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1.  Assessment of Antiobesity Potential of Achyranthes aspera Linn. Seed 
The present study was designed to evaluate the quality control parameters, quantitative phytochemical analysis (total phenols, total flavonoids, and total saponin content), and the antiobesity effect of ethanol extract of Achyranthes aspera Linn. seed (EAA) by employing in vitro and in vivo models. In in vitro study, the inhibitory activity of EAA on pancreatic amylase and lipase was measured. The in vivo pancreatic lipase activity was evaluated by measurement of plasma triacylglycerol levels after oral administration of EAA along with lipid emulsion to Swiss albino mice. The EAA inhibited pancreatic amylase and lipase activity in vitro and elevations of plasma triacylglycerol level in mice. Furthermore, the antiobesity effect of EAA (900 mg/kg) was assessed in mice fed a high-fat diet with or without EAA for 6 weeks. EAA significantly suppressed the increase in body, retroperitoneal adipose tissue, liver weights, and serum parameters, namely; total cholesterol, total triglyceride, and LDL-cholesterol level. The anti obesity effects of EAA in high-fat-diet-treated mice may be partly mediated through delaying the intestinal absorption of dietary fat by inhibiting pancreatic amylase and lipase activity. Histopathological effects of EAA on the liver of mice were also assessed.
doi:10.1155/2012/715912
PMCID: PMC3418711  PMID: 22919417
2.  Anti-obesity effects of chikusetsusaponins isolated from Panax japonicus rhizomes 
Background
The rhizomes of Panax japonicus are used as a folk medicine for treatment of life-style related diseases such as arteriosclerosis, hyperlipidemia, hypertension and non-insulin-dependent diabetes mellitus as a substitute for ginseng roots in China and Japan. Obesity is closely associated with life-style-related diseases. This study was performed to clarify whether chikusetsusaponins prevent obesity induced in mice by a high-fat diet for 9 weeks.
Methods
We performed two in vivo experiments. In one, female ICR mice were fed a high-fat diet with or without 1 or 3% chikusetsusaponins isolated from P. japonicus rhizomes for 9 weeks. In the other, lipid emulsion with or without chikusetsusaponins was administered orally to male Wistar rats, and then the plasma triacylglycerol level was measured 0.5 to 5 h after the orally administered lipid emulsion. For in vitro experiments, the inhibitory effects of total chikusetsusaponins and various purified chikusetsusaponins on pancreatic lipase activity were determined by measuring the rate of release of oleic acid from triolein in an assay system using triolein emulsified with lecithin.
Results
Total chikusetsusaponins prevented the increases in body weight and parametrial adipose tissue weight induced by a high-fat diet. Furthermore, consumption of a high-fat diet containing 1 or 3% total chikusetsusaponins significantly increased the fecal content and triacylglycerol level at day 3 compared with the high-fat diet groups. Total chikusetsusaponins inhibited the elevation of the plasma triacylglycerol level 2 h after the oral administration of the lipid emulsion. Total chikusetsusaponins, chikusetsusaponin III, 28-deglucosyl-chikusetsusaponin IV and 28-deglucosyl-chikusetsusaponin V inhibited the pancreatic lipase activity.
Conclusion
The anti-obesity effects of chikusetsusaponins isolated from P. japonicus rhizomes in mice fed a high-fat diet may be partly mediated through delaying the intestinal absorption of dietary fat by inhibiting pancreatic lipase activity. The present study clearly indicated that the saponin fractions of P. japonicus rhizomes had a significant anti-obesity action and supports the traditional usage as a substitute drug for ginseng roots.
doi:10.1186/1472-6882-5-9
PMCID: PMC1097713  PMID: 15811191
3.  Anti-obesity activity of hen egg anti-lipase immunoglobulin yolk, a novel pancreatic lipase inhibitor 
Background
There is completely no report about both hen egg anti-lipase immunoglobulin yolk (IgY) and its anti-obesity action. Thus, we tried to isolate and characterize a novel anti-lipase immunoglobulin from hen egg yolk. Moreover, we investigated whether hen egg yolk anti-lipase IgY inhibits pancreatic lipase activity in vitro, and examined its ability to prevent obesity in a murine high fat diet-induced obesity model.
Methods
We determined the inhibitory action of Anti-lipase IgY on lipase activity in vitro. We also focused our evaluation on the anti-obesity properties of Anti-lipase IgY in a murine high fat diet-induced obesity model.
Results
Anti-lipase IgY blocked porcine lipase activity with an IC50 of 0.49 μM. Supplementing the high fat diet with only 0.2% (w/w) of Anti-lipase IgY for 35 days significantly decreased the weights of intraperitoneal adipose tissues, epididymal, mesenteric, retroperitoneal and perirenal adipose tissues, and the amounts of hepatic total lipid, triglyceride, and cholesterol. This was accompanied by a significant increase in the fecal excretion of triglyceride in the absence of diarrhea. Furthermore, Anti-lipase IgY treatment restored body weight gain to levels similar to mice fed with Control IgY.
Conclusions
This study provides the first report of the development of anti-lipase IgY and the direct evidence that inhibition of pancreatic lipase using Anti-lipase IgY is an effective anti-obesity treatment due to the associated increase in fecal excretion of triglyceride.
doi:10.1186/1743-7075-10-70
PMCID: PMC4028892  PMID: 24321125
Obesity; IgY; Pancreatic lipase; Lipid; Mice
4.  Study of Antiobesity Effect through Inhibition of Pancreatic Lipase Activity of Diospyros kaki Fruit and Citrus unshiu Peel 
BioMed Research International  2016;2016:1723042.
