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Inhibition of Adipogenesis in 3T3-L1 Cells and Suppression of Abdominal International Journal of Obesity (2014) 38, 1035–1043 & 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo ORIGINAL ARTICLE Inhibition of adipogenesis in 3T3-L1 cells and suppression of abdominal fat accumulation in high-fat diet-feeding C57BL/6J mice after downregulation of hyaluronic acid EJi1,5, MY Jung1,5, JH Park2, S Kim1, CR Seo1, KW Park1, EK Lee3, CH Yeom4 and S Lee1 OBJECTIVE: Adipogenesis can be spatially and temporally regulated by extracellular matrix (ECM). We hypothesized that the regulation of hyaluronic acid (HA), a component of the ECM, can affect adipogenesis in fat cells. The effects of HA on adipogenesis were investigated in vitro in 3T3-L1 cells and in vivo in high-fat diet-feeding C57BL/6J mice. METHODS: We investigated the effects of HA by degradation of pre-existing or synthesized HA and artificial inhibition of HA synthesis in adipogenesis. RESULTS: In vitro adipogenesis in 3T3-L1 cells was inhibited by treating them with exogenous hyaluronidase (HYAL) and with 4-methylumbelliferone, which inhibited the synthesis of HA in a concentration-dependent manner. In vivo, abdominal fat accumulation in high-fat diet-feeding C57BL/6J mice was suppressed by exogenous HYAL 104 IU injections, which was associated with reduction of lipid accumulation in liver and increase of insulin sensitivity. CONCLUSION: Changes in the ECM such as accumulation of high molecular weight of HA by HAS and degradation of HA by endogenous HYAL were essential for adipogenesis both in vitro and in vivo. International Journal of Obesity (2014) 38, 1035–1043; doi:10.1038/ijo.2013.202 Keywords: extracellular matrix; hyaluronic acid; adipogenesis; 3T3-L1 cells; high-fat diet-induced obesity INTRODUCTION cytoskeletal elements is necessary for the transformation of 11–13 Obesity is defined as a condition in which excessive fat accumulates pre-adipocytes into mature adipocytes. Several reports have in the body, which can result in many health-related problems. examined the relationship between the ECM and the Obesity is one of the main factors responsible for the increased differentiation of 3T3-L1 cells, including changes in the protein incidence of cardiovascular disease, Type 2 diabetes and several types composition and reorganization of the ECM during 3T3-L1 14,15 16 of cancer. The resultant increases in morbidity and reductions in life differentiation. Demeulemeester et al. reported that weight expectancy are both personally and economically damaging.1 As a gain in C57BL/6J mice was reduced by treatment with a matrix result, obesity is a serious public health problem, and mechanisms to metalloproteinase (MMP) inhibitor. Therefore, appropriate control obesity have been actively studied worldwide. Though regulation of the ECM has a role in adipose tissue development several drugs have been developed to treat obesity, an ideal in vivo as well as in vitro. Hyaluronic acid (also known as pharmacological therapy has not yet been implemented. Therefore, hyaluronan or hyaluronate (HA)) is a critical component of the a novel approach for the treatment of obesity is needed. ECM, and is found both at the cell surface and within the cells. Adipocyte differentiation has previously been studied in vitro, HA is a negatively charged, non-sulfated, glycosaminoglycan (GAG) using specific cell lines to establish ideal conditions for composed of repeating disaccharides of D-glucuronic acid and differentiation.2–5 Likewise, adipocytes studied using in vitro N-acetyl-glucosamine. HA is synthesized as a large unbranched systems shared common characteristics and mechanisms of polymer (molecular weight ranging from 20 kDa to 42 MDa) on differentiation with adipocytes in vivo.6,7 For example, it has the cytoplasmic side of the plasma membrane by HA synthase been demonstrated that peroxisome proliferator-activated (HAS), which is an integral membrane glycosyltransferase, and is receptor gamma (PPARg), which is a transcription factor of the subsequently extruded to the extracellular surface.17,18 Despite its ligand-dependent nuclear receptor type,8 and CCAAT-enhancer- simple structure, HA has numerous functions, as it is progressively binding proteins (C/EBPs), which are a family of transcription degraded by enzymes of the hyaluronidase (HYAL) family at the factors of the leucine zipper type,9 play important roles in cellular level.19 Recently, it has been suggested that the specific adipogenesis. In addition, the extracellular matrix (ECM) was found functions of HA fragments are polymer-size-dependent,19 though to be involved in adipogenesis through changes in protein the location and the concentration of the polymers as well as of composition and dynamics.10 various HA-size-specific binding proteins are also variables.20 During adipogenesis, regulation of the expression of various Native high molecular weight (Mw) HA acts as a scaffold on which genes that are