains elusive. Emerging evidence indicates a potential role for neuroinflammation and microglial activation in the pathophysiology of BD. MethodsWe employed a reverse-translational approach to generate directly induced microglia-like (iMG) cells from peripheral blood monocytes of a single patient with BD, repeatedly sampled across depressive, manic, and subsequent depressive phases. RNA sequencing was performed on iMG cells at each time point to identify differentially expressed genes related to mood state transitions. ResultsA thorough analysis of longitudinal gene expression data has led to the identification of three functional gene categories: "state-dependent genes", "depression-to-mania transition genes (named: firing genes)", and "mania-to-depression transition genes (named: extinguishing genes)". A total of 168 firing, 59 extinguishing, and 77 state-dependent genes were identified. Notably, functional annotation revealed that, compared to the extinction gene set, the firing gene set was enriched in immune and inflammatory response pathways, particularly early-response cytokines such as IL1B and TNF. ConclusionsBased on these findings, we propose that inflammatory immunomodulation by microglia contributes to mood switching in BD, especially in the process of depression-to-mania transition. The classification of genes by their relationship to state transitions offers a novel framework for understanding the molecular mechanisms underlying this complex disorder and may identify potential therapeutic targets to stabilize mood. Further validation with larger cohorts is warranted.

neuroscience↗

bioRxiv2026

A Structural Domain in the genomic RNA of SARS-CoV-2 Folds into a Compact Granular Structure without the N protein: A Single-Molecule Fluorescence Spectroscopic Investigation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) packages its single-stranded genomic RNA (gRNA) having about 30,000 nucleotides into virions by forming 35-40 granular ribonucleoprotein (RNP) units. Each RNP unit has a diameter of [~]15 nm. While it is generally assumed that the assembly of these RNPs is driven by the binding of the nucleocapsid (N) protein to the gRNA in the cytoplasm, the precise molecular mechanism remains to be fully elucidated. In this study, we develop an experimental strategy based on single-molecule fluorescence and fluorescence correlation spectroscopies to examine the formation of long-range base pairing within a candidate structural domain corresponding to nt 12230-12686 of the gRNA (gRNA12k). Our results demonstrate that the 5 and 3 regions of gRNA12k autonomously form long-range base pairing in near-physiological buffers containing mono- and divalent cations, independently of the N protein. This domain possesses an extensive secondary structure, is compact, and can unfold and refold reversibly upon heat treatment and cooling. Notably, the addition of the N protein melts the long-range base pairs, and causes the aggregation of multiple molecules of gRNA12k. Based on these observations, we propose a refined mechanism for the genome assembly in SARS-CoV-2: gRNA initially forms autonomous granular structures, which are subsequently reorganized and condensed by the N protein to chaperone the assembly of the entire gRNA. SignificanceSARS-CoV-2 organizes its exceptionally long genomic RNA (gRNA) having about 30,000 nt into 35-40 granular ribonucleoprotein (RNP) units for viral packaging. It has been assumed that the nucleocapsid (N) protein drives the formation of the RNP granules. In this study, we challenge this prevailing view by demonstrating that a specific region of the gRNA sequence inherently encodes the information to fold into a compact, granular architecture independently of any proteins. Unexpectedly, we found that the N protein partially melts the autonomous structures, suggesting that it acts as an RNA chaperone to facilitate flexible genome assembly. Our findings redefine the interplay between viral proteins and gRNA, offering a new perspective on the mechanism of coronavirus replication.

biophysics↗

bioRxiv2026

Co-targeting an AMPK--MAPK axis reprograms CAFs and suppresses PDAC

Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer characterized by limited therapeutic options and a highly treatment-resistant tumor microenvironment. Beyond tumor-intrinsic genetic alterations, growing evidence indicates that host-microbiome interactions influence cancer progression through microbial metabolites. However, how microbiome-derived metabolites influence oncogenic signaling in PDAC remains unclear. Here, integrated profiling revealed a consistent reduction of the microbial metabolite acetic acid in fecal samples from treatment-naive patients with PDAC and in a genetically defined Drosophila model recapitulating key PDAC driver alterations. Acetic acid activates AMP-activated protein kinase, and pharmacological activation of this pathway together with inhibition of mitogen-activated protein kinase signaling suppressed tumor growth in fly and mouse models. Combined pathway targeting restored AMPK activity and suppressed cancer-associated fibroblast activation. These findings identify a microbiome-associated metabolic vulnerability in PDAC and suggest that coordinated targeting of metabolic and oncogenic signaling may restrain tumor progression and improve therapeutic strategies.