Pancreatic lipase is the enzyme responsible for digestion and absorption of triglycerides, being its inhibition one of the widest studied methods used to determine the potential activity of natural products to inhibit dietary fat absorption. Decrease of energy intake from dietary fat through inhibition of this enzyme may be an excellent strategy to prevent and treat obesity. The inhibitory activity on pancreatic lipase enzyme of Diospyros kaki fruit and Citrus unshiu peel mixture extract (PCM) was evaluated in vitro and its antiobesity effects were studied based on the serum lipid parameters analysis from high-fat diet- (HFD-) fed mice in vivo. PCM was orally administered at a dose of 50 and 200 mg/kg body weight for 6 weeks. In addition, the activity of pancreatic lipase was assessed using orlistat (positive control). PCM exhibited inhibitory effect on lipase activity with IC50 value of 507.01 μg/mL. Moreover, serum triacylglycerol, total cholesterol levels, and visceral fat weight were significantly reduced compared to HFD control mice in PCM 200 mg/kg-treated mice (p < 0.05). These results suggest that PCM administration may be a novel potential antiobesity agent for reduction of fat absorption via inhibition of pancreatic lipase.
doi:10.1155/2016/1723042
PMCID: PMC4978832  PMID: 27529064
5.  Antiobesity effect of Stellaria media against drug induced obesity in Swiss albino mice 
Ayu  2011;32(4):576-584.
The whole plant of Stellaria media (family: Caryophyllaceae) has been tested for its antiobesity activity by using progesterone-induced obesity model in female albino mice. The effect of S. media on food consumption pattern, change in body weight, thermogenesis, lipid metabolism, and histology of fat pad. were examined. Methanolic and alcoholic extracts of the S. media were used in the study. Methanolic extract of S. media (MESM) have prevented the increase in body weight, adipose tissue weight and size, and upturned obesity and associated complications. MESM has also shown promising effects compared with alcoholic extract of S. media may be because of its multiple mechanisms. These findings suggest that antiobesity activity produced by MESM is because of its anorexic property mediated by saponin and flavonoid and partly of by its β-sitosterol content. β-Sitosterol in the plant extract was confirmed by thin-layer chromatography study. β-sitosterol is plant sterol having structural similarity with dietary fat which do the physical competition in the gastrointestinal tract and reduces fat absorption. Before carrying in vivo activity detail pharmacognostic and phytochemical analysis of the extracts was carried out. The plant has shown the presence of saponin, flavonoids, steroids and triterpenoids, glycosides, and anthocynidine. By this study, it can be concluded that, MESM is beneficial in suppression of obesity induced by progesterone.
doi:10.4103/0974-8520.96137
PMCID: PMC3361939  PMID: 22661858
Anorexia; histology of fat pads; obesity; progesterone; Stellaria media; β-sitosterol
6.  Dohaekseunggi-tang extract inhibits obesity, hyperlipidemia, and hypertension in high-fat diet-induced obese mice 
Background
Dohaekseunggi-tang (DHSGT) is a traditional plant-based medicine prescribed to promote blood circulation and to treat obesity and hypertension. The present study aimed to identify potential anti-obesity activities of DHSGT extract.
Methods
Anti-obesity, anti-hyperlipidemic, and anti-hypertensive effects of orally-administered DHSGT extract were evaluated in high-fat diet- (HFD)-induced obese mice. Serum biochemistry profiles and expression of diverse metabolic regulatory gene mRNAs in mouse visceral fat were assessed by RT-PCR. The effects of DHSGT on angiotensin-1 converting enzyme (ACE) and pancreatic lipase activities were determined using in vitro inhibition assays.
Results
Oral DHSGT treatment reduced obese HFD C57BL/6 J mouse body weight, liver and adipose tissue mass, adipocyte size, and blood pressure versus untreated HFD mice. DHSGT also decreased serum total cholesterol, LDL-cholesterol, triglyceride, glucose, and leptin concentrations, and increased HDL-cholesterol and adiponectin levels in HFD mice. Furthermore, DHSGT markedly increased mRNA expression of peroxisome proliferator activated receptor-gamma, uncoupling protein-2, and adiponectin in visceral adipose tissue of HFD mice. In vitro tests revealed that DHSGT effectively inhibited porcine pancreatic lipase and ACE activities, with IC50 values of 7.58 mg/ml and 0.56 mg/ml, respectively.
Conclusions
These results validate traditional knowledge and suggest that DHSGT may be potentially useful for managing hyperlipidemia, hyperglycemia, hypertension, and obesity.
doi:10.1186/1472-6882-14-372
PMCID: PMC4193160  PMID: 25280587
Angiotensin-1 converting enzyme; Body weight; Dohaekseunggi-tang; High-fat diet; Pancreatic lipase; Visceral adipose tissue
7.  Anti-Obesity Effects of Melastoma malabathricum var Alba Linn in Rats Fed with a High-Fat Diet 
AAPS PharmSciTech  2014;16(3):548-553.
Obesity is one of the major public health problems worldwide and it is generally associated with many diseases. Although synthetic drugs are available for the treatment of obesity, herbal remedies may provide safe, natural, and cost-effective alternative to synthetic drugs. One example of such drugs is Melastoma malabathricum var Alba Linn (MM). Although several studies have been reported for the pharmacological activities of MM, there is no report on the anti-obesity effect of MM. The aim of the present study is to evaluate the anti-obesity potential of methanolic extract of MM. The anti-obesity effect of MM on rats fed with a high-fat diet was investigated through determination of the changes in body weight, fat weight, organ weights, and blood biochemicals. The animals in this study were divided into three groups: a normal group with a standard diet (N), a control group fed with high-fat diet (C), and a MM treatment group fed with high-fat (HFD + MM) diet for 8 weeks. There was no significant difference in the amount of food intake between control and HFD + MM treatments. These results also suggest that MM does not induce a dislike for the diet due to its smell or taste. The study shows that MM significantly prevented increases in body weight, cholesterol, LDL, HDL, and total lipids that resulted from the high-fat diet. MM also decreased the epididymal fat (E-fat) and retroperitoneal fat (R-fat) weights and phospholipid concentrations induced by the high-fat diet. On the basis of these findings, it was concluded that MM had anti-obesity effects by suppressing body weight gain and abdominal fat formation.
doi:10.1208/s12249-014-0245-1
PMCID: PMC4444635  PMID: 25374344
Anti-obesity; High-fat diet; Melastoma malabathricum var Alba Linn
8.  Effects of Fortunella margarita Fruit Extract on Metabolic Disorders in High-Fat Diet-Induced Obese C57BL/6 Mice 
PLoS ONE  2014;9(4):e93510.
