High-fat Diet-induced Obese Mouse Model Research Articles

Comparison of potential preventive effects of pomegranate flower, peel and seed oil on insulin resistance and inflammation in high-fat and high-sucrose diet-induced obesity mice model

Objective: The potentially beneficial effects of pomegranate peel (PPE), flower (PFE) and seed oil (PSO) extracts, in comparison with rosiglitazone, on adiposity, lipid profile, glucose homoeostasis, as well as on the underlying inflammatory mechanisms, were examined in high-fat and high-sucrose (HF/HS) diet-induced obese (DIO) mice. Measurements: Body weight, body fat, energy expenditure, food and liquid intake, blood glucose, and plasma levels of insulin, lipids and cytokines were measured. Results: After two weeks, PSO (2 ml/kg/day) and rosiglitazone (3 mg/kg/day) had not improved glucose intolerance. After 4 weeks, both treatments significantly reduced fasting blood glucose and an insulin tolerance test showed that they also improved insulin sensitivity. Treatment with PPE, PFE and PSO, reduced the plasma levels of the pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), and PFE increased the level of the anti-inflammatory cytokine interleukin-10 (IL-10). Conclusion: PPE, PFE and PSO have anti-inflammatory properties. PSO also improved insulin sensitivity.

Anti-inflammatory and anti-diabetic effects of brown seaweeds in high-fat diet-induced obese mice.

BACKGROUND/OBJECTIVESSeaweeds have been reported to have various health beneficial effects. In this study, we investigated the potential anti-obesity and anti-inflammatory effects of four types of domestic brown seaweeds in a high-fat diet-induced obese mouse model and bone marrow-derived macrophages (BMDM).MATERIALS/METHODSMale C57BL/6N mice were fed low-fat diet (LFD), high-fat diet (HFD) or HFD containing Undaria Pinnatifida, HFD containing Laminaria Japonica (LJ), HFD containing Sargassum Fulvellum, or HFD containing Hizikia Fusiforme (HF) for 16 weeks.RESULTSBrown seaweed supplementation did not affect long-term HFD-associated changes in body weight or adiposity, although mice fed HFD + LJ or HFD + HF gained slightly less body weight compared with those fed HFD at the beginning of feeding. Despite being obese, mice fed HFD + LJ appeared to show improved insulin sensitivity compared to mice fed HFD. Consistently, we observed significantly reduced blood glucose concentrations in mice fed HFD + LJ compared with those of mice fed HFD. Although no significant differences in adipocyte size were detected among the HFD-fed groups, consumption of seaweeds decreased formation of HFD-induced crown-like structures in gonadal adipose tissue as well as plasma inflammatory cytokines. BMDM from mice fed HFDs with seaweeds showed differential regulation of pro-inflammatory cytokines such as IL-1β and IL-6 compared with BMDM from mice fed HFD by LPS stimulation.CONCLUSIONAlthough seaweed consumption did not prevent long-term HFD-induced obesity in C57BL/6N mice, it reduced insulin resistance (IR) and circulation of pro-inflammatory cytokines. Therefore, seaweeds may ameliorate systemic inflammation and IR in obesity partially due to inhibition of inflammatory signaling in adipose tissue cells as well as bone marrow-derived immune cells.

New ethanol extraction improves the anti-obesity effects of black tea.

Black tea has been reported to have anti-obesity effects in both rodents and humans. Gallic acid, an active component of black tea, decomposes quickly into pyrogallol in high-temperature solutions. This study introduced a new, aqueous ethanol extraction of black tea, which resulted in extracts with higher concentrations of gallic acid than conventional black tea extracts prepared by hot-water extraction or hot-ethanol extraction. We confirmed that, compared with the hot-water extract of black tea, the cold-ethanol extract of black tea (CE-BTE) had greater effects on reducing body weight and body fat, improving fatty liver, regulating blood glucose, and reducing blood cholesterol in the high-fat diet-induced obese mouse model. Nonetheless, although CE-BTE significantly reduced fat content, it did not reduce peroxisome proliferator-activated receptor (PPARγ) protein in epididymal fat tissue of HFD mice. We also showed that CE-BTE did not inhibit the function of PPARγ protein to drive adipogenesis of mouse 3T3-L1 preadipocytes. Considering that PPARγ is a master transcription factor not only for adipocyte differentiation, but also for adipose tissue function, such as glucose and lipid metabolism and insulin sensitivity, these results suggest that CE-BTE reduced fat mass and body weight without dampening fat cell homeostasis and insulin sensitivity.

