Publications by authors named "Je Kyung Seong"

236 Publications

Asian Mouse Mutagenesis Resource Association (AMMRA): mouse genetics and laboratory animal resources in the Asia Pacific.

Mamm Genome 2021 Sep 5. Epub 2021 Sep 5.

National Laboratory Animal Center (NLAC), NARLabs, Taipei, Taiwan.

The Asian Mouse Mutagenesis Resource Association (AMMRA) is a non-profit organization consisting of major resource and research institutions with rodent expertise from within the Asia Pacific region. For more than a decade, aiming to support biomedical research and stimulate international collaboration, AMMRA has always been a friendly and passionate ally of Asian and Australian member institutions devoted to sharing knowledge, exchanging resources, and promoting biomedical research. AMMRA is also missioned to global connection by working closely with the consortiums such as the International Mouse Phenotyping Consortium and the International Mouse Strain Resource. This review discusses the emergence of AMMRA and outlines its many roles and responsibilities in promoting, assisting, enriching research, and ultimately enhancing global life science research quality.
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http://dx.doi.org/10.1007/s00335-021-09912-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418786PMC
September 2021

Suppression of Osteoarthritis progression by post-natal Induction of Nkx3.2.

Biochem Biophys Res Commun 2021 Sep 27;571:188-194. Epub 2021 Jul 27.

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Electronic address:

Osteoarthritis (OA) is an incurable joint disease affecting 240 million elderly population, and major unmet medical needs exist for better therapeutic options for OA. During skeletal development, Nkx3.2 has been shown to promote chondrocyte differentiation and survival, but to suppress cartilage hypertrophy and blood vessel invasion. Here we show that Nkx3.2 plays a key role in osteoarthritis (OA) pathogenesis. Marked reduction of Nkx3.2 expression was observed in three different murine OA models. Consistent with these findings, analyses of surgery-induced and age-driven OA models revealed that cartilage-specific post-natal induction of Nkx3.2 can suppress OA progression in mice. These results suggest that Nkx3.2 may serve as a promising target for OA drug development.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.074DOI Listing
September 2021

The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice.

Sci Rep 2021 Jul 22;11(1):15027. Epub 2021 Jul 22.

Laboratory of Signal Transduction, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, South Korea.

Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) plays a role in various diseases. Here, the anti-diabetic effects of NAG-1 were evaluated using a high-fat diet/streptozotocin-induced diabetic mouse model. NAG-1-overexpressing transgenic (NAG-1 Tg) mice exhibited lower body weight, fasting blood glucose levels, and serum insulin levels than wild-type (WT) mice. The homeostatic model assessment of insulin resistance scores of NAG-1 Tg mice were lower than those of WT mice. Hematoxylin and eosin staining revealed a smaller lipid droplet size in the adipose tissues, lower lipid accumulation in the hepatocytes, and larger beta cell area in the pancreas of NAG-1 Tg mice than in those of WT mice. Immunohistochemical analysis revealed downregulated expression of cleaved caspase-3, an apoptosis marker, in the beta cells of NAG-1 Tg mice. Adiponectin and leptin mRNA levels were upregulated and downregulated in NAG-1 Tg mice, respectively. Additionally, the expression of IRS1/PI3K/AKT signaling pathway components, especially Foxo1, which regulates gluconeogenesis in the muscle and white adipose tissue, was downregulated in NAG-1 Tg mice. Furthermore, NAG-1 overexpression promoted the expression of As160 in both muscles and adipocytes, and the mRNA levels of the NLRP3 pathway members were downregulated in NAG-1 Tg mice. Our findings suggest that NAG-1 expression alleviates diabetes in mice.
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http://dx.doi.org/10.1038/s41598-021-94581-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298384PMC
July 2021

New insights into the microbiota of wild mice.

Mamm Genome 2021 08 9;32(4):311-318. Epub 2021 Jul 9.

Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK 21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, South Korea.

Laboratory mice have long been an invaluable tool in biomedical science and have made significant contributions in research into life-threatening diseases. However, the translation of research results from mice to humans often proves difficult due to the incomplete nature of laboratory animal-based research. Hence, there is increasing demand for complementary methods or alternatives to laboratory mice that can better mimic human physiological traits and potentially bridge the translational research gap. Under these circumstances, the natural/naturalized mice including "wild", "dirty", "wildling", and "wilded" systems have been found to better reflect some aspects of human pathophysiology. Here, we discuss the pros and cons of the laboratory mouse system and contemplate how wild mice and wild microbiota are able to help in refining such systems to better mimic the real-world situation and contribute to more productive translational research.
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http://dx.doi.org/10.1007/s00335-021-09887-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295133PMC
August 2021

Introduction to mammalian genome special issue: the microbiome in human health and disease.