cancer biology↗

bioRxiv2026

Lactate dehydrogenase is associated with cholesterol/lipid metabolism, and fluvastatin plus dipyridamole suppresses canine hemangiosarcoma growth in patient-derived xenograft models

Tumor cells commonly exhibit aerobic glycolysis and produce lactate despite oxygen availability. Lactate dehydrogenase (LDH) catalyzes pyruvate-lactate interconversion and regulates intracellular lactate levels. Endothelial cells also depend on glycolysis for ATP production, which prompted us to investigate LDH in canine hemangiosarcoma (HSA), a malignant endothelial tumor. We inhibited LDH with (R)-GNE-140 or sodium oxamate in two canine HSA cell lines (HU-HSA-2 and HU-HSA-3) and generated HU-HSA-3 clones with knockout of LDHA or LDHB to evaluate the effects of LDH perturbation. (R)-GNE-140 and sodium oxamate suppressed proliferation and reduced global histone lactylation levels in both cell lines. mRNA-sequencing (mRNA-seq) of (R)-GNE-140-treated HU-HSA-2 cells identified cholesterol/lipid metabolism-related gene sets among the top negatively enriched pathways. Representative cholesterol/lipid metabolism genes responded differently depending on cell lines and inhibitors. (R)-GNE-140 decreased these genes in HU-HSA-2 but not HU-HSA-3, whereas sodium oxamate decreased them in HU-HSA-3 with limited effects in HU-HSA-2. In HU-HSA-3, LDHA and LDHB knockout clones decreased SREBP2 expression and reduced the number of lipid droplets. Fluvastatin, a cholesterol metabolism inhibitor, inhibited HSA cell growth in vitro but did not significantly suppress tumor growth in two HSA patient-derived xenograft (PDX) models. In contrast, combined fluvastatin and dipyridamole treatment inhibited proliferation in vitro and tumor growth in PDX models. Collectively, these results suggest a context-dependent association between LDH and cholesterol/lipid metabolism in canine HSA cell lines and provide a rationale for further evaluation of combined cholesterol pathway inhibition.

cancer biology↗

bioRxiv2026

Cryo-EM structure of pro-aggregant P301L/S320F double-mutant tau filaments formed in mouse brains following peripheral AAV delivery

Tauopathies are characterized by the accumulation of abnormally phosphorylated tau filaments, with disease-specific folds revealed by cryo-electron microscopy (cryo-EM). Here, we delivered a recombinant human tau carrying the P301L/S320F double mutation into AppNL-G-F/MAPT double knock-in mice using a blood-brain-barrier-permeable AAV (AAV-PHP.eB), enabling rapid induction of tau aggregation in vivo. The mutant tau was systemically administered via retro-orbital injection, providing a minimally invasive approach for widespread neuronal transduction. Phosphorylated tau aggregation, as well as seeding activity, were observed without the need for exogenous seeds. Our cryo-EM analysis resolved a novel filament fold incorporating residues 279-329, in which the P301L and S320F mutations introduced stabilizing interactions that reinforced filament assembly. This conformation was distinct from previously reported folds, including Alzheimer and Pick tau filaments. Moreover, the filaments adopted a more compact architecture than those observed in patient-derived samples or other model mice. This finding demonstrates that P301L/S320F double-mutant tau adopts a structurally unique, highly aggregation-prone fold, and that this system provides a rapid platform for modeling tau filament formation.

neuroscience↗

bioRxiv2025

The number of anal fin-rays is decided by two heritable traits, anteroposterior length of the anal fin and interval between the anal fin-rays.

