1.In vitro effect of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide on differentiation from human adipose-derived mesenchymal stem cells to endothelial cells.
Yu-jia ZHAI ; Jia CHEN ; Hong-gang ZHANG ; Jing ZHANG ; Qiu-Ju ZHANG ; Rui-juan XIU
Acta Academiae Medicinae Sinicae 2011;33(3):306-312
OBJECTIVETo explore the effect of N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide(W7) on the differentiation from human adipose-derived mesenchymal stem cells (hADSCs) to endothelial cells.
METHODShADSCs were cultured with serum-free differential medium containing 40 ng/ml vascular endothelial growth factor (VEGF) and 10ng/ml basic fibroblast growth factor (bFGF). Cells were divided into control group (differential medium without W7), high-dose group (containing 30 μmol/L W7), medium-dose group (containing 20 μmol/L W7), and low-dose group ( containing 10 μmol/L W7). The hADSCs were cultured for 8 days, and then the changes in the phenotypes of von Willebrand factor (vWF) and vessel-selective cadherin (VE-Cadherin) were detected by flow cytometry (FCM). The intracellular Ca(2+) labeled with Fluo-3 was detected by laser confocal microscopy. After hADSCs planting on Matrigel, their angiogenic potentials were observed under the inverted phase contrast microscope, and the expression of extracellular regulated kinase (ERK) and phosphorylated extracellular regulated kinase (p-ERK) were evaluated by Western blot.
RESULTSAfter the hADSCs were cultured for 8 days, compared with the control group, the expressions of vWF and VE-Cadherin significantly increased along with the decrease of W7 level and the intracellular Ca(2+) also significantly increased (Pü0.01). Lumina-like vascular structure was formed in W7 treatment groups, but not in the blank control group. Compared with the blank control group, the expression of ERK showed no significant in W7 treatment groups (high-, medium-, and low-dose groups)(P>0.05); however, along with the decrease of W7 levels, the expression of p-ERK significantly increased(P<0.05).
CONCLUSIONW7 in proper levels can effectively induce the differentiation from hADSCs to endothelium by increasing the intracellular Ca(2+) level and thus activating the ERK/MAPK pathway.
Adipose Tissue ; cytology ; Cell Differentiation ; drug effects ; Cells, Cultured ; Endothelial Cells ; cytology ; drug effects ; metabolism ; Humans ; Mesenchymal Stromal Cells ; cytology ; drug effects ; metabolism ; Sulfonamides ; pharmacology
2.The Increase in Hepatic Uncoupling by Fenofibrate Contributes to a Decrease in Adipose Tissue in Obese Rats.
Mi Kyoung PARK ; Hye Jeong LEE ; Sook Hee HONG ; Sun Seob CHOI ; Young Hyun YOO ; Kyung Il LEE ; Duk Kyu KIM
Journal of Korean Medical Science 2007;22(2):235-241
Fenofibrate is a drug that has been suggested to inhibit weight gain by increasing the catabolism of fatty acid in the hepatic mitochondria. We hypothesized that fenofibrate induces an increase in energy expenditure in the hepatic mitochondria, which results in the reduction of adipose tissue. In this study we measured hepatic uncoupling protein (UCP)-2, -3, core temperatures and abdominal fat composition with MRI in Otsuka Long-Evans Tokushima Fatty rats. The fenofibrate group (n=7) was fed fenofibrate (320 mg/kg) mixed chow. The control group (n=7) was fed chow only. The body weight (531.6+/-7.6 g) of the fenofibrate group was significantly lower than that (744.3+/-14.9 g) of the control group (p<0.005). The areas of visceral and subcutaneous fat in the fenofibrate group (11.0+/-0.9 cm2, 4.2+/-0.3 cm2) were significantly less than those in the control group (21.0+/-0.7 cm2, 7.4+/-0.4 cm2) (p=0.046, respectively). The esophageal and rectal temperatures of the fenofibrate group (37.7+/-0.1 degrees C, 33.1+/-0.2 degrees C) were significantly higher than those of the control group (37.3+/-0.1 degrees C, 32.2+/-0.1 degrees C) (p=0.025, p=0.005). There was de novo expression of UCP-3 in the liver of the fenofibrate group. These data suggest that increased energy dissipation, via hepatic UCP-3 by fenofibrate, contribute to decreased weight gain in obese rats.