Mamm Genome 2021 08 30;32(4):205. Epub 2021 Jun 30.

Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.

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http://dx.doi.org/10.1007/s00335-021-09888-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244925PMC
August 2021

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue.

Diabetes 2021 Jun 29. Epub 2021 Jun 29.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. In this study we aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling-mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA sequencing analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator-activated receptor α signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, the results of our study demonstrate that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggest that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.
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http://dx.doi.org/10.2337/db21-0145DOI Listing
June 2021

Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-Diamond syndrome.

Blood 2021 Jun 11. Epub 2021 Jun 11.

Seoul National University College of Medicine, Seoul, Korea, Republic of.

Shwachman-Diamond syndrome (SDS; OMIM: #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present three unrelated Korean SDS patients that carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy (UPD) in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiological consequences. Still, the milder EFL1 variant was solely able to impair 80S ribosome assembly and induce SDS features in cell line and animal models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligo-pyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.
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http://dx.doi.org/10.1182/blood.2021010913DOI Listing
June 2021

Targeted mutagenesis in mouse cells and embryos using an enhanced prime editor.

Genome Biol 2021 06 3;22(1):170. Epub 2021 Jun 3.

Department of Physiology, Korea University College of Medicine, Seoul, 02841, Republic of Korea.

Prime editors, novel genome-editing tools consisting of a CRISPR-Cas9 nickase and an engineered reverse transcriptase, can induce targeted mutagenesis. Nevertheless, much effort is required to optimize and improve the efficiency of prime-editing. Herein, we introduce two strategies to improve the editing efficiency using proximal dead sgRNA and chromatin-modulating peptides. We used enhanced prime-editing to generate Igf2 mutant mice with editing frequencies of up to 47% and observed germline transmission, no off-target effects, and a dwarf phenotype. This improved prime-editing method can be efficiently applied to cell research and to generate mouse models.
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http://dx.doi.org/10.1186/s13059-021-02389-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173820PMC
June 2021

Depletion of in Adipocytes Impairs Glucose Homeostasis in Diet-Induced Obesity.

Diabetes 2021 08 26;70(8):1664-1678. Epub 2021 May 26.

Division of Life Sciences, Korea University, Seoul, Korea

Protein arginine methyltransferase (PRMT) 1 is involved in the regulation of various metabolic pathways such as glucose metabolism in liver and atrophy in the skeletal muscle. However, the role of PRMT1 in the fat tissues under the disease state has not been elucidated to date. In this study, we delineate the function of this protein in adipocytes in vivo. PRMT1 expression was abundant in the white adipose tissues (WAT), which was induced upon a high-fat diet in mice and by obesity in humans. We found that adipocyte-specific depletion of resulted in decreased fat mass without overall changes in body weight in mice. Mechanistically, the depletion of in WAT led to the activation of the AMPK pathway, which was causal to the increased lipophagy, mitochondrial lipid catabolism, and the resultant reduction in lipid droplet size in WAT in vivo. Interestingly, despite the increased energy expenditure, we observed a promotion of adipose tissue inflammation and an ectopic accumulation of triglycerides in the peripheral tissues in adipocyte-specific knockout mice, which promoted the impaired insulin tolerance that is reminiscent of mouse models of lipodystrophy. These data collectively suggest that PRMT1 prevents WAT from excessive degradation of triglycerides by limiting AMPK-mediated lipid catabolism to control whole-body metabolic homeostasis in diet-induced obesity conditions.
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http://dx.doi.org/10.2337/db20-1050DOI Listing
August 2021

Overexpression of translationally controlled tumor protein ameliorates metabolic imbalance and increases energy expenditure in mice.

Int J Obes (Lond) 2021 07 30;45(7):1576-1587. Epub 2021 Apr 30.

Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.

Background/objectives: Translationally controlled tumor protein (TCTP) exhibits numerous biological functions. It has been shown to be involved in the regulation of glucose. However, its specific role in metabolism has not yet been clearly elucidated. Here, we aimed to assess the effect of TCTP overexpression on metabolic tissues and systemic energy metabolism.

Subjects/methods: We investigated whether TCTP can ameliorate the metabolic imbalance that causes obesity using TCTP-overexpressing transgenic (TCTP TG) mice. The mice were subjected to biochemical, morphological, physiological and protein expression studies to define the role of TCTP in metabolic regulation in response to normal chow diet (NCD) compared to high-fat diet (HFD) conditions, and cold environment.