Introduction
Obesity is a nutritional disorder associated with many health problems such as dyslipidemia, type 2 diabetes and cardiovascular diseases. In the present study, we investigated the anti-metabolic disorder effects of kumquat (Fortunella margarita Swingle) fruit extract (FME) on high-fat diet-induced C57BL/6 obese mice.
Methods
The kumquat fruit was extracted with ethanol and the main flavonoids of this extract were analyzed by HPLC. For the preventive experiment, female C57BL/6 mice were fed with a normal diet (Chow), high-fat diet (HF), and high-fat diet with 1% (w/w) extract of kumquat (HF+FME) for 8 weeks. For the therapeutic experiment, female C57BL/6 mice were fed with high-fat diet for 3 months to induce obesity. Then the obese mice were divided into two groups randomly, and fed with HF or HF+FME for another 2 weeks. Body weight and daily food intake amounts were recorded. Fasting blood glucose, glucose tolerance test, insulin tolerance test, serum and liver lipid levels were assayed and the white adipose tissues were imaged. The gene expression in mice liver and brown adipose tissues were analyzed with a quantitative PCR assay.
Results
In the preventive treatment, FME controlled the body weight gain and the size of white adipocytes, lowered the fasting blood glucose, serum total cholesterol (TC), serum low density lipoprotein cholesterol (LDL-c) levels as well as liver lipid contents in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, FME decreased the serum triglyceride (TG), serum TC, serum LDL-c, fasting blood glucose levels and liver lipid contents, improved glucose tolerance and insulin tolerance. Compared with the HF group, FME significantly increased the mRNA expression of PPARα and its target genes.
Conclusion
Our study suggests that FME may be a potential dietary supplement for preventing and ameliorating the obesity and obesity-related metabolic disturbances.
doi:10.1371/journal.pone.0093510
PMCID: PMC3976270  PMID: 24705395
9.  Platycodon grandiflorum extract represses up-regulated adipocyte fatty acid binding protein triggered by a high fat feeding in obese rats 
AIM: To investigate the effect of Platycodon grandi-florum extract (PGE) on lipid metabolism and FABP mRNA expression in subcutaneous adipose tissue of high fat diet-induced obese rats.
METHODS: PGE was treated to investigate the inhibitory effect on the pre-adipocyte 3T3-L1 differentiation and pancreatic lipase activity. Male Sprague-Dawley rats with an average weight of 439.03 ± 7.61 g were divided into four groups: the control groups that fed an experimental diet alone (C and H group) and PGE treatment groups that administered PGE along with a control diet or HFD at a concentration of 150 mg/kg body weight (C + PGE and H + PGE group, respectively) for 7 wk. Plasma total cholesterol (TC) and triglycerol (TG) concentrations were measured from the tail vein of rats. Adipocyte cell area was measured from subcutaneous adipose tissue and the fatty acid binding protein (FABP) mRNA expression was analyzed by northern blot analysis.
RESULTS: PGE treatment inhibited 3T3-L1 pre-adipocyte differentiation and fat accumulation, and also decreased pancreatic lipase activity. In this experiment, PGE significantly reduced plasma TC and TG concentrations as well as body weight and subcutaneous adipose tissue weight. PGE also significantly decreased the size of subcutaneous adipocytes. Furthermore, it significantly repressed the up-regulation of FABP mRNA expression induced by a high-fat feeding in subcutaneous adipose tissue.
CONCLUSION: PGE has a plasma lipid lowering-effect and anti-obesity effect in obese rats fed a high fat diet. From these results, we can suggest the possibility that PGE can be used as a food ingredient or drug component to therapeutically control obesity.
doi:10.3748/wjg.v13.i25.3493
PMCID: PMC4146786  PMID: 17659697
Obesity; High fat diet; Platycodon grandi-florum extract; Fatty acid binding protein; Subcutaneous adipose tissue
10.  Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation 
Genes & Nutrition  2013;9(1):361.
Quercetin exhibits a wide range of biological functions. The first aim of the present work was to analyze the effects of quercetin on fat accumulation in adipose tissue and glycemic control in rats. Any potential involvement of muscle fatty acid oxidation in its effect on glycemic control was also assessed. Animals were fed a high-fat high-sucrose diet either supplemented with quercetin (30 mg/kg body weight/day), or not supplemented, for 6 weeks. One week before killing, a glucose tolerance test was carried out. Muscle triacylglycerol content, serum glucose, insulin, fructosamine and free fatty acids were measured, and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. The activities of lipogenic enzymes and lipoprotein lipase in adipose tissue, carnitine palmitoyl transferase-1b (CPT-1b) and citrate synthase in skeletal muscle, and the expression of several genes, ACO, CD36, CPT-1b, PPAR-α, PGC-1α, UCP3, TFAM and COX-2 in skeletal muscle were analyzed. Quercetin caused no significant reduction in body weight or adipose tissue sizes. However, fructosamine, basal glucose and insulin, and consequently HOMA-IR, were significantly reduced by quercetin. No changes were observed in the activity of lipogenic enzymes and lipoprotein lipase. Muscle triacylglycerol content was similar in both experimental groups. The expression of ACO, CD36, CPT-1b, PPAR-α, PGC-1α, UCP3, TFAM and COX-2 remained unchanged. It can be concluded that quercetin is more effective as an anti-diabetic than as an anti-obesity biomolecule. The improvement in insulin resistance induced by this flavonoid is not mediated by a delipidating effect in skeletal muscle.
doi:10.1007/s12263-013-0361-7
PMCID: PMC3896623  PMID: 24338341
Quercetin; Glycemic control; Fat accumulation; Adipose tissue; Muscle; Fatty acid oxidation; Rat
11.  OA01.38. Anti-obesity activity of Zizyphyus mauritiana lam: a potent pancreatic lipase inhibitor 
Ancient Science of Life  2012;32(Suppl 1):S38.
