Trans-anethole ameliorates obesity via induction of browning in white adipocytes and activation of brown adipocytes

Kang, Nam Hyeon,Mukherjee, Sulagna,Min, Taesun,Kang, Sun Chul,Yun, Jong Won Elsevier 2018 Biochimie Vol.151 No.-

<P><B>Abstract</B></P> <P>To treat obesity, suppression of white adipose tissue (WAT) expansion and activation of brown adipose tissue (BAT) are considered as potential therapeutic targets. Recent advances have been made in the induction of brown fat-like adipocytes (beige) in WAT, which represents an attractive potential strategy for the management and treatment of obesity. Use of natural compounds for browning of white adipocytes can be considered as a safe and novel strategy against obesity. Here, we report that trans-anethole (TA), a flavoring substance present in the essential oils of various plants, alleviated high fat diet (HFD)-induced obesity in mice models via elevation of the expression of beige-specific genes such as <I>Ppargc1α, Prdm16, Ucp1, Cd137, Cited1, Tbx1,</I> and <I>Tmem26</I>. TA also regulated lipid metabolism in white adipocytes via reduction of adipogenesis and lipogenesis as well as elevation of lipolysis and fat oxidation. Moreover, TA exhibited thermogenic activity by increasing mitochondrial biogenesis in white adipocytes and activating brown adipocytes. In addition, molecular docking analysis enabled us to successfully predict core proteins for fat browning such as β3-adrenergic receptor (β3-AR) and sirtuin1 (SIRT1) based on their low binding energy interactions with TA for promotion of regulatory mechanisms. Indeed, agonistic and antagonistic studies demonstrated that TA induced browning of 3T3-L1 adipocytes through activation of β3-AR as well as the AMPK-mediated SIRT1 pathway regulating PPARα and PGC-1α. In conclusion, TA possesses potential therapeutic implications for treatment of obesity by playing multiple modulatory roles in the induction of white fat browning, activation of brown adipocytes, and promotion of lipid catabolism.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Trans-anethole (TA) regulates lipid metabolism in white adipocytes and induces browning. </LI> <LI> TA reduces obesity by activating brown adipocytes. </LI> <LI> TA demonstrates thermogenesis via increased mitochondrial biogenesis. </LI> <LI> TA shows more effective binding with SIRT1 and follows a direct pathway of browning rather than β3-AR. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Adipocyte-Derived FABP4 Regulates of Cancer Stemness and Drug Resistance in Hepatocellular Carcinoma

( Shilpa Gurung ),( Terence Kin-wah Lee ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world. Increasing reports showed significant correlation between non-alcoholic fatty liver disease (NAFLD) and HCC development. Given cancer stem cells (CSCs) play a critical role in regulating the tumor relapse and therapeutic resistance, we hypothesize that adipocytes, one of the key cellular factors within the tumor microenvironment, may play a critical role in HCC pathogenesis via regulation of liver CSCs. Methods: We have employed a co-culture system to dissect the potential cross-talk between fully differentiated adipocytes and HCC cells. The conditioned medium (CM) of adipocytes was collected to examine the potential paracrine effect of adipocytes in regulating liver CSCs. The secretome of adipocytes was analyzed by using Orbitrap Liquid Chromatography-Mass spectrometry. Molecular pathway mediating the phenotypic alterations was identified through RNA sequencing analysis and functional rescue experiments. Results: Using co-culture system, we found that adipocytes enhanced the self-renewal and tumorigenicity of HCC cells through paracrine secretion. Consistently, conditioned medium of adipocytes showed enhanced tumorigenicity, self-renewal, invasiveness and resistance to doxorubicin and sorafenib treatment. By Orbitrap Liquid Chromatography-Mass spectrometry, we identified 209 proteins, among which we have focused on FABP4 as it is preferentially secreted from adipocytes. Consistently, recombinant FABP4 enhanced CSC properties of HCC cells; while FABP4 inhibitor (BMS309403) abolished the CSC enhancing effect of CM of adipocytes. Clinically, FABP4 overexpression was significantly correlated with poorer patients survival. Conclusions: We demonstrated the pivotal role of adipocytes on regulation of liver CSCs through paracrine secretion. Adipocyte-derived FABP4 signaling cascade may be a novel therapeutic target for treatment of NAFLD induced HCC.