Results: We found that TCTP TG mice show improved metabolic homeostasis under both of NCD and HFD conditions with simultaneous enhancements in glucose tolerance and insulin sensitivity. In particular, we found coincident increases in energy expenditure with significant upregulation of uncoupling protein 1 (UCP1) in the brown adipose tissue (BAT). Moreover, TCTP overexpressing mice exhibit significantly enhanced adaptive thermogenesis of BAT in response to cold exposure.

Conclusions: Overexpression of TCTP ameliorated systemic metabolic homeostasis by stimulating UCP1-mediated thermogenesis in the BAT. This suggests that TCTP may function as a modulator of energy expenditure. This study suggests TCTP may serve as a therapeutic target for obesity and obesity-associated metabolic disorders including type 2 diabetes.
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http://dx.doi.org/10.1038/s41366-021-00821-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236403PMC
July 2021

Ahnak deficiency attenuates high-fat diet-induced fatty liver in mice through FGF21 induction.

Exp Mol Med 2021 Mar 30;53(3):468-482. Epub 2021 Mar 30.

Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Korea.

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis.
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http://dx.doi.org/10.1038/s12276-021-00573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080712PMC
March 2021

STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure.

Nat Metab 2021 03 23;3(3):428-441. Epub 2021 Mar 23.

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.

Obesity reduces adipocyte mitochondrial function, and expanding adipocyte oxidative capacity is an emerging strategy to improve systemic metabolism. Here, we report that serine/threonine-protein kinase 3 (STK3) and STK4 are key physiological suppressors of mitochondrial capacity in brown, beige and white adipose tissues. Levels of STK3 and STK4, kinases in the Hippo signalling pathway, are greater in white than brown adipose tissues, and levels in brown adipose tissue are suppressed by cold exposure and greatly elevated by surgical denervation. Genetic inactivation of Stk3 and Stk4 increases mitochondrial mass and function, stabilizes uncoupling protein 1 in beige adipose tissue and confers resistance to metabolic dysfunction induced by high-fat diet feeding. Mechanistically, STK3 and STK4 increase adipocyte mitophagy in part by regulating the phosphorylation and dimerization status of the mitophagy receptor BNIP3. STK3 and STK4 expression levels are elevated in human obesity, and pharmacological inhibition improves metabolic profiles in a mouse model of obesity, suggesting STK3 and STK4 as potential targets for treating obesity-related diseases.
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http://dx.doi.org/10.1038/s42255-021-00362-2DOI Listing
March 2021

PARsylated transcription factor EB (TFEB) regulates the expression of a subset of Wnt target genes by forming a complex with β-catenin-TCF/LEF1.

Cell Death Differ 2021 Sep 22;28(9):2555-2570. Epub 2021 Mar 22.

Department of Life Science, University of Seoul, Seoul, Republic of Korea.

Wnt signaling is mainly transduced by β-catenin via regulation of the β-catenin destruction complex containing Axin, APC, and GSK3β. Transcription factor EB (TFEB) is a well-known master regulator of autophagy and lysosomal biogenesis processes. TFEB's nuclear localization and transcriptional activity are also regulated by various upstream signals. In this study, we found that Wnt signaling induces the nuclear localization of TFEB and the expression of Wnt target genes is regulated by TFEB-β-catenin-TCF/LEF1 as well as β-catenin-TCF/LEF1 complexes. Our biochemical data revealed that TFEB is a part of the β-catenin destruction complex, and destabilization of the destruction complex by knockdown of either Axin or APC causes nuclear localization of TFEB. Interestingly, RNA-sequencing analysis revealed that about 27% of Wnt3a-induced genes were TFEB dependent. However, these "TFEB mediated Wnt target genes" were different from TFEB target genes involved in autophagy and lysosomal biogenesis processes. Mechanistically, we found that Tankyrase (TNKS) PARsylates TFEB with Wnt ON signaling, and the nuclear localized PARsylated TFEB forms a complex with β-catenin-TCF/LEF1 to induce the "TFEB mediated Wnt target genes". Finally, we found that in various types of cancer, the levels of TFEB mediated Wnt target genes exhibit strong correlations with the level of Axin2, which represents the activity of Wnt signaling. Overall, our data suggest that Wnt signaling induces the expression of a subset of genes that are distinct from previously known genes regulated by the β-catenin-TCF/LEF1 complex or TFEB, by forming a transcription factor complex consisting of PARsylated TFEB and β-catenin-TCF/LEF1.
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http://dx.doi.org/10.1038/s41418-021-00770-7DOI Listing
September 2021

Metagenomic Analysis of the Gut Microbiota of Wild Mice, a Newly Identified Reservoir of .

Front Cell Infect Microbiol 2020 2;10:596149. Epub 2021 Feb 2.

College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, South Korea.