Purpose:
To study anti-obesity activity of Ziziphus mauritiana Lam bark powder (ZMBP) on High Fat Diet (HFD) induced obesity in rats.
Method:
Obesity was induced in Wistar rats by feeding high fat diet (HFD) for 70 days. The obese rats were distributed in 4 groups (n=5). Group 1: Normal (lean) Control, Group 2: Obese Control, Group 3: Obese rats administered orally 250 mg/kg ZMBP daily, Group 4: Obese rats dosed with 500 mg/kg ZMBP daily, Group 5: Obese rats dosed with Standard Drug Sibutramine, 0.90 mg/kg. The rats were dosed orally daily for a period of 90 days. The animals were screened for induction of obesity by analysing obesity parameters such as Body weight, Anthropological Parameters, Serum Tryglycerides, Serum Cholesterol, Glucose tolerance test, Insulin resistance Test, DEXA analysis and MRI Scan.
Result:
At the end of 90 days treatment with ZMBP the obese rats showed 16.33 % reduction in body weight gain at 250 mg/kg and 17.38 % (P<0.05) reduction in body weight gain at 500 mg/kg when compared with the obese control group respectively. The standard drug Sibutramine showed 5.52% reduction in body weight gain when compared with the obese control group. The DEXA analysis at the end of 90 days of treatment showed 68.99 % (P<0.01) decrease in the Fat mass at 250 mg/kg dose and 72.84 % (P<0.001) decrease in the Fat mass at 500 mg/kg dose when compared with the obese control group. The pancreatic lipase activity in 250mg/kg (5.13+0.71 U/mg of protein) and in 500 mg/kg (4.01+0.86 I/mg of protein) reduced significantly (P<0.001) when compared with the obese control group (9.73+2.39 U/mg of protein)
Conclusion:
The ZMBP has anti-obesity activity at 250 mg/kg and 500-mg/kg dose. It has lipase inhibitory activity.
PMCID: PMC3800916
12.  Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass 
PLoS Biology  2013;11(2):e1001485.
Partial inhibition of adipose tissue lipolysis does not increase fat mass but improves glucose metabolism and insulin sensitivity through modulation of fatty acid turnover and induction of fat cell de novo lipogenesis.
When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.
Author Summary
In periods of energy demand, mobilization of fat stores in mammals (i.e., adipose tissue lipolysis) is essential to provide energy in the form of fatty acids. In excess, however, fatty acids induce resistance to the action of insulin, which serves to regulate glucose metabolism in skeletal muscle and liver. Insulin resistance (or low insulin sensitivity) is believed to be a cornerstone of the complications of obesity such as type 2 diabetes and cardiovascular diseases. In this study, our clinical observation of natural variation in fat cell lipolysis in individuals reveals that a high lipolytic rate is associated with low insulin sensitivity. Furthermore, partial genetic and pharmacologic inhibition of hormone-sensitive lipase, one of the enzymes involved in the breakdown of white adipose tissue lipids, results in improvement of insulin sensitivity in mice without gain in body weight and fat mass. We undertake a series of mechanistic studies in mice and in human fat cells to show that blunted lipolytic capacity increases the synthesis of new fatty acids from glucose in fat cells, a pathway that has recently been shown by others to be a major determinant of whole body insulin sensitivity. In conclusion, partial inhibition of adipose tissue lipolysis is a plausible strategy in the treatment of obesity-related insulin resistance.
doi:10.1371/journal.pbio.1001485
PMCID: PMC3576369  PMID: 23431266
13.  Biochemical and histological impact of Vernonia amygdalina supplemented diet in obese rats 
This study was carried out to evaluate the anti-obesity effect of Vernonia amygdalina Del. (VA) supplemented diet. VA leaf powder was fed at 5% and 15% to diet-induced obese rats for 4 weeks and its effect compared with orlistat (5.14 mg/kg p.o.), an anti-obesity drug. Food intake, body and organ weights, total body fat, some lipid components and amino transaminase activities in serum, hepatocytes and brain; as well as serum glucose, were measured during or at end of the study. Result showed respective decrease of 12.78% and 38.51% in body weight gain, of VA fed rats against 17.45% of orlistat at end of study (P < 0.05); but with no effect on food intake. Total body fat was lowered by 28.04% and 30.02% vs. obese control rats (CDC) (P < 0.05). Furthermore, serum triacylglycerol (TG), serum and brain total cholesterol (TCHOL), were down regulated at 15% VA supplementation (P < 0.05). Serum glucose which increased in obese rats by 46.26% (P < 0.05) vs. NC, indicating intolerance, was restored by VA (38.75% and 34.65%) and orlistat (31.80%) vs. CDC (P < 0.05). VA diet also exerted hepato-protection, via lowering serum alanine amino transaminase (ALT) (41.35% and 27.13%) and aspartate amino transaminase (AST) (17.09% and 43.21%) activities (P < 0.05). Orlistat had no effect on these enzymes. Histology of adipose tissue corroborated the changes on total body fat. We concluded that, diet supplemented with VA can attenuate dietary obesity as well as ameliorates the potential risks of hepato-toxicity and glucose intolerance associated with obesity.
doi:10.1016/j.sjbs.2012.05.003
PMCID: PMC3730893  PMID: 23961200
Vernonia amygdalina Del.; Adipose tissue; Histology; Total body fat; Lipid profile; Glucose intolerance; Diet-induced obesity
14.  Extracts of Pomelo Peels Prevent High-Fat Diet-Induced Metabolic Disorders in C57BL/6 Mice through Activating the PPARα and GLUT4 Pathway 
PLoS ONE  2013;8(10):e77915.
Objective
Metabolic syndrome is a serious health problem in both developed and developing countries. The present study investigated the anti-metabolic disorder effects of different pomelo varieties on obese C57BL/6 mice induced by high-fat (HF) diet.