Rats, Inbred OLETF
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Rats
;
Procetofen/*pharmacology
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Obesity/*physiopathology
;
Muscle, Skeletal/drug effects/physiopathology
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Liver/drug effects/*physiopathology
;
Energy Metabolism/*drug effects
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Body Weight/*drug effects
;
Body Temperature/*drug effects
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Antilipemic Agents/administration & dosage
;
Animals
;
Adipose Tissue/*drug effects
3.Supplementation of Fermented Barley Extracts with Lactobacillus Plantarum dy-1 Inhibits Obesity via a UCP1-dependent Mechanism.
Xiang XIAO ; Juan BAI ; Ming Song LI ; Jia Yan ZHANG ; Xin Juan SUN ; Ying DONG
Biomedical and Environmental Sciences 2019;32(8):578-591
OBJECTIVE:
We aimed to explore how fermented barley extracts with Lactobacillus plantarum dy-1 (LFBE) affected the browning in adipocytes and obese rats.
METHODS:
In vitro, 3T3-L1 cells were induced by LFBE, raw barley extraction (RBE) and polyphenol compounds (PC) from LFBE to evaluate the adipocyte differentiation. In vivo, obese SD rats induced by high fat diet (HFD) were randomly divided into three groups treated with oral gavage: (a) normal control diet with distilled water, (b) HFD with distilled water, (c) HFD with 800 mg LFBE/kg body weight (bw).
RESULTS:
In vitro, LFBE and the PC in the extraction significantly inhibited adipogenesis and potentiated browning of 3T3-L1 preadipocytes, rather than RBE. In vivo, we observed remarkable decreases in the body weight, serum lipid levels, white adipose tissue (WAT) weights and cell sizes of brown adipose tissues (BAT) in the LFBE group after 10 weeks. LFBE group could gain more mass of interscapular BAT (IBAT) and promote the dehydrogenase activity in the mitochondria. And LFBE may potentiate process of the IBAT thermogenesis and epididymis adipose tissue (EAT) browning via activating the uncoupling protein 1 (UCP1)-dependent mechanism to suppress the obesity.
CONCLUSION
These results demonstrated that LFBE decreased obesity partly by increasing the BAT mass and the energy expenditure by activating BAT thermogenesis and WAT browning in a UCP1-dependent mechanism.
3T3 Cells
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Adipocytes
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drug effects
;
physiology
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Adipose Tissue, Brown
;
drug effects
;
physiology
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Adipose Tissue, White
;
drug effects
;
physiology
;
Animal Feed
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analysis
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Animals
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Anti-Obesity Agents
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administration & dosage
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metabolism
;
Cell Differentiation
;
drug effects
;
Diet
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Fermentation
;
Hordeum
;
chemistry
;
Lactobacillus plantarum
;
chemistry
;
Male
;
Mice
;
Obesity
;
drug therapy
;
genetics
;
Plant Extracts
;
chemistry
;
Probiotics
;
administration & dosage
;
metabolism
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Random Allocation
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Rats
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Rats, Sprague-Dawley
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Uncoupling Protein 1
;
genetics
;
metabolism
4.Anti-obesity effects of Lysimachia foenum-graecum characterized by decreased adipogenesis and regulated lipid metabolism.