, the most common etiologic agent of zoonotic gastroenteritis in humans, is present in many reservoirs including livestock animals, wildlife, soil, and water. Previously, we reported a novel strain SCJK02 (MLST ST-8388) from the gut of wild mice () using culture-dependent methods. However, due to fastidious growth conditions and the presence of viable but non-culturable spp., it is unclear whether is a reservoir. This study aimed to: 1) determine the distribution and proportion of spp. in the gut microbiota of wild mice using culture-independent methods and 2) investigate the gut microbiota of wild mice and the relationship of spp. with other gut microbes. The gut microbiota of 38 wild mice captured from perilla fields in Korea and without any clinical symptoms (18 and 20 ) were analyzed. Metagenomic analysis showed that 77.8% (14 of 18) of the captured harbored spp. (0.24-32.92%) in the gut metagenome, whereas none of the captured carried spp. in their guts. Notably, 75% (6 of 8) of determined to be -negative using culture-dependent methods showed a high proportion of through metagenome analysis. The results of metagenome analysis and the absence of clinical symptoms suggest that may be a component of the normal gut flora of wild . Furthermore, linear discriminant analysis (LDA) showed that was the most enriched genus in the gut microbiota of (LDA score, 5.37), whereas was the most enriched genus in (LDA score, -5.96). The differences in the presence of between the two species of wild mice may be attributed to the differential abundance of and in their respective gut microbiota. In conclusion, the results indicate that wild may serve as a potential reservoir. This study presents the first metagenomics analysis of the gut microbiota to explore its possible role as an environmental reservoir and provides a basis for future studies using culture-independent methods to determine the role of environmental reservoirs in transmission.
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http://dx.doi.org/10.3389/fcimb.2020.596149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884769PMC
June 2021

Depletion of Adipocyte Leads to Lipodystrophy and Metabolic Dysregulation.

Diabetes 2021 01 12;70(1):182-195. Epub 2020 Oct 12.

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

/ is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.
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http://dx.doi.org/10.2337/db19-1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881852PMC
January 2021

Ventromedial hypothalamic primary cilia control energy and skeletal homeostasis.

J Clin Invest 2021 01;131(1)

Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea.

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH primary cilia are not yet known. In this study, we identify VMH primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88-KOSF-1) using steroidogenic factor 1-Cre (SF-1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone-density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function and was also associated with insulin and leptin resistance. The effect of bone-density accrual was independent of obesity, as it was caused by decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88-KOSF-1 and VMH primary cilia knockdown mice. Overall, our current study identifies VMH primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.
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http://dx.doi.org/10.1172/JCI138107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773357PMC
January 2021

Inhibition of Pendrin by a small molecule reduces Lipopolysaccharide-induced acute Lung Injury.

Theranostics 2020 7;10(22):9913-9922. Epub 2020 Aug 7.

Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea.

Pendrin is encoded by and its mutation leads to congenital hearing loss. Additionally, pendrin is up-regulated in inflammatory airway diseases such as chronic obstructive pulmonary disease, allergic rhinitis, and asthma. In this study, the effects of a novel pendrin inhibitor, YS-01, were investigated in an LPS-induced acute lung injury (ALI) mice model, and the mechanism underlying the effect of YS-01 was examined. Lipopolysaccharide (LPS, 10 mg/kg) was intranasally instilled in wild type (WT) and pendrin-null mice. YS-01 (10 mg/kg) was administered intra-peritoneally before or after LPS inhalation. Lung injury parameters were assessed in the lung tissue and bronchoalveolar lavage fluid (BALF). Pendrin levels in the BALF of 41 patients with acute respiratory distress syndrome (ARDS) due to pneumonia and 25 control (solitary pulmonary nodule) patients were also measured. LPS instillation induced lung injury in WT mice but not in pendrin-null mice. Pendrin expression was increased by LPS stimulation both and . YS-01 treatment dramatically attenuated lung injury and reduced BALF cell counts and protein concentration after LPS instillation in WT mice. Proinflammatory cytokines and NFB activation were suppressed by YS-01 treatment in LPS-induced ALI mice. In BALF of patients whose ARDS was caused by pneumonia, pendrin expression was up-regulated compared to that in controls (mean, 24.86 vs. 6.83 ng/mL, 0.001). A novel pendrin inhibitor, YS-01, suppressed lung injury in LPS-induced ALI mice and our data provide a new strategy for the treatment of inflammatory airway diseases including sepsis-induced ALI.
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http://dx.doi.org/10.7150/thno.46417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481407PMC
May 2021

Fas mutation reduces obesity by increasing IL-4 and IL-10 expression and promoting white adipose tissue browning.

Sci Rep 2020 07 20;10(1):12001. Epub 2020 Jul 20.