Design
The peels of four pomelo varieties were extracted with ethanol and the total phenols and flavonoids content of these extracts were measured. For the animal experiment, the female C57BL/6 mice were fed with a Chow diet or a HF diet alone or supplemented with 1% (w/w) different pomelo peel extracts for 8 weeks. Body weight and food intake were measured every other day. At the end of the treatment, the fasting blood glucose, glucose tolerance and insulin (INS) tolerance test, serum lipid profile and insulin levels, and liver lipid contents were analyzed. The gene expression analysis was performed with a quantitative real-time PCR assay.
Result
The present study showed that the Citrus grandis liangpinyou (LP) and beibeiyou (BB) extracts were more potent in anti-metabolic disorder effects than the duanshiyou (DS) and wubuyou (WB) extracts. Both LP and BB extracts blocked the body weight gain, lowered fasting blood glucose, serum TC, liver lipid levels, and improved glucose tolerance and insulin resistance, and lowered serum insulin levels in HF diet-fed mice. Compared with the HF group, LP and BB peel extracts increased the mRNA expression of PPARα and its target genes, such as FAS, PGC-1α and PGC-1β, and GLUT4 in the liver and white adipocyte tissue (WAT).
Conclusion
We found that that pomelo peel extracts could prevent high-fat diet-induced metabolic disorders in C57BL/6 mice through the activation of the PPARα and GLUT4 signaling. Our results indicate that pomelo peels could be used as a dietary therapy and the potential source of drug for metabolic disorders.
doi:10.1371/journal.pone.0077915
PMCID: PMC3797771  PMID: 24147098
15.  Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice* 
The Journal of biological chemistry  2007;282(34):24642-24649.
This study evaluated the contributions of carboxyl ester lipase (CEL) and pancreatic triglyceride lipase (PTL) in lipid nutrient absorption. Results showed PTL deficiency has minimal effect on triacylglycerol (TAG) absorption under low fat dietary conditions. Interestingly, PTL−/− mice displayed significantly reduced TAG absorption compared with wild type mice under high fat/high cholesterol dietary conditions (80.1 ± 3.7 versus 91.5 ± 0.7%, p < 0.05). Net TAG absorption was reduced further to 61.1 ± 3.8% in mice lacking both PTL and CEL. Cholesterol absorption was 41% lower in PTL−/− mice compared with control mice (p < 0.05), but this difference was not exaggerated in PTL−/−,CEL−/− mice. Retinyl palmitate absorption was reduced by 45 and 60% in PTL−/− mice (p < 0.05) and PTL−/−,CEL−/− mice (p < 0.01), respectively. After 15 weeks of feeding, the high fat/high cholesterol diet, wild type, and CEL−/− mice gained ∼24 g of body weight. However, body weight gain was 6.2 and 8.6 g less (p < 0.01) in PTL−/− and PTL−/−,CEL−/− mice, respectively, despite their consumption of comparable amounts of the high fat/high cholesterol diet. The decrease body weight gain in PTL−/− and PTL−/−,CEL−/− mice was attributed to their absorption of fewer calories from the high fat/high cholesterol diet, thereby resulting in less fat mass accumulation than that observed in wild type and CEL−/− mice. Thus, this study documents that PTL and CEL serve complementary functions, working together to mediate the absorption of a major portion of dietary fat and fat-soluble vitamin esters. The reduced lipid absorption efficiency due to PTL and CEL inactivation also resulted in protection against diet-induced obesity.
doi:10.1074/jbc.M702530200
PMCID: PMC2045644  PMID: 17604277
16.  Liver Fatty Acid Binding Protein Gene-Ablated Female Mice Exhibit Increased Age-Dependent Obesity123 
The Journal of nutrition  2008;138(10):1859-1865.
Previous work done in our laboratory suggested a role for liver fatty acid binding protein (L-FABP) in obesity that develops in aging female L-FABP gene-ablated (−/−) mice. To examine this possibility in more detail, cohorts of wild-type (+/+) and L-FABP (−/−) female mice were fed a standard low-fat nonpurified rodent diet for up to 18 mo. Various obesity-related parameters were examined including body weight and fat and lean tissue mass. Obesity in (−/−) mice was associated with increased expression of nuclear receptors that induce peroxisome proliferator-activated receptor α (PPARα) (e.g., hepatocyte nuclear factor 1α, genotype effectα and of PPARα-regulated proteins involved in uptake of free (lipoprotein lipase and fatty acid transport protein, genotype and/or age effect) and esterified (scavenger receptor class B type 1, genotype effect) long chain fatty acids (LCFAs). Hepatic total lipid and neutral lipid levels were not affected by age or genotype, consistent with absence of gross and histologic steatosis. There was increased mRNA expression of liver proteins involved in LCFA oxidation [mitochondrial 3-oxoacyl-CoA thiolase (genotype effect) and butyryl-CoA dehydrogenase (genotype and/or age effect)], increased expression of LCFA esterification enzymes [glycerol-3-phosphate acyltransferase (age × genotype effect) and acyl-CoA:cholesterol acyltransferase-2 (genotype and/or age effect)], and increased expression of proteins involved in intracellular transfer and secretion of esterified LCFA [liver microsomal triacylglycerol transfer protein (genotype effect), serum apolipoprotein B (genotype or age effect), and liver apolipoprotein B (age and age × genotype effect)]. The data support a working model in which obesity development in these mice results from shifts toward reduced energy expenditure and/or more efficient energy uptake in the gut.
PMCID: PMC2835297  PMID: 18806093
17.  Effects of prolonged ethanol intake and malnutrition on rat pancreas. 
Gut  1996;38(2):285-292.