The number of median fin-rays is a readily quantifiable trait that has been previously studied due to its interspecific variation. I observed in F2 progeny from two inbred lines of medaka with differing anal fin-ray numbers (Kaga and Hd-rRII1) that individuals exhibited the same ray number but differed in the anteroposterior length of the anal fin and the interval between the anal fin-rays. Inducing vertebral fusion to shorten the anal fin anteroposterior length resulted in a decrease in ray number. Given reports of an increased ray number during low-temperature development, I reared Hd-rRII1 fry at 17{degrees}C post-hatching, which resulted in an increase in the number of rays. At this temperature, the anal fin anteroposterior length and the interval between the anal fin-rays were also slightly reduced. Since the posterior boundary of the anal fin is determined by Hox genes, I hypothesize that a temperature-sensitive signaling pathway exists downstream of these genes. Collectively, our results suggest that the medaka anal fin-ray number is determined by at least two genetic traits: the anal fin anteroposterior length and the interval between the anal fin-rays.

developmental biology↗

bioRxiv2025

Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo, PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

biochemistry↗

bioRxiv2025

G3BP1 Maintains Lysosomal Homeostasis to Limit Tau Aggregate Accumulation

Tau aggregation is a pathological hallmark of a group of neurodegenerative diseases collectively termed tauopathies. While impaired proteostasis is known to drive the accumulation of abnormal proteins, the molecular factors influencing Tau aggregate clearance remain incompletely understood. In this study, we employed a cell-based Tau reporter assay combined with a lentivirus-based pooled CRISPR-Cas9 loss-of-function library to identify genes that regulate Tau aggregation. Genome-wide screening revealed that candidate genes were significantly enriched in categories related to mRNA metabolic processes and autophagy. Among them, we focused on the RNA-binding protein G3BP1, which is functionally associated with both processes. Detailed analyses showed that G3BP1 deficiency promoted the accumulation of Tau aggregates without affecting stress granule formation or autophagic flux. Instead, G3BP1 dysfunction resulted in impaired lysosomal homeostasis, as evidenced by reduced lysosomal abundance and acidification. Furthermore, lysosomal damage induced by L-leucyl-L-leucine methyl ester (LLOMe) enhanced Tau aggregation, particularly in G3BP1-deficient cells. Conversely, pharmacological activation of TFEB by the curcumin analog C1 restored lysosomal function and suppressed Tau aggregate accumulation to wild-type levels. These findings highlight a role of G3BP1 in maintaining lysosomal homeostasis and promoting Tau clearance. Our results further suggest that therapeutic strategies aimed at enhancing lysosomal biogenesis, such as TFEB activation, may hold promise for the treatment of tauopathies.

cell biology↗

bioRxiv2025

Pharmacological potentiation of Nav1.1 channels in interneurons mitigates tau depositions and neuronal death in a mouse model of neurodegenerative dementias

Epileptiform discharges and neuronal hyperexcitability are key pathophysiological features of Alzheimers disease and related tauopathies. We previously identified selective dynfuntion of parvalbumin-positive GABAergic interneurons (PV neurons), which regulate neural network excitability, in a tauopathy mouse model. However, the mechanistic link between PV neuron deficits, tau pathology, and neurodegeneration remains unclear. Here, we demonstrate that pharmacological enhancement of phasic PV neuron activity markedly attenuates tau accumulation and neuronal loss in a tauopathy mouse model. We developed DSR-143630, a novel activator of voltage-gated sodium channel Nav1.1, selectively expressed in PV neurons. Administration of DSR-143630 alleviated febrile seizures in Nav1.1 haploinsufficient mice and suppressed high-frequency oscillations (HFOs), an electrophysiological signature of hyperexcitability associated with cognitive impairments, in rTg4510 tau transgenic mice. Longitudinal tau PET and volumetric MRI demonstrated that DSR-143630 treatment from 4 to 11 months of age profoundly reduced age-dependent tau deposition and atrophy in the neocortex and hippocampus. Postmortem analyses further revealed decreased levels of phosphorylated tau, preservation of neuronal populations, and attenuated neuroinflammatory responses, including reactive gliosis. These findings establish PV neuron dysfunctions and consequent network hyperexcitability as key drivers of tau pathogenesis and highlight pharmacological Nav1.1 activation as a promising disease-modifying strategy for neurodegenerative tauopathies. One Sentence SummaryPharmacological potentiation of interneuronal activities attenuates aberrant network excitability, progressive tau deposition, and neurodegeneration.