Extracellular Vimentin Alters Energy Metabolism And Induces Adipocyte Hypertrophy

박지혜,권소연,박영미 대한당뇨병학회 2024 Diabetes and Metabolism Journal Vol.48 No.2

Background: Previous studies have reported that oxidative stress contributes to obesity characterized by adipocyte hypertrophy. However, mechanism has not been studied extensively. In the current study, we evaluated role of extracellular vimentin secreted by oxidized low-density lipoprotein (oxLDL) in energy metabolism in adipocytes.Methods: We treated 3T3-L1-derived adipocytes with oxLDL and measured vimentin which was secreted in the media. We evaluated changes in uptake of glucose and free fatty acid, expression of molecules functioning in energy metabolism, synthesis of adenosine triphosphate (ATP) and lactate, markers for endoplasmic reticulum (ER) stress and autophagy in adipocytes treated with recombinant vimentin.Results: Adipocytes secreted vimentin in response to oxLDL. Microscopic evaluation revealed that vimentin treatment induced increase in adipocyte size and increase in sizes of intracellular lipid droplets with increased intracellular triglyceride. Adipocytes treated with vimentin showed increased uptake of glucose and free fatty acid with increased expression of plasma membrane glucose transporter type 1 (GLUT1), GLUT4, and CD36. Vimentin treatment increased transcription of GLUT1 and hypoxia-inducible factor 1α (Hif-1α) but decreased GLUT4 transcription. Adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), diacylglycerol O-acyltransferase 1 (DGAT1) and 2 were decreased by vimentin treatment. Markers for ER stress were increased and autophagy was impaired in vimentin-treated adipocytes. No change was observed in synthesis of ATP and lactate in the adipocytes treated with vimentin.Conclusion: We concluded that extracellular vimentin regulates expression of molecules in energy metabolism and promotes adipocyte hypertrophy. Our results show that vimentin functions in the interplay between oxidative stress and metabolism, suggesting a mechanism by which adipocyte hypertrophy is induced in oxidative stress.

Theobromine, a Methylxanthine in Cocoa Bean, Stimulates Thermogenesis by Inducing White Fat Browning and Activating Brown Adipocytes

장명환,강남현,술라그나 무케르지,윤종원 한국생물공학회 2018 Biotechnology and Bioprocess Engineering Vol.23 No.6

Natural medicinal compounds to treat obesity have recently attracted a great deal of attention because of the serious side effects of synthetic anti-obesity drugs. Recent advances have been made to identify natural products showing thermogenic activity, which is responsible for energy expenditure in brown or brown-like (beige) adipocytes. Here, we explored the thermogenic effects of theobromine, one of the most abundant methylxanthines in cocoa, on 3T3-L1 white adipocytes and HIB1B brown adipocytes. Theobromine markedly increased the expression levels of brown-fat signature proteins (PGC-1α, PRDM16, and UCP1) and beige-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmen26) in 3T3-L1 white adipocytes and remarkably elevated the expression levels of brown fatspecific genes (Cidea, Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1) in HIB1B brown adipocytes. Theobromine also reduced the expression of the key adipogenic transcription factors, C/EBPα and PPARγ, in white adipocytes, while enhancing their expression in HIB1B cells. In addition, theobromine regulated lipolytic events and fat oxidation by upregulating the expression of pACC, ATGL, pHSL, ACOX, and CPT1. Additional mechanistic study revealed that theobromine activates β3-AR and AMPK. In summary, our results provide evidence for the first time indicating that theobromine has a potential beneficial effect on browning of white adipocytes and improves lipid catabolic metabolism in both cultured white and brown adipocytes via β-adrenergic signaling and AMPK activation. Consumption of theobromine may be a feasible way to activate thermogenesis and improve systematic lipid metabolism to protect against obesity and other metabolic disorders.