Nutritional factors, especially the protein and fat content of the diet, may change pancreatic morphology after ethanol induced injury. This study was performed to delineate the combined effects of a low fat diet and longterm ethanol ingestion on the rat pancreas. Male Sprague-Dawley rats were maintained with five different diets for 12 weeks and the pancreas removed on the day they were killed. Rats fed a very low fat diet without ethanol (5% of total calories as lipid) developed malnutrition, pancreatic steatosis, and reduction in zymogen granules content. Animals fed a 35% lipid diet with ethanol also developed pancreatic steatosis but changes in zymogen granules content were not detected. Both malnutrition and longterm ethanol consumption increased pancreatic cholesterol ester content, and their effects were additive. Pancreatic steatosis was accompanied with hypercholesterolaemia. Amylase, lipase, and cholesterol esterase content were reduced in malnourished rats; but longterm ethanol ingestion, regardless of the nutritional state, increased lipase content and decreased amylase. It is suggested that high serum cholesterol concentrations and increased pancreatic lipase activity could cause accumulation of cholesterol esters in acinar cells. Fat accumulation in the pancreas has been reported as the earliest histopathological feature in alcoholic patients and may be responsible for cytotoxic effects on the acinar cells at the level of the cell membrane. Although it is difficult to extrapolate results in this animal study to the human situation, the results presented in this work might explain the higher incidence of pancreatitis is malnourished populations as well as in alcoholic subjects that is reported in dietary surveys.
Images
PMCID: PMC1383039  PMID: 8801213
18.  Body Fat Accumulation in Zebrafish Is Induced by a Diet Rich in Fat and Reduced by Supplementation with Green Tea Extract 
PLoS ONE  2015;10(3):e0120142.
Fat-rich diets not only induce obesity in humans but also make animals obese. Therefore, animals that accumulate body fat in response to a high-fat diet (especially rodents) are commonly used in obesity research. The effect of dietary fat on body fat accumulation is not fully understood in zebrafish, an excellent model of vertebrate lipid metabolism. Here, we explored the effects of dietary fat and green tea extract, which has anti-obesity properties, on body fat accumulation in zebrafish. Adult zebrafish were allocated to four diet groups and over 6 weeks were fed a high-fat diet containing basal diet plus two types of fat or a low-fat diet containing basal diet plus carbohydrate or protein. Another group of adult zebrafish was fed a high-fat diet with or without 5% green tea extract supplementation. Zebrafish fed the high-fat diets had nearly twice the body fat (visceral, subcutaneous, and total fat) volume and body fat volume ratio (body fat volume/body weight) of those fed low-fat diets. There were no differences in body fat accumulation between the two high-fat groups, nor were there any differences between the two low-fat groups. Adding green tea extract to the high-fat diet significantly suppressed body weight, body fat volume, and body fat volume ratio compared with the same diet lacking green tea extract. 3-Hydroxyacyl-coenzyme A dehydrogenase and citrate synthase activity in the liver and skeletal muscle were significantly higher in fish fed the diet supplemented with green tea extract than in those fed the unsupplemented diet. Our results suggest that a diet rich in fat, instead of protein or carbohydrate, induced body fat accumulation in zebrafish with mechanisms that might be similar to those in mammals. Consequently, zebrafish might serve as a good animal model for research into obesity induced by high-fat diets.
doi:10.1371/journal.pone.0120142
PMCID: PMC4364667  PMID: 25785691
19.  Modulation of lipid metabolism by mixtures of protamine and chitooligosaccharide through pancreatic lipase inhibitory activity in a rat model 
Laboratory Animal Research  2012;28(1):31-38.
Overweight and obesity are usually related with high fat and calorie intake, and seriously causative of lifestyle-related diseases such as cardiovascular disorders, arteriosclerosis, and colon cancer. In this study, we propose a novel dietary therapy against overweight and obesity using mixtures of protamine and chitooligosaccharide (COS), which are known to interrupt the lipid metabolism in the body. Protamine is a dietary protein originated from salmon reproductive organ, and COS is an oligosaccharide made from chitin or chitosan by chemical or enzymatic hydrolysis. In the enzyme activity analysis in vitro, protamine and COS strongly suppressed the activity of pancreatic lipase, which is the primary enzyme for the digestion and absorption of lipids in the intestine. In in vivo animal test, the mixtures of protamine and COS significantly reduced the serum levels of triglyceride (TG), total cholesterol (T-CHO), and low density lipoprotein-cholesterol (LDLC) and inhibited the accumulation of lipids in liver tissue of Sprague Dawley (SD) rats fed high fat diets. On the other hand, they increased fecal TG and T-CHO contents. From these alterations in lipid metabolism, we verified that protamine and COS mixtures could effectively interrupt the digestion and absorption of dietary lipids in the body by inhibiting pancreatic lipase activity. In addition, protamine and COS mixtures increased the serum level of high density lipoprotein-cholesterol (HDLC), responsible for removing cholesterol from cells and protecting atherosclerosis, and therefore decreased the potential risks of cardiovascular diseases by lowering values of the atherogenic index (AI) and cardiac risk factor (CRF). Taken together, we suggest protamine and COS mixtures as a prominent dietary therapy for the prevention of overweight, obesity, and further cardiovascular diseases related with hyperlipidemia.
doi:10.5625/lar.2012.28.1.31
PMCID: PMC3315200  PMID: 22474472
Protamine; chitooligosaccharide; high fat diet; triglyceride; cholesterol
20.  Anti-obesity and cardioprotective effects of cinnamic acid in high fat diet- induced obese rats 
Obesity is a chronic metabolic disorder that is associated with numerous diseases including hyperlipidemia, diabetes mellitus, hypertension, atherosclerosis, cardiovascular disease, and cancer. Cinnamic acid is a phytochemical compound having many biological effects and could be considered for the management of obesity. This study is aimed to assess the possible anti-obesity and cardioprotective properties of cinnamic acid (CA) in high fat diet-fed rats (HFD). Male Wistar rats were divided into 4 groups. They received normal diet, HFD diet, HFD supplemented with fluvastatin (2 mg/kg/day) or cinnamic acid (30 mg/kg/day) for 7 weeks. The results showed an increase in body weight of HFD rats by ~27 % as compared to control group. Moreover, serum lipase activity underwent a significant rise by 103 % which led to an increase in the levels of total cholesterol (T-Ch), triglycerides (TG), LDL-cholesterol in serum of untreated HFD-fed rats. Furthermore, the concentration of leptin and angiotensin-converting enzyme (ACE) activity exhibited remarkable increases in serum of HFD-fed rats as compared to controls. Whereas, the administration of CA to HFD-fed rats improved the body weight gain and serum lipid profile and reverted back near to normal the activities of lipase and ACE. In addition, the echocardiography evidenced that CA is able to protect the aorta and aortic arch and avoided vasoconstriction by increasing their diameters and improved liver steatosis and kidney indices of toxicity. Overall, these results suggest that cinnamic acid exerts anti-obesity and antihypertensive effects through inhibition of lipid digestive enzymes and ACE.