Jong Bae SEO ; Sung Sik CHOE ; Hyun Woo JEONG ; Sang Wook PARK ; Hyun Jung SHIN ; Sun Mi CHOI ; Jae Young PARK ; Eun Wook CHOI ; Jae Bum KIM ; Dong Seung SEEN ; Jae Yeon JEONG ; Tae Gyu LEE
Experimental & Molecular Medicine 2011;43(4):205-215
Lysimachia foenum-graecum has been used as an oriental medicine with anti-inflammatory effect. The anti-obesity effect of L. foenum-graecum extract (LFE) was first discovered in our screening of natural product extract library against adipogenesis. To characterize its anti-obesity effects and to evaluate its potential as an anti-obesity drug, we performed various obesity-related experiments in vitro and in vivo. In adipogenesis assay, LFE blocked the differentiation of 3T3-L1 preadipocyte in a dose-dependent manner with an IC50 of 2.5 microg/ml. In addition, LFE suppressed the expression of lipogenic genes, while increasing the expression of lipolytic genes in vitro at 10 microg/ml and in vivo at 100 mg/kg/day. The anti-adipogenic and anti-lipogenic effect of LFE seems to be mediated by the inhibition of PPARgamma and C/EBPalpha expression as shown in in vitro and in vivo, and the suppression of PPARgamma activity in vitro. Moreover, LFE stimulated fatty acid oxidation in an AMPK-dependent manner. In high-fat diet (HFD)-induced obese mice (n = 8/group), oral administration of LFE at 30, 100, and 300 mg/kg/day decreased total body weight gain significantly in all doses tested. No difference in food intake was observed between vehicle- and LFE-treated HFD mice. The weight of white adipose tissues including abdominal subcutaneous, epididymal, and perirenal adipose tissue was reduced markedly in LFE-treated HFD mice in a dose-dependent manner. Treatment of LFE also greatly improved serum levels of obesity-related biomarkers such as glucose, triglycerides, and adipocytokines leptin, adiponectin, and resistin. All together, these results showed anti-obesity effects of LFE on adipogenesis and lipid metabolism in vitro and in vivo and raised a possibility of developing LFE as anti-obesity therapeutics.
3T3-L1 Cells
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Adipogenesis/*drug effects
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Adipose Tissue/drug effects/metabolism
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Adipose Tissue, White
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Animals
;
Anti-Obesity Agents/administration & dosage/pharmacology/*therapeutic use
;
Body Weight/drug effects
;
CCAAT-Enhancer-Binding Protein-alpha/genetics
;
Cell Differentiation/drug effects
;
Eating/drug effects
;
Fatty Acids/metabolism
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Gene Expression/drug effects
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Lipid Metabolism/*drug effects
;
Lipids
;
Lipogenesis/drug effects
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Mice
;
Mice, Inbred C57BL
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Obesity/prevention & control
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PPAR gamma/antagonists & inhibitors/genetics
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Plant Extracts/*pharmacology
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Plants, Medicinal
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Primulaceae/*chemistry
5.Effects of timely insulin treatment on protection of beta cells in a rat model of type 2 diabetes mellitus.
Ying-sheng ZHOU ; Yan GAO ; Xiao-hui GUO ; Bin LI ; Shu WANG ; Jia-min CHI
Chinese Medical Journal 2004;117(10):1523-1529
BACKGROUNDInsulin treatment plays a key role in management of diabetes mellitus. Clinical researches showed that extra improvements in restoration of insulin secretion of pancreatic beta cells were found in patients with newly diagnosed type 2 diabetes. The purpose of this study was to investigate the effects of early insulin treatment on insulin mRNA expression and morphological alterations of beta cells in a Sprague Dawley (SD) rat model of type 2 diabetes.
METHODSA rat model of type 2 diabetes mellitus (T2DM) was induced by a high fat diet (high energy, HE) and low doses of streptozotoxin (STZ, 40 mg/kg). A group of diabetic rats was then injected with protamine zinc insulin [PZI, 1 - 2 U x kg(-1) x d(-1)] for one week. Insulin mRNA expression, morphological features of pancreatic islets, and metabolic parameters were examined in rats using reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry, and other techniques.