Laboratory of Developmental Biology and Genomics, BK21 Plus Program for Advanced Veterinary Science, Research Institute for Veterinary Science, College of Veterinary Medicine, and Korea Mouse Phenotyping Center, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

Brown adipose tissue generates heat via the mitochondrial uncoupling protein UCP1 to protect against obesity and hypothermia. Fas mutant MRL/lpr mice exhibit a significantly leaner phenotype compared to wild type MRL/MpJ mice. In this study, we evaluated the inflammatory cell population in the adipose tissue of MRL/lpr mice, which could potentially influence their lean phenotype. Furthermore, we compared beige fat activity between the MRL/MpJ and MRL/lpr mice. Fas mutation resulted in high body temperature, improved glucose tolerance, and decreased fat mass and adipocyte size. Fas mutation prevented high-fat diet-induced obesity and decreased the white adipose tissue M1:M2 ratio. When mice were fed a high-fat diet, UCP1, IL-4, IL-10, and tyrosine hydroxylase genes had significantly higher expression in Fas-mutant mice than in wild type mice. After a cold challenge, UCP1 expression and browning were also significantly higher in the Fas-mutant mice. In summary, Fas-mutant mice are resistant to high-fat diet-induced obesity due to increased IL-4 and IL-10 levels and the promotion of thermogenic protein activity and browning in their adipose tissues. STAT6 activation might contribute to M2 polarisation by increasing IL-4 and IL-10 levels while increases in M2 and tyrosine hydroxylase levels promote browning in response to Fas mutation.
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http://dx.doi.org/10.1038/s41598-020-68971-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371740PMC
July 2020

Polymethoxyselenoflavones exert anti-obesity effects through activation of lipolysis and brown adipocyte metabolism.

Int J Obes (Lond) 2021 01 28;45(1):122-129. Epub 2020 May 28.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

Background/objectives: Polymethoxyselenoflavone (PMSF) is a compound that substitutes the oxygen atom in a flavonoid with selenium. This study aimed to investigate the effects of PMSFs on lipid metabolism in adipocytes and their anti-obesity potential.

Subjects/methods: To test lipolytic and thermogenic effects of the compounds in vitro, adipocytes differentiated from immortalized pre-brown adipocyte progenitors and pre-white adipocyte cell lines were treated with 19 PMSFs. The expression levels of brown adipocyte markers and genes related to mitochondrial metabolism were analyzed by qPCR and western blot. In vivo anti-obesity effect was investigated using diet-induced obesity mouse models and adipocyte-specific ATGL knockout mice.

Results: The qPCR analysis identified 2-(3,4-dimethoxyphenyl)-4H-selenochromen-4-one (DMPSC) as the most potent brown adipogenic candidate among the 19 compounds tested in this study. DMPSC treatment significantly increased the mitochondrial content and oxidative metabolism in adipocytes in vitro. Mechanistically, DMPSC treatment increased lipolysis through activation of PKA downstream signaling. Consistently, the in vivo treatment of DMPSC increased energy consumption, reduced body weight, and improved glucose tolerance in mice fed with high-fat diets. Moreover, DMPSC treatment increased brown adipocyte marker expression and mitochondrial content in adipose tissue of mice. The anti-obesity effects were absent in adipocyte-specific ATGL knockout mice, indicating that the DMPSC effect is mediated by cytosolic lipase-dependent mechanisms.

Conclusions: Collectively, our results indicated that DMPSC exerted anti-obesity effects partially through the PKA signaling-mediated activation of lipolysis and brown adipose tissue metabolism.
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http://dx.doi.org/10.1038/s41366-020-0606-7DOI Listing
January 2021

High glucose-mediated PICALM and mTORC1 modulate processing of amyloid precursor protein via endosomal abnormalities.

Br J Pharmacol 2020 08 14;177(16):3828-3847. Epub 2020 Jul 14.

Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, Seoul National University, Seoul, South Korea.

Background And Purpose: Although diabetes mellitus (DM) is an important risk factor for Alzheimer's disease (AD), the detailed mechanism(s) by which DM regulates amyloid β (Aβ) processing is still unclear. The longer residence time of amyloid precursor protein (APP) in endosomes is critical for Aβ production and DM is known to cause endosomal dysregulation. Here we have examined the effects of high glucose on APP-producing endosomes and related signaling pathways.

Experimental Approach: To identify the underlying mechanisms, we investigated the effects of high glucose on abnormalities in early endosomes and related signalling pathways in human neuroblastoma cells. In vivo, diabetic mice treated with pharmacological inhibitors were used to examine endosomal dysfunction.

