Jae Bum Kim

Keimyung University, Sŏul, Seoul, South Korea

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Publications (121)

  • Sung Sik Choe · Mira Ham · Kyung Cheul Shin · [...] · Jae Bum Kim
    Article · Oct 2016
  • Hagoon Jang · Gung Lee · Jae Bum Kim
    Article · Sep 2016 · Cell cycle (Georgetown, Tex.)
  • Jung Hyun Lee · Ji Seul Han · Jinuk Kong · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial to maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened lifespan, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RIα and RIIβ via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism.
    Article · Aug 2016 · Journal of Biological Chemistry
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    Hagoon Jang · Gha Young Lee · Christopher P. Selby · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Supplementary Figures 1-13 and Supplementary Tables 1-2
    File available · Data · Jul 2016
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    Hagoon Jang · Gha Young Lee · Christopher P. Selby · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: SREBP1c is a key lipogenic transcription factor activated by insulin in the postprandial state. Although SREBP1c appears to be involved in suppression of hepatic gluconeogenesis, the molecular mechanism is not thoroughly understood. Here we show that CRY1 is activated by insulin-induced SREBP1c and decreases hepatic gluconeogenesis through FOXO1 degradation, at least, at specific circadian time points. SREBP1c-/-and CRY1-/-mice show higher blood glucose than wild-type (WT) mice in pyruvate tolerance tests, accompanied with enhanced expression of PEPCK and G6Pase genes. CRY1 promotes degradation of nuclear FOXO1 by promoting its binding to the ubiquitin E3 ligase MDM2. Although SREBP1c fails to upregulate CRY1 expression in db/db mice, overexpression of CRY1 attenuates hyperglycaemia through reduction of hepatic FOXO1 protein and gluconeogenic gene expression. These data suggest that insulin-activated SREBP1c downregulates gluconeogenesis through CRY1-mediated FOXO1 degradation and that dysregulation of hepatic SREBP1c-CRY1 signalling may contribute to hyperglycaemia in diabetic animals.
    Full-text available · Article · Jul 2016 · Nature Communications
  • Mira Ham · Sung Sik Choe · Kyung Cheul Shin · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation along with de novo lipogenesis. Recently, it has been demonstrated that aberrant up-regulation of G6PD in obese adipose tissue mediates insulin resistance due to imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study, we have shown that hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied with reduced adipose tissue inflammation. Compared to wild-type littermates, G6PD-deficient mutant (G6PD(mut)) mice were glucose tolerant upon high fat diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated whereas that of anti-oxidant genes was enhanced in the adipose tissue of HFD-fed G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased expression of inflammatory cytokines, accompanied with down-regulated pro-inflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced pro-inflammatory signaling cascades, leading to enhance insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) bone marrow to wild type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of pro-inflammatory responses.
    Article · Jun 2016 · Diabetes
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    Sung Sik Choe · Jin Young Huh · In Jae Hwang · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.
    Full-text available · Article · Apr 2016 · Frontiers in Endocrinology
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    Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Experimental & Molecular Medicine is an open access journal that publishes the highest quality articles in translational research and biomedical studies.
    Full-text available · Article · Mar 2016
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    A Young Kim · Yoon Jeong Park · Xuebo Pan · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.