RESULTSIn insulin-treated diabetic rats, insulin mRNA levels prominently increased by 81.3% (P < 0.05), as compared with untreated diabetic rats. Moreover, timely insulin treatment noticeably improved the insulin content of beta cells, with an increase of 10.2% (P < 0.05), despite a slight reduction in fasting blood glucose (FBG), triglyceride (TG), and free fatty acid (FFA) levels, as compared to an untreated diabetic group.
CONCLUSIONInsulin treatment at the onset of T2DM effectively improves insulin synthesis, as confirmed by morphological changes to beta cells in a rat model of type 2 diabetes.
Adipose Tissue ; metabolism ; Animals ; Body Weight ; drug effects ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; Insulin ; administration & dosage ; analysis ; genetics ; Islets of Langerhans ; drug effects ; Male ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Streptozocin
6.Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues.
Ying-Ying CHEN ; Yan YAN ; Zheng ZHAO ; Mei-Jing SHI ; Yu-Bin ZHANG
Chinese Journal of Natural Medicines (English Ed.) 2016;14(6):449-456
The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05), including blood glucose (Glu), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.
Adipose Tissue, Brown
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drug effects
;
immunology
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Adipose Tissue, White
;
drug effects
;
immunology
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Animals
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Cytokines
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genetics
;
metabolism
;
Drugs, Chinese Herbal
;
administration & dosage
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Energy Metabolism
;
drug effects
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Female
;
Humans
;
Interleukin-6
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genetics
;
immunology
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Mice
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Obesity
;
drug therapy
;
genetics
;
immunology
;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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genetics
;
immunology
;
Tumor Necrosis Factor-alpha
;
genetics
;
immunology
;
Uncoupling Protein 1
;
genetics
;
metabolism
7.Di (2-ethylhexyl) phthalate Disorders Lipid Metabolism via TYK2/STAT1 and Autophagy in Rats.
Yue Zhu ZHANG ; Zhao Ming ZHANG ; Li Ting ZHOU ; Jian ZHU ; Xiao Han ZHANG ; Wen QI ; Shuang DING ; Qi XU ; Xu HAN ; Ya Ming ZHAO ; Xin Yue SONG ; Tian Yang ZHAO ; Lin YE
Biomedical and Environmental Sciences 2019;32(6):406-418
OBJECTIVE:
Previous studies have indicated that the plasticizer di (2-ethylhexyl) phthalate (DEHP) affects lipid accumulation; however, its underlying mechanism remains unclear. We aim to clarify the effect of DEHP on lipid metabolism and the role of TYK2/STAT1 and autophagy.
METHODS:
In total, 160 Wistar rats were exposed to DEHP [0, 5, 50, 500 mg/(kg•d)] for 8 weeks. Lipid levels, as well as mRNA and protein levels of TYK2, STAT1, PPARγ, AOX, FAS, LPL, and LC3 were detected.
RESULTS:
The results indicate that DEHP exposure may lead to increased weight gain and altered serum lipids. We observed that DEHP exposure affected liver parenchyma and increased the volume or number of fat cells. In adipose tissue, decreased TYK2 and STAT1 promoted the expression of PPARγ and FAS. The mRNA and protein expression of LC3 in 50 and 500 mg/(kg•d) groups was increased significantly. In the liver, TYK2 and STAT1 increased compensatorily; however, the expression of FAS and AOX increased, while LPL expression decreased. Joint exposure to both a high-fat diet and DEHP led to complete disorder of lipid metabolism.
CONCLUSION
It is suggested that DEHP induces lipid metabolism disorder by regulating TYK2/STAT1. Autophagy may play a potential role in this process as well. High-fat diet, in combination with DEHP exposure, may jointly have an effect on lipid metabolism disorder.