Intravenous injection of microvesicle-delivery miR-130b alleviates high-fat diet-induced obesity in C57BL/6 mice through translational repression of PPAR-γ.

BackgroundWe have shown previously that microvesicle (MV)-delivered miR-130b (miR-130b-MV) is able to target PPAR-γ and subsequently reduce the lipid accumulation in vitro. However, the in vivo effect of miR-130b on fat deposition and glucose homeostasis remains unknown.ResultsThree-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks and then intravenously injected with MV-packaged scrambled control microRNA (miRNA) or miR-130b every other day for 10 days. Glucose tolerance test was performed and body weight, epididymal fat weight, as well as the expression of lipid metabolic genes were determined. We showed that mice fed on high-fat diet for 8 weeks demonstrated significantly higher body weight, elevated blood glucose and impaired glucose tolerance. miR-130b-MV injection significantly reduced body weight and epididymal fat weight and partly restored glucose tolerance. miR-130b expression was significantly increased in the epididymal fat after miR-130b-MV injection while the protein content of its target gene PPAR-γ was significantly suppressed, together with a significant up-regulation of the lipolysis genes, hormone sensitive lipase, monoglyceride lipase and leptin. Moreover, miR-130b-MV injection increased the expression of miR-378a and miR-378-3p that are reported to participate in the regulation of fat deposition.ConclusionOur results indicate that miR-130b-MV is able to reduce the epididymal fat deposition and partly restore glucose tolerance, through translational repression of PPAR-γ in a high-fat diet-induced obese mouse model.

Involvement of resveratrol in crosstalk between adipokine adiponectin and hepatokine fetuin-A in vivo and in vitro

Metabolic homeostasis is maintained by the coordinated regulation of several physiological processes and organ crosstalk. Especially, the interaction between adipose tissue and liver is critical for the regulation of glucose and lipid metabolism. This study investigated the involvement of resveratrol (RSV) in the crosstalk between adipokine adiponectin and hepatokine fetuin-A. Adipocytes-hepatocytes co-culture system and a high-fat (HF) diet-induced obesity (DIO) mouse model were utilized. Protein levels of adiponectin and fetuin-A were analyzed in adipocytes and hepatocytes with the knockdown of adiponectin and fetuin-A, respectively. After six weeks of the HF diet treatment, RSV was delivered via an osmotic pump for four weeks. The experimental groups were lean control fed with a standard diet, HF diet-induced obese control and HF_RSV (8 mg/kg/day). After 4 weeks of each treatment, blood and tissues were collected, and the levels of adiponectin and fetuin-A were analyzed. RNA interference during co-culture of adipocytes and hepatocytes demonstrated the existence of crosstalk between adiponectin and fetuin-A. The four-week RSV treatment resulted in increased serum adiponectin and decreased serum fetuin-A in diet-induced obesity mice. The serum levels of adiponectin and fetuin-A were inversely related. In epididymal fat depots, RSV increased adiponectin, peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, sirtuin1 and AMP-activated protein kinase (AMPK). RSV lowered fetuin-A and NF-κB, and increased liver AMPK. These results demonstrate the crosstalk between adiponectin and fetuin-A, and suggest that RSV may be involved in adipose tissue and liver crosstalk through the interaction between adiponectin and fetuin-A.

Thalidomide controls adipose tissue inflammation associated with high-fat diet-induced obesity in mice.

Immunosuppressant agents modulate the activity of the immune system and control adipose tissue inflammatory responses associated with obesity. Controlling adipose tissue inflammation represents an interesting option for inhibiting the low-grade inflammatory state in obese subjects and for preventing obesity-associated pathologies. In this work, we assessed the effects of thalidomide on the inflammatory response in adipose tissue as well as on systemic inflammatory marker expression in the well-established high-fat diet-induced obesity mouse model. Swiss male mice were fed a high-fat diet (60% kcal from fat) for 12 weeks and received thalidomide for the last 10 days (100 mg.kg-1). Adipokine levels were measured in serum and adipose tissue by EIA and real-time quantitative PCR, respectively. Adipose tissue infiltrating macrophages were identified by immunohistochemistry and western blot analysis of F4/80 marker expression. Other inflammatory markers, such as c-Jun N-terminal kinase (JNK) phosphorylation and monocyte chemoattractant protein-1 (MCP-1) production, were also evaluated by western blot analysis. In vitro assays using 3T3-L1 adipocytes were also conducted to evaluated adipokine release. In obese mice, thalidomide administration induced a reduction in adiposity accompanied by a reduction of tumor necrosis factor-α (TNF-α), leptin and MCP-1 adipose tissue production, macrophage infiltration and JNK activation. TNF-α and leptin serum levels were also reduced by thalidomide treatment in obese mice. In vitro, the release of basal TNF-α and lipopolysaccharide (LPS)-induced MCP-1 was inhibited in 3T3-L1 cells. Our results suggest that drugs that can modulate the inflammatory status as well as control adipose tissue expansion could represent an interesting approach in the management of obesity, highlighting the need for further development of such compounds.