specifically involved in the formation of ECM and other macromolecules are assembled and has a remarkable ability 1Department of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea; 2Institute of Cancer Research, College of Medicine, The Catholic University of Korea, Seoul, Korea; 3Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea and 4Yeom’s Family Medicine Clinic, Seoul, Korea. Correspondence: Dr S Lee, Department of Biotechnology and Bioengineering, Sungkyunkwan University, 300, Cheoncheon-dong, Jangan-gu, Suwon, 440-746, Korea. E-mail: [email protected] 5These authors contributed equally to this work. Received 3 May 2013; revised 24 September 2013; accepted 4 October 2013; accepted article preview online 31 October 2013; advance online publication, 26 November 2013 Reduction of hyaluronic acid blocks adipogenesis EJiet al 1036 to retain water, thus contributing to the organization and light/dark cycle. When mice were 6.5 weeks of age, they were divided into maintenance of the integrity and hydrodynamic properties of five groups (n ¼ 5 in all groups except group B, in which n ¼ 4). Mice in one the ECM.21 In 1993, it was reported first by Calvo et al.22 that HA of two groups fed NFD were injected with phosphate-buffered saline (PBS) as a negative control for fat accumulation, while the other group was existed in the extracellular media of differentiated 3T3-L1 4 pre-adipocyte cultures and after that a few papers regarding injected with 10 IU of HYAL (BMI Korea, Jeju, Korea) as a negative control for high-dose HYAL injection. Three groups were given a high-fat diet the relationship between HA and adipogenesis have 23,24 containing 60% fat (HFD; Research Diets Inc., New Brunswick, NJ, USA). Two been published. Interestingly, it was shown by Allingham groups of mice fed HFD were injected with 102 IU and 104 IU of HYAL, et al. that the expression of genes for the biosynthesis and respectively. The third group was injected with PBS every 3 days as a degradation of HA was positively involved in the differentiation positive control for HFD-induced fat accumulation. Food intake was of adipocytes.23 Also, HA-modified matrix has been studied measured every 3 days, and body weight was monitored every 6 days for in vitro and in vivo for adipose tissue engineering.25–27 2 months. Therefore, it has been expected that HA is important in adipogenesis. Intraperitoneal glucose tolerance test (IPGTT) In this study, we examined if the regulation of HA inhibited IPGTTs were performed in all mice at 13.5 weeks of age. After overnight adipogenesis and thus lipid accumulation based on this associa- fasting, animals received an intraperitoneal injection of D-glucose tion between HA and adipogenesis. We observed the inhibitory (2 g kg À 1) in 0.9% NaCl.30 A drop of blood was taken from the tail vein effects of HA on adipogenesis in 3T3-L1 cells in vitro, and the before the glucose injection (0), as well as 15, 30, 60, 90, and 120 min after prevention of insulin resistance and non-alcoholic fatty liver the injection in order to determine blood glucose levels using a disease (NAFLD) caused by excess accumulation of abdominal fat glucometer (Accu-Chek Active; Roche Diagnostics GmbH). in HFD-feeding C57BL/6J mice in vivo by artificially reducing HA levels. Micro-CT At 14 weeks of age, the mice were imaged using Micro-CT (Skyscan model 1076; Skyscan, Kontich, Belgium) under anesthesia. The resolution of the MATERIALS AND METHODS micro-CT was 35 mm. Culture and differentiation of 3T3-L1 pre-adipocytes 3T3-L1 pre-adipocytes were purchased from American Type Culture Sample and serum analysis Collection (ATCC; Manassas, VA, USA). The pre-adipocytes were maintained At 14.5 weeks of age, the mice were put under deep anesthesia after in Dulbecco’s modified Eagle’s medium (DMEM; Hyclone, South Logan, UT, overnight fasting. Blood samples were taken from the inferior vena cava, USA), and supplemented with 10% newborn calf serum (Hyclone) and and serum samples were collected by centrifuging at 14 000 r.p.m. for antibiotics (Hyclone) at 37 1Cin5%CO2. To induce adipocyte differentia- 5 30 min after being kept at room temperature for 1 h. Aspartate tion, the pre-adipocytes were plated at a density of 2 Â 10 cells per well transaminase (AST), alanine transaminase (ALT), alkaline phosphatase on six-well plates. After confluence, cells were incubated in DMEM (ALP), total cholesterol (T.cho), triglycerides (TG), high-density lipoprotein supplemented with 10% fetal bovine serum (Hyclone) and antibiotics, (HDL-C), low-density lipoprotein (LDL-C) and insulin levels were analysed and treated with DMI (1 mM dexamethasone (Sigma-Aldrich, St Louis, MO, À 1 by the Korea Animal Medical Science Institute (KAMESI, Seoul, Korea). USA), 0.5 mM 3-iso-butyl-1-methylxantine (Sigma-Aldrich) and 1 mgml The weights of fat tissues and organs were also measured. insulin (Roche Diagnostics GmbH, Mannheim, Germany)) for 3 days followed by treatment with insulin alone.
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