The Soy Peptide Phe–Leu–Val Reduces TNFα-Induced Inflammatory Response and Insulin Resistance in Adipocytes

곽수진,김추숙,최명숙,박태선,성미경,윤종원,유훈,Yoshinori Mine,유리나 한국식품영양과학회 2016 Journal of medicinal food Vol.19 No.7

Obesity-induced adipose inflammation plays a crucial role in the development of obesity-induced metabolic disorders such as insulin resistance and type 2 diabetes. In the presence of obesity, hypertrophic adipocytes release inflammatory mediators, including tumor necrosis factor-alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1), which enhance the recruitment and activation of macrophages, and in turn augment adipose inflammation. We demonstrate that the soy peptide Phe–Leu–Val (FLV) reduces inflammatory responses and insulin resistance in mature adipocytes. Specifically, the soy peptide FLV inhibits the release of inflammatory cytokines (TNFα, MCP-1, and IL-6) from both TNFα-stimulated adipocytes and cocultured adipocytes/macrophages. This inhibition is mediated by the inactivation of the inflammatory signaling molecules c-Jun N-terminal kinase (JNK) and IκB kinase (IKK), and the downregulation of IκBα in the adipocytes. In addition, soy peptide FLV enhances insulin responsiveness and increases glucose uptake in adipocytes. More importantly, we, for the first time, found that adipocytes express peptide transporter 2 (PepT2) protein, and the beneficial action of the soy peptide FLV was disrupted by the peptide transporter inhibitor GlySar. These findings suggest that soy peptide FLV is transported into adipocytes by PepT2 and then downregulates TNFα-induced inflammatory signaling, thereby increasing insulin responsiveness in the cells. The soy peptide FLV, therefore, has the potential to prevent obesity-induced adipose inflammation and insulin resistance.

Regulation of Lipoprotein Lipase by Fasting in Epididymal and Mesenteric Adipocytes of Rats

Lee, Jae Joon,Chung, Chung Soo,Lee, Myung Yul Asian Australasian Association of Animal Productio 2008 Animal Bioscience Vol.21 No.5

There are marked variations in the activity of lipoprotein lipase (LPL) among adipose depots. The aim of this study was to compare the mechanisms of 24 h of fasting on LPL regulation between epididymal (EPI) adipocytes and mesenteric (MES) adipocytes in rats. 1-Day fasting consistently decreased activities of heparin-releasable LPL, total extractable LPL and cellular LPL markedly in both EPI and MES fat pads. LPL activity in MES fat pads was relatively lower than in the EPI fat pads. Consistent with data on LPL activity, the levels of expression of LPL mRNA in both nutritional states were lower in MES than EPI adipose tissue and isolated adipocytes. The decreased LPL activity after 1 day of fasting in MES adipocytes was explained mainly by a 50% decrease in the relative abundance of LPL mRNA level and a parallel 50% decrease in relative rate of LPL synthesis. In contrast, fasting of 1 day in EPI adipocytes decreased total LPL activity by 47% but did not affect LPL mRNA level or relative rate of LPL synthesis. A decrease in overall protein synthesis contributed to the decreased LPL activity after 1 day fasting both in EPI and MES adipocytes. In MES adipocytes the decrease in LPL activity, LPL mRNA and LPL synthesis were comparable, but in EPI adipocytes the changes in LPL activity were substantially larger than the changes in LPL mRNA level and LPL synthesis. Therefore, fasting decreased fat cell size, LPL activity, LPL mRNA level and relative rate of LPL synthesis in rats, and these effects were more marked in the MES adipocytes. These results clearly demonstrate the regional variations in the metabolic response of adipose tissue and LPL functions to fasting.

High-fat diet alters the thermogenic gene expression to β-agonists or 18-carbon fatty acids in adipocytes derived from the white and brown adipose tissue of mice

Seonjeong Park,Seung A Ock,Yun Jeong Park,Yoo-Hyun Lee,Chan Yoon Park,Sunhye Shin 한국영양학회 2024 Journal of Nutrition and Health Vol.57 No.2

조위승청탕(調胃升淸湯)의 알코올 및 열수(熱水) 추출물이 지방세포 대사에 미치는 영향

이재은,김병우,임태진,김동희,권기록,Lee, Jae-Eun,Kim, Byoung-Woo,Rhim, Tae-Jin,Kim, Dong-Heui,Kwon, Ki-Rok 대한약침학회 2008 Journal of pharmacopuncture Vol.11 No.1