Key Results: The hippocampus of diabetic animals presented endosomal abnormalities and Aβ up-regulation. High glucose increased Aβ production through early endosomal enlargement achieved by increased lipid raft-mediated APP endocytosis. High glucose induced ROS-stimulated Sp1 activation, up-regulating phosphatidylinositol binding clathrin assembly protein (PICALM), clathrin heavy chain, and adaptor-related protein complex 2 alpha 1. PICALM facilitated clathrin-mediated APP endocytosis resulting in early endosomal enlargement. Meanwhile, AMPK/mTORC1-mediated autophagy defect and ROS- and mTORC1-mediated lysosomal dysfunction aggravated early endosomal enlargement under high glucose. Moreover, the increased Aβ production and cognitive deficits in diabetic mice were reversed by inhibition of early endosomal enlargement.

Conclusion And Implications: High glucose induces early endosomal abnormalities through PICALM-induced APP endocytosis and mTORC1-inhibited endosomal clearance, up-regulating Aβ production. Thus, targeting PICALM and mTORC1 to prevent endosomal disorders is a promising strategy for managing diabetes-induced AD.
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http://dx.doi.org/10.1111/bph.15131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393198PMC
August 2020

Adipogenic effects of prenatal exposure to bisphenol S (BPS) in adult F1 male mice.

Sci Total Environ 2020 Aug 19;728:138759. Epub 2020 Apr 19.

Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea; Institute of Health and Environment, Graduate School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Electronic address:

Bisphenol S (BPS) has been increasingly used as a substitute for bisphenol A (BPA), a known endocrine disruptor. Early-life exposure to BPA affects fetal development and the risk of obesity in adolescence and adulthood. However, the effects of fetal exposure BPS in later life are unknown. This study aimed to investigate the effects of prenatal BPS exposure on adiposity in adult F1 mice. Pregnant C57BL/6 N mice were exposed to BPS (0, 0.05, 0.5, 5, and 50 mg/kg/d) via drinking water from gestation day 9 until delivery. Thereafter, two groups of offspring (6 weeks old) were either administered a standard diet (STD) or a high-fat diet (HFD) for 4 weeks until euthanasia. The body weight and gonadal white adipose tissue (gWAT) mass were determined, and the energy expenditure for the adiposity phenotype was computed especially for male mice, followed by histological analysis of the gWAT. Thereafter, the expression levels of adipogenic marker genes (Pparg, Cebpa, Fabp4, Lpl, and Adipoq) were analyzed in the gWAT via reverse-transcription PCR analysis. BPS-exposed male mice displayed apparent gWAT hypertrophy, consistent with the significant increase in adipocyte size in the gWAT and upregulation of Pparg and its direct target genes among HFD mice in comparison with the control mice. These results suggest that prenatal BPS exposure potentially increases the susceptibility to HFD-induced adipogenesis in male adult mice.
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http://dx.doi.org/10.1016/j.scitotenv.2020.138759DOI Listing
August 2020

Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3.

Exp Mol Med 2020 05 7;52(5):793-803. Epub 2020 May 7.

Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Yonsei-ro 50-1, Seodaemun-gu, Seoul, 03722, Korea.

Neuronal regulation of energy and bone metabolism is important for body homeostasis. Many studies have emphasized the importance of synaptic adhesion molecules in the formation of synapses, but their roles in physiology still await further characterization. Here, we found that the synaptic adhesion molecule Calsyntenin-3 (CLSTN3) regulates energy and bone homeostasis. Clstn3 global knockout mice show reduced body mass with improved leptin sensitivity and increased energy expenditure compared to their wild-type littermates. In addition, Clstn3 knockout mice show reduced marrow volume and cortical bone mass without alteration of trabecular bone microarchitecture. This reduced bone mass is not bone cell-autonomous because neither osteoblast- nor osteoclast-specific Clstn3 knockout mice show bone defects; similarly, in vitro cultures of both Clstn3 knockout osteoblasts and osteoclasts do not show any defects. These reduced body and bone mass phenotypes can be attributed instead to neuronal CLSTN3 because they are recapitulated by pan-neuronal but not sympathetic neuron-specific deletion of Clstn3. This study reveals novel physiological functions of neuronal Clstn3 as a key regulator of energy and bone homeostasis.
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http://dx.doi.org/10.1038/s12276-020-0419-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272401PMC
May 2020

Adipocyte-specific Beclin1 deletion impairs lipolysis and mitochondrial integrity in adipose tissue.

Mol Metab 2020 09 25;39:101005. Epub 2020 Apr 25.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

Objective: Beclin1 is a core molecule of the macroautophagy machinery. Although dysregulation of macroautophagy is known to be involved in metabolic disorders, the function of Beclin1 in adipocyte metabolism has not been investigated. In the present study, we aimed to study the role of Beclin1 in lipolysis and mitochondrial homeostasis of adipocytes.