doi:10.1007/s13197-014-1488-2
PMCID: PMC4486570  PMID: 26139902
ACE; HFD; Lipase; Leptin
21.  Structured triacylglycerol containing behenic and oleic acids suppresses triacylglycerol absorption and prevents obesity in rats 
Background
Dietary 1(3)-behenoyl-2,3(1)-dioleoyl-rac-glycerol (BOO) has been reported to inhibit pancreatic lipase activity in vitro and suppress postprandial hypertriacylglycerolemia in humans. In the present study, the anti-obesity activities of BOO and its inhibitory effects on lymphatic triacylglycerol (TAG) absorption were investigated in rats.
Methods
In Experiment 1, rats were fed either BOO or soybean oil (SO) diet for 6 weeks. In the BOO diet, 20% of SO was replaced with an experimental oil rich in BOO. In Experiments 2 and 3, rats cannulated in the thoracic duct were administered an emulsions containing trioleoylglycerol (OOO) or an oil mixture (OOO:BOO, 9:1). Tri[1-14C]oleoylglycerol (14C-OOO) was added to the emulsions administered in Experiment 3.
Results
No observable differences were detected in food intake or body weight gain between the BOO and SO groups in Experiment 1. Plasma and liver TAG concentrations and visceral fat weights were significantly lower in the BOO group than in the SO group. The apparent absorption rate of fat was significantly lower in the BOO group than in the SO group. In Experiment 2, the lymphatic recovery of oleic and behenic acids was significantly lower at 5 and 6 h after BOO administration than after OOO administration. In Experiment 3, the lymphatic recovery of 14C-OOO was significantly lower at 5 and 6 h after BOO administration than after OOO administration.
Conclusions
These results suggest that BOO prevents deposition of visceral fat and hepatic TAG by lowering and delaying intestinal absorption of TAG.
doi:10.1186/1476-511X-9-77
PMCID: PMC2918615  PMID: 20653972
22.  Citrus junos Tanaka Peel Extract Exerts Antidiabetic Effects via AMPK and PPAR-γ both In Vitro and In Vivo in Mice Fed a High-Fat Diet 
The antidiabetic effect of the Citrus junos Tanaka (also known as yuja or yuzu) was examined. Ethanol extract of yuja peel (YPEE) significantly stimulated 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) uptake in C2C12 myotubes. However, ethanol extract of yuja pulp (YpEE) and water extract of yuja peel (YPWE) or pulp (YpWE) did not stimulate glucose uptake. In addition, peroxisome proliferator-activated receptor gamma (PPAR-γ) and AMP-activated protein kinase (AMPK) activities were increased by YPEE in a dose-dependent manner. Pretreatment of AMPK inhibitor decreased the glucose uptake stimulated by YPEE in C2C12 myotubes. We confirmed the anti-diabetic effect of YPEE in mice fed a high fat-diet (HFD). Compared with control mice on a normal diet (ND), these mice showed increased body weight, liver fat, insulin resistance, triacylglycerol (TG), and total cholesterol content. Addition of 5% YPEE significantly reduced the weight gain and rise in liver fat content, serum triacylglycerol (TG), total cholesterol, and insulin resistance found in mice fed a high-fat diet (HFD). Moreover, YPEE reduced the secretion of HFD-induced adipocytokines such as leptin and resistin. YPEE also resulted in increased phosphorylation of AMPK in muscle tissues. These results suggest that ethanol extract of yuja peel exerts anti-diabetic effects via AMPK and PPAR-γ in both cell culture and mouse models.
doi:10.1155/2013/921012
PMCID: PMC3674686  PMID: 23762167
23.  The inhibitory activity of herbal medicines on the keys enzymes and steps related to carbohydrate and lipid digestion 
Background
Obesity and overweight are consistently associated with metabolic disorders including hyperglycemia and hyperlipidemia. Herbal medicines have been currently suggested as an alternative source of potentially useful antihyperglycemic, antihyperlipidemic, antioxidant activities. The objective of this study was to assess the in vitro inhibitory effects of eleven herbal medicines on carbohydrate and lipid digestive enzymes and the key steps of lipid digestion including the inhibition of micelle formation and the ability to bind bile acid. In addition, antioxidant activity of herbal medicines was also investigated.
Methods
α-Glucosidase, pancreatic α-amylase, pancreatic lipase, and pancreatic cholesterol esterase inhibitory activities of aqueous extract of herbal medicines were measured using the enzymatic colorimetric assay. The formation of cholesterol micelles was determined using the cholesterol assay kit. The bile acid binding was measured using the colorimetric assay. Antioxidant activities were assessed by using four methods including Trolox equivalent antioxidant capacity (TEAC), oxygen radical absorbance capacity ORAC), superoxide radical scavenging activity (SRSA), and hydroxyl radical scavenging activity (HRSA).