Objectives : The purpose of this study is to investigate the effects of Chowiseungcheng-tang extracts on the preadipocytes proliferation in 3T3-L1 cell line, lipolysis of adipocytes in rat's epididymal adipocytes and localized fat accumulation of porcine by extraction methods(alcohol and water). Methods : Diminish preadipocytes proliferation and promote lipolysis of adipocytes do primary role to reduce obesity. So, we used 3T3-L1 mouse embryo fibroblasts(preadipocytes) and rat epididymal adipocytes from Sprague-Dawley rats to investigate the effects of Chowiseungcheng-tang extracts on the preadipocytes proliferation, lipolysis of adipocytes. They were treated with 0.01, 0.1, $1.0mg/m{\ell}$ Chowiseungcheng-tang alcohol and water extracts. And for the purpose of investigating the effects of Chowiseungcheng-tang alcohol and water extracts on the localized fat accumulation, we injected 0.1, 1.0, $10.0mg/m{\ell}$ Chowiseungcheng-tang extracts to porcine fat tissues and observed histological changes of them. Results : Following results were obtained from the preadipocytes proliferation and lipolysis of adipocytes and histological investigation of fat tissues. 1. Chowiseungcheng-tang extracts suppressed preadipocytes proliferation on the high dosage(especially $1.0mg/m{\ell}$), and especially alcohol extracts had better effects. 2. The alcohol extracts of Chowiseungcheng-tang decreased the activity of glycerol-3-phosphate dehydrogenase (GPDH) on the concentrations of 0.1, $1.0mg/m{\ell}$. Alcohol extracts had better effects than water extracts. 3. Chowiseungcheng-tang extracts increased lipolysis of adipocytes on the concentrations of 0.1, $1.0mg/m{\ell}$, and especially on the concentration of $1.0mg/m{\ell}$ alcohol extract of Chowiseungcheng-tang had better effect. 4. The water extract of Chowiseungcheng-tang had significant activity to the destruction of porcine fat cell membranes only on the concentration of $10.0mg/m{\ell}$, but alcohol extracts of Chowiseungcheng-tang had it on all concentrations. Conclusions : The alcohol extracts of Chowiseungcheng-tang had much better effects on the preadipoeytes proliferaton, lipolysis of adipocytes and localized fat accumulation than water extracts.

Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes

KIM PRAISE CHANMEE,이지선,Chung Sung Soo,박경수 대한당뇨병학회 2023 Diabetes and Metabolism Journal Vol.47 No.3

Background: Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)–peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues.Methods: The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed <i>in vivo</i> using adipocyte-specific <i>Senp2</i> knockout (<i>Senp2</i>-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (<i>Cpt1b</i>) and long-chain acyl-coenzyme A synthetase 1 (<i>Acsl1</i>) using transfection/reporter assays and chromatin immunoprecipitation.Results: SENP2 mediated the increased expression of FAO-associated enzymes, <i>CPT1b</i> and <i>ACSL1</i>, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of <i>Cpt1b</i> and <i>Acsl1</i> were increased by 2-fold 24 hours after leptin injection in control mice but not in <i>Senp2</i>-aKO mice. Leptin increased PPARα binding to the <i>Cpt1b</i> and <i>Acsl1</i> promoters in adipocytes through SENP2.Conclusion: These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation

우창윤,장정은,이승은,고은희,이기업 대한당뇨병학회 2019 Diabetes and Metabolism Journal Vol.43 No.3

Adipose tissue inflammation is considered a major contributing factor in the development of obesity-associated insulin resistance and cardiovascular diseases. However, the cause of adipose tissue inflammation is presently unclear. The role of mitochondria in white adipocytes has long been neglected because of their low abundance. However, recent evidence suggests that mitochondria are essential for maintaining metabolic homeostasis in white adipocytes. In a series of recent studies, we found that mitochondrial function in white adipocytes is essential to the synthesis of adiponectin, which is the most abundant adipokine synthesized from adipocytes, with many favorable effects on metabolism, including improvement of insulin sensitivity and reduction of atherosclerotic processes and systemic inflammation. From these results, we propose a new hypothesis that mitochondrial dysfunction in adipocytes is a primary cause of adipose tissue inflammation and compared this hypothesis with a prevailing concept that “adipose tissue hypoxia” may underlie adipose tissue dysfunction in obesity. Recent studies have emphasized the role of the mitochondrial quality control mechanism in maintaining mitochondrial function. Future studies are warranted to test whether an inadequate mitochondrial quality control mechanism is responsible for mitochondrial dysfunction in adipocytes and adipose tissue inflammation.