Adipose Tissue
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drug effects
;
metabolism
;
Animals
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Autophagy
;
drug effects
;
Body Weight
;
drug effects
;
Diet, High-Fat
;
adverse effects
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Diethylhexyl Phthalate
;
toxicity
;
Endocrine Disruptors
;
toxicity
;
Female
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Lipid Metabolism
;
drug effects
;
Lipid Metabolism Disorders
;
chemically induced
;
Liver
;
drug effects
;
metabolism
;
Male
;
Rats, Wistar
;
STAT1 Transcription Factor
;
metabolism
;
TYK2 Kinase
;
metabolism
8.Short-term intensive atorvastatin therapy improves endothelial function partly via attenuating perivascular adipose tissue inflammation through 5-lipoxygenase pathway in hyperlipidemic rabbits.
Xiaoqiao WANG ; Yongqin LIN ; Niansang LUO ; Zhongqing CHEN ; Miaoning GU ; Jingfeng WANG ; Yangxin CHEN ;
Chinese Medical Journal 2014;127(16):2953-2959
BACKGROUNDAtherosclerosis is a kind of disease with multiple risk factors, of which hyperlipidemia is a major classical risk factor resulting in its pathogenesis and development. The aim of this study was to determine the effects of short-term intensive atorvastatin (IA) therapy on vascular endothelial function and explore the possible mechanisms that may help to explain the clinical benefits from short-term intensive statin therapy.
METHODSAfter exposure to high-fat diet (HFD) for 8 weeks, the animals were, respectively, treated with IA or low-dose atorvastatin (LA) for 5 days. Blood lipids, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO), endothelin-1 (ET-1), and endothelium-dependent vasorelaxation function were, respectively, measured. mRNA and protein expression of CRP, TNF-α, IL-6, macrophage chemoattractant protein-1 (MCP-1), and 5-lipoxygenase (5-LO) were also evaluated in pericarotid adipose tissue (PCAT) and cultured adipocytes.
RESULTSHFD increased serum inflammatory factor levels; induced significant hyperlipidemia and endothelial dysfunction, including imbalance between NO and ET-1; enhanced inflammatory factors and 5-LO expression; and promoted macrophage infiltration into adipose tissue. Five-day IA therapy could significantly decrease serum inflammatory factor levels and their expression in PCAT; restore the balance between NO and ET-1; and improve endothelial function and macrophage infiltration without significant changes in blood lipids. However, all of the above were not observed in LA therapy. In vitro experiment found that lipopolysaccharide (LPS) enhanced the expression of inflammatory factors and 5-LO in cultured adipocytes, which could be attenuated by short-time (6 hours) treatment of high-dose (5 µmol/L) but not low-dose (0.5 µmol/L) atorvastatin. In addition, inhibiting 5-LO by Cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC, a potent and direct 5-LO inhibitor) could significantly downregulate the above-mentioned gene expression in LPS-treated adipocytes.
CONCLUSIONShort-term IA therapy could significantly ameliorate endothelial dysfunction induced by HFD, which may be partly due to attenuating inflammation of PCAT through inhibiting 5-LO pathway.
Adipose Tissue ; drug effects ; immunology ; Animals ; Arachidonate 5-Lipoxygenase ; metabolism ; Atorvastatin Calcium ; Heptanoic Acids ; therapeutic use ; Hyperlipidemias ; drug therapy ; immunology ; Inflammation ; drug therapy ; immunology ; Lipid Metabolism ; drug effects ; Male ; Pyrroles ; therapeutic use ; Rabbits
9.Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism.