Results
The extracts (1 mg/mL) markedly inhibited intestinal maltase (5.16 − 44.33 %), sucrase (1.25–45.86 %), pancreatic α-amylase (1.75–12.53 %), pancreatic lipase (21.42–85.93 %), and pancreatic cholesterol esterase (2.92–53.35 %). The results showed that all extracts exhibited the inhibitory activity against pancreatic lipase with the IC50 values ranging from 0.015 to 4.259 mg/mL. In addition, the incorporation of cholesterol into micelles was inhibited by the extracts (6.64–33.74 %). The extracts also bound glycodeoxycholic acid (9.9–15.08 %), taurodeoxycholic acid (12.55–18.18 %), and taurocholic acid (11.91 − 18.4 %). Furthermore, the extracts possessed various antioxidant activities including the TEAC values (0.50 − 4.70 μmol trolox/mg dried extract), the ORAC values (9.14–44.41 μmol trolox/mg dried extract), the SRSA (0.31 − 18.82 mg trolox/mg dried extract), and the HRSA (0.05–2.29 mg trolox/mg dried extract). The findings indicated that Syzygium aromaticum, Phyllanthus amarus, Thunbergia laurifolia were the effective promising antihyperglycemic and antihyperlipidemic agents. Statistical analysis demonstrated strong positive significant correlations between the contents of phenolic compounds and % inhibition of pancreatic lipase (r = 0.885, p < 0.001), % inhibition of pancreatic cholesterol esterase (r = 0.761, p < 0.001), and the TEAC value (r = 0.840, p < 0.001). Furthermore, there was a strongly positive correlation between the TEAC value and % inhibition of pancreatic cholesterol esterase (r = 0.851, p < 0.001) and % inhibition of pancreatic lipase (r = 0.755, p < 0.001).
Conclusions
Three herbal medicines including Syzygium aromaticum, Thunbergia laurifolia, and Phyllanthus amarus markedly inhibited the intestinal α-glucosidase, pancreatic α-amylase, pancreatic lipase, and pancreatic cholesterol esterase. They also reduced formation of cholesterol micelle and bound bile acid. The findings indicate that these herbal medicines might be a promising agent for antihyperglycemic, antihyperlipidemic, and antioxidant activities.
doi:10.1186/s12906-016-1424-2
PMCID: PMC5097378  PMID: 27814716
Herbal medicines; Antihyperglycemia; Antihyperlipidemia; Antioxidant
24.  Korean solar salts reduce obesity and alter its related markers in diet-induced obese mice 
Nutrition Research and Practice  2016;10(6):629-634.
BACKGROUND/OBJECTIVES
The aim of this experiments was to show anti-obesity effects of Korean solar salt from different salt fields in diet-induced obese mice.
SUBJECTS/METHODS
Diet-induced obesity (DIO) was induced by a high-fat diet (HFD; 45% cal from fat) in C57BL/6J mice for eight weeks. The mice were fed with the designated diets (chow diet for Normal, HFD for Control, 0.47%-salt-mixed HFD for purified salt (PS), Guerande solar salt from France (SS-G), solar salt from Y salt field (SS-Y), solar salts from T salt field (SS-T) and S salt field (SS-S)) for another eight weeks. We checked body weight, food efficiency ratio (FER) and tissue weights (liver and epididymal adipose tissue (EAT)), and observed serum concentrations of triacylglycerol (TG), total cholesterol (TC), leptin and insulin. We also evaluated gene expressions of adipogenic / lipogenic mRNAs of C/EBPα, PPARγ and FAS and beta-oxidation-related factors (PPARα and CPT-1) in liver and EAT. The mineral composition of salt samples were analyzed using inductively coupled plasma optical emission spectrometry (ICP-OES).
RESULTS
SS-T and SS-S significantly reduced body weight gain, FER, and weight of EAT compared to control and other samples (P < 0.05). SS-T and SS-S also significantly decreased serum levels of TG, TC, leptin and insulin (P < 0.05). SS-T and SS-S suppressed expressions of adipogenic / lipogenic mRNAs in liver and EAT, while promoting expression of beta-oxidation-related factors. The lowest sodium concentration was observed in SS-T (30.30 ± 0.59%), and the lowest sodium-to-potassium (Na/K) ratio was found in SS-S (17.81).
CONCLUSIONS
Our study shows that well-processed Korean solar salt may have anti-obesity effects in vivo, probably owing to its differences in mineral composition and other components, presumably resulting from the manufacturing processes. Further research is needed into the mechanism and to explore optimal manufacturing processes.
doi:10.4162/nrp.2016.10.6.629
PMCID: PMC5126413  PMID: 27909561
Salt; obesity; obese mouse
25.  Time-course microarray analysis for identifying candidate genes involved in obesity-associated pathological changes in the mouse colon 
Genes & Nutrition  2016;11:30.
Background
Obesity is known to increase the risk of colorectal cancer. However, mechanisms underlying the pathogenesis of obesity-induced colorectal cancer are not completely understood. The purposes of this study were to identify differentially expressed genes in the colon of mice with diet-induced obesity and to select candidate genes as early markers of obesity-associated abnormal cell growth in the colon.
Methods
C57BL/6N mice were fed normal diet (11% fat energy) or high-fat diet (40% fat energy) and were euthanized at different time points. Genome-wide expression profiles of the colon were determined at 2, 4, 8, and 12 weeks. Cluster analysis was performed using expression data of genes showing log2 fold change of ≥1 or ≤−1 (twofold change), based on time-dependent expression patterns, followed by virtual network analysis.
Results
High-fat diet-fed mice showed significant increase in body weight and total visceral fat weight over 12 weeks. Time-course microarray analysis showed that 50, 47, 36, and 411 genes were differentially expressed at 2, 4, 8, and 12 weeks, respectively. Ten cluster profiles representing distinguishable patterns of genes differentially expressed over time were determined. Cluster 4, which consisted of genes showing the most significant alterations in expression in response to high-fat diet over 12 weeks, included Apoa4 (apolipoprotein A-IV), Ppap2b (phosphatidic acid phosphatase type 2B), Cel (carboxyl ester lipase), and Clps (colipase, pancreatic), which interacted strongly with surrounding genes associated with colorectal cancer or obesity.
Conclusions
Our data indicate that Apoa4, Ppap2b, Cel, and Clps are candidate early marker genes associated with obesity-related pathological changes in the colon. Genome-wide analyses performed in the present study provide new insights on selecting novel genes that may be associated with the development of diseases of the colon.
Electronic supplementary material
The online version of this article (doi:10.1186/s12263-016-0547-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12263-016-0547-x
PMCID: PMC5120484  PMID: 27895803
Obesity; Colorectal cancer; Time-course microarray analysis; Gene expression; Clustering; Virtual network analysis

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