neuroscience↗

bioRxiv2025

High-speed atomic force microscopy reveals surface-catalyzed elongation mechanism of fungal functional amyloid, hydrophobin RolA

Hydrophobins, a type of functional amyloid, are conserved in filamentous fungi and act as a protective coat in the fibrous form called rodlet. Rodlets form hierarchical structures where they are bundled and densely aligned, contributing to the hydrophobicity of the mycelium surface. However, the formation mechanism of the hierarchical structures is completely unknown. In this study we used high-speed atomic force microscopy to directly observe the structural dynamics of hierarchical structure formation by hydrophobin RolA from the industrial fungus Aspergillus oryzae at a single-fibril level and revealed its mechanism. The elongation of rodlets occurred at both ends and was discontinuous, alternating between periods when they could elongate (growth state) and could not elongate (pause state). This suggests an equilibrium of two distinct structural states at the rodlet ends. We also discovered an aggregation pathway, termed "surface-catalyzed elongation", in which elongation is promoted by lateral interactions between bundled rodlets. Surface-catalyzed elongation decreased the energy barrier of both structural switching between growth and pause states and elongation at rodlet ends, doubling the elongation rate in bundled rodlets. The rodlet surface could be considered as a catalyst for the elongation of neighboring rodlets. Surface-catalyzed elongation could contribute to rodlet bundling, whereby rodlets tend to form oriented domain structures, and our Monte Carlo simulations confirmed this. Surface-catalyzed elongation may be a universal concept to explain the hierarchical assembly mechanism of amyloid fibrils, so it could contribute to the advancement of amyloid research in general.

biophysics↗

bioRxiv2025

Lysine lactylation regulates ATF4-mediated stress responses under glucose starvation in canine hemangiosarcoma

Hemangiosarcoma (HSA) is a malignant endothelial tumor that occurs frequently in dogs but is rare in other species including humans. Due to its aggressive behavior and limited therapeutic options, patient prognosis is generally poor. Tumor cells produce excess lactate via anerobic glycolysis, and it regulate gene expressions through histone lactylation in response to cellular metabolic conditions. However, how histone lactylation affects biological behavior under glucose-limited conditions in HSA remains unknown. Here, we established canine HSA cell lines and patient-derived xenograft models and investigated the role of histone lactylation during glucose deprivation. HSA cells exhibited higher global histone lactylation levels than normal endothelial cells. Although glucose restriction reduced global histone lactylation levels, Cleavage Under Targets and Tagmentation (CUT&Tag) analysis revealed enrichment of lactylation peaks at transcription-start sites (TSSs) of ATF4-regulated stress-response, asparagine biosynthesis and immune-related genes. TSSs of stress-response genes were co-occupied with RNA polymerase II phosphorylated at serine 5 and showed increased gene expressions, suggesting that lactylation at TSSs activated transcription under glucose-deprived conditions. [U-13C]glutamine tracing indicated that HSA cells synthesized asparagine from glutamine when glucose was scarce. Asparagine supplementation modestly activated cell proliferation. In HSA patient tissues, H3K18la levels were heterogeneous, and M2-like macrophages preferentially infiltrated tumor regions showing low histone lactylation levels. Consistently, glucose-starved HSA cells attracted macrophages and induced M2-like polarization in vitro. These findings demonstrate that lysine lactylation, possibly histone lactylation, persists even under glucose-deprived conditions and regulate transcription that supports tumor cell survival and fosters a pro-tumor microenvironment. One Sentence SummaryLysine lactylation is enriched at TSSs of stress-response genes under glucose starvation and associated with their transcription in canine hemangiosarcoma.

cancer biology↗

bioRxiv2025

ttc39bl, one of the two duplicated paralogs of the tetratricopeptide repeat domain 39B gene, is essential for carotenoid coloration in medaka (Oryzias latipes) and is the gene responsible for the r locus.