    Full-text available · Article · Jul 2015 · Nature Communications
  • Meejung Kim · Jong In Kim · Jae Bum Kim · Senyon Choe
    [Show abstract] [Hide abstract] ABSTRACT: Several of the bone morphogenetic proteins (BMPs) have been reported to induce white as well as brown adipogenesis. Here, we characterized the adipogenic potential of AB204, a recombinant chimeric protein of activin-βA and BMP-2, in in vitro, ex vivo and in vivo settings. BMP-2 is generally known to promote adipogenesis. When compared with BMP-2, which previously showed varying degrees of adipogenesis, AB204 displayed superior in vitro adipogenic differentiation of mouse 3 T3-L1 pre-adipocytes and human adipose-derived stem cells (hASCs). Surprisingly, implantation of hASCs, preconditioned with AB204 for as short a time as 48 h, into the subcutaneous space of athymic nude mice effectively produced fat pads, but not with BMP-2. When BMP-2 and AB204 were injected intraperitoneally, AB204 promoted dramatic systemic adipogenesis of C57BL/6 mice on a high-fat diet very effectively. The results implicate the novel clinical potential of AB204, including induction of fat tissue ex vivo or in vivo for tissue re-engineering and regenerative medicinal purposes, more than any known natural protein ligand. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Article · Jun 2015 · Journal of Tissue Engineering and Regenerative Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Recent evidence in adipocytes points to a role for synuclein-γ in metabolism and lipid droplet dynamics, but interestingly this factor is also robustly expressed in peripheral neurons. Specific regulation of the synuclein-γ gene (Sncg) by PPARγ requires further evaluation, especially in peripheral neurons, prompting us to test if Sncg is a bona fide PPARγ target in murine adipocytes and peripheral somatosensory neurons derived from the dorsal root ganglia (DRG). Sncg mRNA was decreased in 3T3-L1 adipocytes (~68%) by rosiglitazone, and this effect was diminished by the PPARγ antagonist T0070907. Chromatin immunoprecipitation experiments confirmed PPARγ protein binding at two promoter sequences of Sncg during 3T3-L1 adipogenesis. Rosiglitazone did not affect Sncg mRNA expression in murine cultured DRG neurons. In subcutaneous human WAT samples from two cohorts treated with pioglitazone (>11 wks), SNCG mRNA expression was reduced, albeit highly variable and most evident in type 2 diabetes. Leptin (Lep) expression, thought to be coordinately-regulated with Sncg based on correlations in human adipose tissue, was also reduced in 3T3-L1 adipocytes by rosiglitazone. However, Lep was unaffected by PPARγ antagonist, and the LXR agonist T0901317 significantly reduced Lep expression (~64%) while not impacting Sncg. The results support the concept that synuclein-γ shares some, but not all, gene regulators with leptin and is a PPARγ target in adipocytes but not DRG neurons. Regulation of synuclein-γ by cues such as PPARγ agonism in adipocytes is logical based on recent evidence for an important role for synuclein-γ in the maintenance and dynamics of adipocyte lipid droplets.
    Full-text available · Article · Mar 2015 · PLoS ONE
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    Jong In Kim · Jin Young Huh · Jee Hyung Sohn · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: In obesity, adipocyte hypertrophy and pro-inflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but pro-inflammatory responses were only observed in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplet exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high fat diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone would be crucial to cause insulin resistance in obesity. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Full-text available · Article · Mar 2015 · Molecular and Cellular Biology
  • Injae Hwang · Yoon Jeong Park · Yeon-Ran Kim · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity.-Hwang, I., Park, Y. J., Kim, Y. -R., Kim, Y. N., Ka, S., Lee, H. Y., Seong, J. K., Seok, Y. -J., and Kim, J. B. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. © FASEB.
    Article · Feb 2015 · The FASEB Journal
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    [Show abstract] [Hide abstract] ABSTRACT: Akt2 and its downstream effectors mediate insulin-stimulated GLUT4-storage vesicle (GSV) translocation and fusion with the plasma membrane (PM). Using mass spectrometry, we identify actin-capping protein Tropomodulin 3 (Tmod3) as an Akt2-interacting partner in 3T3-L1 adipocytes. We demonstrate that Tmod3 is phosphorylated at Ser71 on insulin-stimulated Akt2 activation, and Ser71 phosphorylation is required for insulin-stimulated GLUT4 PM insertion and glucose uptake. Phosphorylated Tmod3 regulates insulin-induced actin remodelling, an essential step for GSV fusion with the PM. Furthermore, the interaction of Tmod3 with its cognate tropomyosin partner, Tm5NM1 is necessary for GSV exocytosis and glucose uptake. Together these results establish Tmod3 as a novel Akt2 effector that mediates insulin-induced cortical actin remodelling and subsequent GLUT4 membrane insertion. Our findings suggest that defects in cytoskeletal remodelling may contribute to impaired GLUT4 exocytosis and glucose uptake.