Mi Chung YOON ; Sun Hyo JEONG ; Christopher J NICOL ; Hyung Hee LEE ; Mi Young HAN ; Jung Jae KIM ; Yun Jeong SEO ; Chil Yeol RYU ; Goo Taeg OH
Experimental & Molecular Medicine 2002;34(6):481-488
To determine whether the PPARalpha agonist fenofibrate regulates obesity and lipid metabolism with sexual dimorphism, we examined the effects of fenofibrate on body weight, white adipose tissue (WAT) mass, circulating lipids, and the expression of PPARalpha target genes in both sexes of high fat diet-fed C57BL/6J mice. Both sexes of mice fed a high-fat diet for 14 weeks exhibited increases in body weight, visceral WAT mass, as well as serum triglycerides and cholesterol, although these effects were more pronounced among males. Feeding a high fat diet supplemented with fenofibrate (0.05% w/w) reduced all of these effects significantly in males except serum cholesterol level. Females on a fenofibrate-enriched high fat diet had reduced serum triglyceride levels, albeit to a smaller extent compared to males, but did not exhibit decreases in body weight, WAT mass, and serum cholesterol. Fenofibrate treatment resulted in hepatic induction of PPAR alpha target genes encoding enzymes for fatty acid beta-oxidation, the magnitudes of which were much higher in males compared to females, as evidenced by results for acyl-CoA oxidase, a first enzyme of the beta-oxidation system. These results suggest that observed sexually dimorphic effects on body weight, WAT mass and serum lipids by fenofibrate may involve sexually related elements in the differential activation of PPARalpha.
Adipose Tissue/drug effects/metabolism
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Animals
;
Body Composition/drug effects
;
Body Weight/drug effects
;
Diet
;
Dietary Fats/pharmacology
;
Female
;
Gene Expression Regulation/drug effects
;
Lipids/blood/*metabolism
;
Liver/drug effects/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Obesity/*metabolism/pathology
;
Organ Weight/drug effects
;
Procetofen/*pharmacology
;
Receptors, Cytoplasmic and Nuclear/*agonists
;
*Sex Characteristics
;
Time Factors
;
Transcription Factors/*agonists
10.Anti-obesity effects of Chang-Chul-Eui-Ee-In-Tang see text in female rats with diet-induced obesity.
Sunmin PARK ; Jung Bok LEE ; James W DAILY
Chinese journal of integrative medicine 2011;17(12):925-932
OBJECTIVETo investigate the effects of Chang-Chul-Eui-Ee-In-Tang ([see text], CCEET), modififi ed CCEET (MCCEET), and Semen Coicis (SC, a major component of CCEET) on energy and glucose homeostasis. The possible mechanism of action of CCEET was also determined.
METHODSA total of 100 Sprague Dawley female rats were randomly assigned to 5 groups, with 20 in each group. Rats in 4 groups were fed with a high fat diet supplementation (2 g/kg body weight), and water extracts of CCEET, MCCEET, SC, and cellulose (negative control), respectively. The last group was fed with a low-fat diet as a positive control.
RESULTSCCEET and MCCEET decreased body weight and body fat (mesenteric and retroperitoneal fat) more than SC. This decrease was due to decreased energy intake and increased energy expenditure and fat oxidation. The improvement in energy homeostasis was associated with the enhancement of the hypothalamic leptin signalling pathway involving potentiating the phosphorylation of the signal transducer and activator of transcription-3, as well as attenuating the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Both CCEET and MCCEET improved glucose tolerance without changing serum insulin levels during an oral glucose tolerance test but MCCEET had a better effect than CCEET.
CONCLUSIONSBoth CCEET and MCCEET safely exerted anti-obesity effects by enhancing energy balance in female rats with diet-induced obesity; MCCEET showed a better effect on glucose homeostasis.
Adenylate Kinase ; metabolism ; Adipose Tissue ; drug effects ; Animals ; Anti-Obesity Agents ; adverse effects ; pharmacology ; therapeutic use ; Blood Glucose ; metabolism ; Body Weight ; drug effects ; Calorimetry ; Diet ; Drugs, Chinese Herbal ; adverse effects ; pharmacology ; therapeutic use ; Energy Metabolism ; drug effects ; Female ; Glucose Tolerance Test ; Homeostasis ; drug effects ; Hypothalamus ; drug effects ; enzymology ; Leptin ; metabolism ; Motor Activity ; drug effects ; Obesity ; blood ; drug therapy ; pathology ; physiopathology ; Phosphorylation ; drug effects ; Rats ; Rats, Sprague-Dawley ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; drug effects