Body color plays key roles in fitness, communication with others, and hiding. In poikilothermal vertebrates, the body color is mainly determined by types and distributions of chromatophores. Among them, carotenoid color of xanthophores/erythrophores is important for interspecific diversity and colorful males as sexual dimorphism. Most vertebrates cannot synthesize carotenoids in their bodies and must ingest them from food. However, the genes involved in the uptake process are not fully understood. Therefore, we tried to identify the causal gene of the carotenoid color mutant of medaka. The HdrR-II1 strain used in the genome project has orange body color in males and white body color in females. The orange and white body color was known to be controlled by the sex-linked R locus, but the causal gene of this was unknown. In this study, we identified that the causal gene of the R locus is tetratricopeptide repeat domain 39b like (ttc39bl). In the HdrR-II1, the ttc39bl on the Y chromosome is normal, but the ttc39bl on the X chromosome has an 821 bases insertion in exon 3 and is broken. This insertion is also present on both the X and Y chromosomes of commercially available white medaka.

zoology↗

bioRxiv2025

Human pluripotent stem cell-derived intestinal epithelial cells maintain small intestine-specific functions over time, even with repeated cell division

The human colon cancer-derived cell line Caco-2 is widely used in drug discovery due to its barrier function and transporter activity. However, Caco-2 cells have extremely low drug metabolic capacity, resulting in discrepancies with human physiology. In this study, we conducted experiments on human intestinal epithelial cells generated from pluripotent stem cell-derived organoids. We assessed cell morphology, gene expression, barrier and transporter functions, drug metabolic capacity, and cytotoxicity in relation to cell growth and the effects of cellular aging. The results indicate that organoid-derived intestinal epithelial cells may be helpful as a new model cell for drug discovery. Understanding the advantages of drug metabolic capacity and cytotoxicity among cryopreserved human enterocytes, the human colon cancer-derived cell line Caco-2, and human pluripotent stem cell-derived intestinal epithelial cells within microphysiological systems and organ-on-chip technologies is essential for the development of an appropriate model system for the small intestine.

cell biology↗

bioRxiv2024

Single-nucleus transcriptional and chromatin accessibility analyses of maturing mouse Achilles tendon uncover the molecular landscape of tendon stem/progenitor cells

Tendons and ligaments are crucial connective tissues linking bones and muscles, yet achieving full functional recovery after injury remains challenging. We investigated the characteristics of tendon stem/progenitor cells (TSPCs) by focusing on the declining tendon repair capacity with growth. Using single-cell RNA sequencing on Achilles tendon cells from 2-and 6-week-old mice, we identified Cd55 and Cd248 as novel surface antigen markers for TSPCs. Combining single-cell RNA sequencing with single-nucleus RNA and ATAC sequencing analyses revealed that Cd55 and Cd248 positive fractions in tendon tissue represent TSPCs, as confirmed by their expression of established TSPC markers, with this population decreasing at 6 weeks. We also identified candidate upstream transcription factors regulating these fractions. Functional analyses of isolated CD55/CD248 positive cells demonstrated high clonogenic potential and tendon differentiation capacity, forming functional tendon-like tissue in vitro. This study establishes CD55 and CD248 as novel TSPC surface antigens, potentially advancing tendon regenerative medicine and contributing to the development of new treatment strategies for tendon and ligament injuries.

developmental biology↗

bioRxiv2024

Basic fibroblast growth factor helps protect facial nerve cells in a freeze-induced paralysis model