    Full-text available · Article · Jan 2015 · Nature Communications
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    Full-text available · Article · Jan 2015 · Nature Communications
  • [Show abstract] [Hide abstract] ABSTRACT: Extensive actin cytoskeleton remodeling occurs during adipocyte development. We previously showed that disruption of stress fibers by the actin-severing protein cofilin is a requisite step in adipogenesis. However, it remains unclear whether actin nucleation and assembly into the cortical structure is essential for adipocyte development. Here we investigated the role of cortical actin assembly and of actin nucleation by the Arp2/3 complex in adipogenesis. Cortical actin structure formation started with accumulation of F-actin patches near the plasma membrane during adipogenesis. Depletion of Arp2/3 by knockdown of its subunits Arp3 or ARPC3 strongly impaired adipocyte differentiation, while adipogenesis-initiating factors were unaffected. Moreover, the assembly of F-actin-rich structures at the plasma membrane was suppressed and cortical actin structure poorly developed after adipogenic induction in Arp2/3-deficient cells. Finally, we provide evidence that the cortical actin cytoskeleton is essential for efficient GLUT4 vesicle exocytosis and insulin signal transduction. These results show that the Arp2/3 complex is an essential regulator of adipocyte development by controlling the formation of cortical actin structures, which may facilitate nutrient uptake and signaling events.
    Article · Sep 2014 · Biochemical Journal
  • Jung Hyun Lee · Jinuk Kong · Ju Yeon Jang · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Lipolysis is a delicate process involving complex signaling cascades and sequential enzymatic activations. In Caenorhabditis elegans, fasting induces various physiological changes, including a dramatic decrease in lipid contents through lipolysis. Interestingly, C. elegans lacks perilipin family genes which play a crucial role in the regulation of lipid homeostasis in other species. Here, we demonstrate that in the intestinal cells of C. elegans, a newly identified protein, lipid droplet protein 1 (C25A1.12; LID-1), modulates lipolysis by binding to adipose triglyceride lipase 1 (C05D11.7; ATGL-1) during nutritional deprivation. In fasted worms, lipid droplets were decreased in intestinal cells, whereas suppression of ATGL-1 via RNA interference (RNAi) resulted in retention of stored lipid droplets. Overexpression of ATGL-1 markedly decreased lipid droplets, whereas depletion of LID-1 via RNAi prevented the effect of overexpressed ATGL-1 on lipolysis. In adult worms, short-term fasting increased cyclic AMP (cAMP) levels, which activated protein kinase A (PKA) to stimulate lipolysis via ATGL-1 and LID-1. Moreover, ATGL-1 protein stability and LID-1 binding were augmented by PKA activation, eventually leading to increased lipolysis. These data suggest the importance of the concerted action of lipase and lipid droplet protein in the response to fasting signals via PKA to maintain lipid homeostasis.
    Article · Sep 2014 · Molecular and Cellular Biology
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    Jae Ho Lee · Gha Young Lee · Hagoon Jang · [...] · Jae Bum Kim
    [Show abstract] [Hide abstract] ABSTRACT: Unlabelled: Sterol regulatory element binding protein1c (SREBP1c) is a key transcription factor for de novo lipogenesis during the postprandial state. During nutritional deprivation, hepatic SREBP1c is rapidly suppressed by fasting signals to prevent lipogenic pathways. However, the molecular mechanisms that control SREBP1c turnover in response to fasting status are not thoroughly understood. To elucidate which factors are involved in the inactivation of SREBP1c, we attempted to identify SREBP1c-interacting proteins by mass spectrometry analysis. Since we observed that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of SREBP1c-interacting proteins, we hypothesized that fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this work, we demonstrate that RNF20 physically interacts with SREBP1c, leading to degradation of SREBP1c via ubiquitination. In accordance with these findings, RNF20 represses the transcriptional activity of SREBP1c and turns off the expression of lipogenic genes that are targets of SREBP1c. In contrast, knockdown of RNF20 stimulates the expression of SREBP1c and lipogenic genes and induces lipogenic activity in primary hepatocytes. Furthermore, activation of protein kinase A (PKA) with glucagon or forskolin enhances the expression of RNF20 and potentiates the ubiquitination of SREBP1c via RNF20. In wild-type and db/db mice, adenoviral overexpression of RNF20 markedly suppresses FASN promoter activity and reduces the level of hepatic triglycerides, accompanied by a decrease in the hepatic lipogenic program. Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation. Conclusion: RNF20 acts as a negative regulator of hepatic fatty acid metabolism through degradation of SREBP1c upon PKA activation. Knowledge regarding this process enhances our understanding of how SREBP1c is able to turn off hepatic lipid metabolism during nutritional deprivation.
    Full-text available · Article · Sep 2014 · Hepatology
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    Jae Ho Lee · Gha Young Lee · Hagoon Jang · [...] · Jae Bum Kim
    File available · Data · Jul 2014
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    [Show abstract] [Hide abstract] ABSTRACT: Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-α-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.
    Full-text available · Article · Jul 2014 · Nature Communications