Methods: Autophagic flux during lipolysis was examined in adipocytes cultured in vitro and in the adipose tissue of mice. Adipocyte-specific Beclin1 knockout (KO) mice were used to investigate the activities of Beclin1 in adipose tissues.

Results: cAMP/PKA signaling increased the autophagic flux in adipocytes differentiated from C3H10T1/2 cells. In vivo autophagic flux was higher in the brown adipose tissue (BAT) than that in the white adipose tissue and was further increased by the β3 adrenergic receptor agonist CL316243. In addition, surgical denervation of BAT greatly reduced autophagic flux, indicating that sympathetic nerve activity is a major regulator of tissue autophagy. Adipocyte-specific KO of Beclin1 led to a hypertrophic enlargement of lipid droplets in BAT and impaired CL316243-induced lipolysis/lipid mobilization and energy expenditure. While short-term effects of Beclin1 deletion were characterized by an increase in mitochondrial proteins, long-term Beclin1 deletion led to severe disruption of autophagy, resulting in mitochondrial loss, and dramatically reduced the expression of genes involved in lipid metabolism. Consequently, adipose tissue underwent increased activation of cell death signaling pathways, macrophage recruitment, and inflammation, particularly in BAT.

Conclusions: The present study demonstrates the critical roles of Beclin1 in the maintenance of lipid metabolism and mitochondrial homeostasis in adipose tissues.
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http://dx.doi.org/10.1016/j.molmet.2020.101005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235646PMC
September 2020

TarGo: network based target gene selection system for human disease related mouse models.

Lab Anim Res 2019 13;35:23. Epub 2019 Nov 13.

3Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 Plus Program for Creative Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826 Republic of Korea.

Genetically engineered mouse models are used in high-throughput phenotyping screens to understand genotype-phenotype associations and their relevance to human diseases. However, not all mutant mouse lines with detectable phenotypes are associated with human diseases. Here, we propose the "Target gene selection system for Genetically engineered mouse models" (TarGo). Using a combination of human disease descriptions, network topology, and genotype-phenotype correlations, novel genes that are potentially related to human diseases are suggested. We constructed a gene interaction network using protein-protein interactions, molecular pathways, and co-expression data. Several repositories for human disease signatures were used to obtain information on human disease-related genes. We calculated disease- or phenotype-specific gene ranks using network topology and disease signatures. In conclusion, TarGo provides many novel features for gene function prediction.
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http://dx.doi.org/10.1186/s42826-019-0023-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081697PMC
November 2019

A comparison of the metabolic effects of treadmill and wheel running exercise in mouse model.

Lab Anim Res 2020 7;36. Epub 2020 Feb 7.

1Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.

Aerobic exercise is well known to have a positive impact on body composition, muscle strength, and oxidative capacity. In animal model, both treadmill and wheel running exercise modalities have become more popular, in order to study physiological adaptation associated with aerobic exercise. However, few studies have compared physiological adaptations in response to either treadmill exercise (TE), or voluntary wheel running exercise (WE). We therefore compared each exercise intervention on body composition and oxidative markers in male C57BL/6 N mice. The total distance run was remarkably higher in the WE group than in the TE group. Both forms of exercise resulted in the reduction of body weight, fat mass, and adipocyte size. However, the average for grip strength of WE was higher than for control and TE. Interestingly, PGC-1α expression was increased in the gastrocnemius (glycolytic-oxidative) and soleus (oxidative) muscle of TE group, whereas WE showed a significant effect on PGC-1α expression only in the soleus muscle. However, muscle fiber type composition was not shifted remarkably in either type of exercise. These results suggest that TE and WE may exert beneficial effects in suppressing metabolic risks in mouse model through attenuating body weight, fat mass, size, and increase in mitochondria biogenesis marker, PGC-1α.
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http://dx.doi.org/10.1186/s42826-019-0035-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081706PMC
February 2020

Evaluation of factors related to Anaesthesia-induced Lens opacity in experimental mice.

Lab Anim Res 2020 7;36. Epub 2020 Jan 7.

2Korea Mouse Sensory Phenotyping Center, Yonsei University College of Medicine, Seoul, South Korea.