Severe axonal damage in the peripheral nerves results in retrograde degeneration towards the central side, leading to neuronal cell death, eventually resulting in incomplete axonal regeneration and functional recovery. Therefore, it is necessary to evaluate the facial nerve nucleus in models of facial paralysis and investigate the efficacy of treatments, to identify treatment options for severe paralysis. Consequently, we aimed to examine the percentage of facial nerve cell reduction and the extent to which intratympanic administration of a basic fibroblast growth factor (bFGF) inhibits neuronal cell death in a model of severe facial paralysis. A severe facial paralysis model was induced in Hartley guinea pigs by freezing the facial canal. Animals were divided into two groups: one group was treated with gelatin hydrogel impregnated with bFGF and the other was treated with saline. Facial movement scoring, electrophysiological testing, and histological assessment of facial neurons were performed at different postoperative time points. The freezing-induced facial paralysis model showed a facial neuronal cell death rate of 29.0%; however, bFGF administration reduced neuronal cell death to 15.8%. Facial movement scores also demonstrated improvement in the bFGF group compared with those in the control group. Intratympanic bFGF administration has a protective effect on facial neurons in a model of severe facial paralysis. These findings suggest a potential therapeutic approach for treating patients with refractory facial paralysis. Further studies are required to explore the clinical applicability of this treatment.

neuroscience↗

bioRxiv2024

Quantitative phase imaging with temporal kinetics predicts hematopoietic stem cell diversity

Innovative identification technologies for hematopoietic stem cells (HSCs) have advanced the frontiers of stem cell biology. However, most analytical techniques capture only a single snapshot, disregarding the temporal context. A comprehensive understanding of the temporal heterogeneity of HSCs necessitates live-cell, real-time and non-invasive analysis. Here, we developed a prediction system for HSC diversity by integrating single-HSC ex vivo expansion technology with quantitative phase imaging (QPI)-driven machine learning. By analyzing single-cell kinetics with QPI, we discovered previously undetectable diversity among HSCs that snapshot analysis fails to capture. Our QPI-driven algorithm quantitatively evaluates the stemness of individual HSCs and incorporates temporal information to significantly improve prediction accuracy. This platform marks a paradigm shift from "identification" to "prediction", enabling us to forecast HSC status by analyzing their past temporal kinetics.

cell biology↗

bioRxiv2024

AgRP1 modulates breeding season-dependent feeding behavior in female medaka

Feeding and reproduction are known to be closely correlated with each other, and the seasonal breeders show breeding season-dependent feeding behavior. However, most model animals do not have definite breeding seasonality, and the mechanisms for such feeding behavior remain unclear. Here, we focused on female medaka (Oryzias latipes); they show breeding season-dependent feeding behavior, and their condition of breeding season can be experimentally controlled by day-length. We first demonstrated that, among previously reported feeding-related peptides (neuropeptides involved in feeding), agouti-related peptide 1 (agrp1) and neuropeptide y b (npyb) show higher brain expression under the breeding condition than under the non-breeding one. Combined with analysis of agrp1 knockout medaka, we obtained results to suggest that long day-induced sexually mature condition, especially ovarian estrogenic signals, increase the expressions of agrp1 in the brain, which results in increased food intake to promote reproduction. Our findings advance the understanding of neural mechanisms of feeding behavior for reproductive success.

neuroscience↗

bioRxiv2024

ZIP13 regulates lipid metabolism by changing intracellular iron and zinc balance

Metabolic diseases are caused by a prolonged energy imbalance, and adipose tissue is known to be the main contributor. We previously reported that ZIP13, an Slc39a transporter whose deficiency causes Ehlers-Danlos syndrome spondylocheirodysplastic type 3 associated with lipoatrophy, inhibits the adipocyte browning pathway by modulating intracellular zinc status. The precise mechanisms of how ZIP13 regulates the homeostasis of adipose tissue remain unclear and therefore, we investigated the role of ZIP13 in mature adipocytes using adipocyte-specific Zip13-deficient mice. We herein demonstrate that these mice show accelerated lipolysis and reduced respiratory exchange ratio. In addition, abundance of iron and zinc balance were altered during differentiation in normal adipocytes, whereas iron distribution was substantially affected in Zip13-deficient adipocytes, which downregulated PDE activity and enhanced {beta}-adrenergic receptor signaling pathways. Importantly, we confirmed that ZIP13 could transport both zinc and iron, using the Xenopus oocyte transport system and in silico structural dynamics simulations, and that the defect in iron distribution perturbs proper lipolysis. Together, these results illustrate that ZIP13 acts as a key regulator for lipolysis in adipocytes via the proper use of metals, and that the ZIP13-iron axis plays an important role in regulation of lipid metabolism.

cell biology↗