To investigate conditions that cause temporal lens opacity, we tested chemical and physical factors, such as anaesthesia dose, ocular surface dryness, and infrared (IR) light exposure in anaesthetised C57BL/6 N mice. Mice were anaesthetised with a low (80%; tiletamine/zolazepam 32 mg/kg and xylazine 8 mg/kg, intraperitoneal injection) or high (120%; 48 mg/kg and 12 mg/kg) dose of anaesthetic and examined every 5 min from 10 to 30 min after anaesthesia was induced. Lens opacity levels were assessed and graded (1-6) using the standard classification system. Regardless of the anaesthetic dose, lens opacity grade was 1-2 in moisturised eyes with application of 0.5% carboxymethylcellulose, and 5-6 in dry ocular surface conditions. Lens opacity in mice with high-dose anaesthetic in the dry ocular surface condition was not different from that of mice with low-dose anaesthetic. Lens opacity grade 1-2 was noted in eyes in the wet ocular surface condition, regardless of IR light exposure. During IR light exposure in eyes in the dry ocular surface condition, lens opacity (grade 6) in mice with high-dose anaesthetic was not different from that (grade 6) in mice with low-dose anaesthetic. We demonstrated that ocular surface dryness might be a relevant factor for the formation and progression of lens opacity in anesthetized C57BL/6 N mice. Anaesthesia dose and IR light exposure did not strongly influence lens opacity formation. Furthermore, eyes with corneal dryness-induced lens opacity recovered to normal status without additional intervention.
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http://dx.doi.org/10.1186/s42826-019-0031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081593PMC
January 2020

Intensive morphometric analysis of enormous alterations in skeletal bone system with micro-CT for AHNAK mice.

Anat Sci Int 2020 Jun 17;95(3):323-333. Epub 2020 Feb 17.

Korea Mouse Phenotyping Center (KMPC), Seoul, 08826, Republic of Korea.

AHNAK has been reported to be involved in actin cytoskeleton rearrangement of some cell types, calcium homeostasis, and activation of T cells. Although the functional role of AHNAK in muscle cells, epidermis, and brain has been determined, its association with apparent clinical impairment has not been found yet. During phenotypic analysis of AHNAK knock out (KO) mice for many years, we observed that AHNAK KO mice showed very slow growth. Snouts of these animals were very short, and their bones were easily broken compared to normal mice. It is known that AHNAK is closely related to calcium. However, intensive morphological studies on phenotypes of bone have yet been reported for AHNAK. Thus, the objective of the present study was to analyze the morphology of skull, mandibular, limbs, and caudal bones of AHNAK KO mice intensively using micro-CT with many factors for various ages of these mice (6 weeks, 18 weeks, and 40 weeks). As a result, it was found that the facial region of AHNAK KO mouse showed a large difference in mandible than skull. Their both femur and tibia were shortened, and bone strength was also significantly decreased compared to normal mice. Particularly, the tail bone of AHNAK KO mice exhibited morphological abnormality by age. Taken together, these results suggest that AHNAK plays an important role in bone shape, development, and metabolism. Although our results demonstrated that AHNAK has a distinct role in bone, further investigations are needed to determine various features of bone metabolism related to AHNAK in the future.
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http://dx.doi.org/10.1007/s12565-020-00525-3DOI Listing
June 2020

Lipid alterations in the skeletal muscle tissues of mice after weight regain by feeding a high-fat diet using nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Mar 7;1141:122022. Epub 2020 Feb 7.

Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea. Electronic address:

This study investigated lipid alterations in muscle tissues [gastrocnemius (Gas) and soleus (Sol)] of mice under different diet programs (weight gain, weight maintenance, weight regain, and controls) by nanoflow ultrahigh pressure liquid chromatography-electrospray ionization-tandem mass spectrometry. Since overloaded lipids in the skeletal muscle tissues by excessive fat accumulation are related to insulin resistance leading to type II diabetes mellitus, analysis of lipid alteration in muscle tissues with respect to high-fat diet (HFD) is important to understand obesity related diseases. A total of 345 individual lipid species were identified with their molecular structures, and 184 lipids were quantified by selected reaction monitoring method. Most triacylglycerol (TG) and phosphatidylethanolamine (PE) species displayed a significant (>2-fold, p < 0.01) increase in both the Gas and Sol and to a larger degree in the Gas. However, lipid classes involved in insulin resistance and anti-inflammatory response, including lysophosphatidylcholine (18:0), diacylglycerol (16:0_18:1, 16:0_18:2, and 18:1_18:1), ceramide (d18:1/24:0 and d18:1/24:1), and phosphatidylinositol (18:0/20:4), showed a significant accumulation in the Sol exclusively after HFD treatment. In addition, the lipid profiles were not significantly altered in mice that were fed HFD only for the last 4 weeks (weight gain group), suggesting that consuming HFD in the younger age period can be more effective in the Gas. This study reveals that lipid classes related to insulin resistance accumulated more in the Sol than in the Gas following HFD treatment and the weight regain program perturbed lipid profiles of the Sol to a greater extent than that by the other diet programs, confirming that the Sol tissue is more influenced by HFD than Gas.
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http://dx.doi.org/10.1016/j.jchromb.2020.122022DOI Listing
March 2020
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