Effects of different Lactobacillus reuteri on inflammatory and fat storage in high-fat diet-induced obesity mice model

Lactobacillus reuteri L3 and Lactobacillus reuteri L10 were selected to investigate whether different strains from the same probiotic species, but isolated from different phenotype mice (normal or obese mice), modulated metabolic phenotypes such as obesity. The results indicate that L. reuteri L3 (but not L. reuteri L10) significantly decreased body weight, glucose, insulin, lipopolysaccharide (LPS), and pro-inflammatory cytokine levels and increased energy expenditure (measured by heat production and ambulatory activity) compared with the high-fat diet group. Moreover, the mRNA levels of Ppar-γ, Acc1, and Fas in adipocytes were significantly suppressed, and the mRNA level of Cyp7a1 in liver was promoted by L. reuteri L3, not by L. reuteri L10. These activities may contribute to significant anti-obesity effects of L. reuteri L3. In addition, bacterial strains of the same species showed different effects on inflammatory and obesity, illustrating the complexity of host-bacterial cross-talk and the importance of investigating specific bacterial strains.

High vitamin D and calcium intakes increase bone mineral (Ca and P) content in high-fat diet-induced obese mice

Vitamin D and calcium are essential for bone formation, mineralization, and remodeling. Recent studies demonstrated that an increased body mass can be detrimental to bone health. However, whether an increase in dietary vitamin D and calcium intakes in obesity is beneficial to bone health has not been established. The aim of this study was to examine the effects of increased vitamin D and calcium intakes, alone or in combination, on bone status in a high-fat diet-induced obesity (DIO) mouse model. We hypothesized that DIO in growing mice affects bone mineral status and that high vitamin D and calcium intakes will promote mineralization of the growing bone in obesity via Ca2+ regulatory hormones, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (PTH). Male mice were fed high vitamin D3 (10 000 IU/kg), high calcium (1.2%), or high vitamin D3 plus high-calcium diets containing 60% energy as fat for 10 weeks. Bone weight, specific gravity, mineral (Ca and P), and collagen (hydroxyproline) content were measured in the femur and the tibia. Regulators of Ca2+ metabolism and markers of bone status (PTH, 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D3, and osteocalcin) were measured in blood plasma. Diet-induced obese mice exhibited lower bone Ca and P content and relative bone weight compared with the normal-fat control mice, whereas collagen (hydroxyproline) content was not different between the two groups. High vitamin D3 and calcium intakes significantly increased bone Ca and P content and relative bone weight in DIO mice, which was accompanied by an increase in 1,25(OH)2D3 and a decrease in PTH and osteocalcin concentrations in blood. The findings obtained indicate that increased vitamin D and calcium intakes are effective in increasing mineral (Ca and P) content in the growing bone of obese mice and that the hormonal mechanism of this effect may involve the vitamin D–PTH axis.

Aspergillus oryzae로 생물전환한 감귤박의 항비만 효과

서구화된 식습관의 변화와 편리한 생활에 따른 운동 부족, 유전적 요인, 심리적 요인 등이 복잡하게 얽히면서 비만이 꾸준히 증가하는 추세이다. 한편, 감귤류에는 carotenoid, coumarin, phenylpropanoid, limonoid 등 60여종의 생리활성 물질이 함유되어 있으며 감귤박에는 bioflavonoid, carotenoid, hesperidin, terpenes 등이 풍부하게 함유되어 있다. 감귤박은 항산화 효과, 고혈압 예방, 혈중 LDL 콜레스테롤 함량 감소 효과 등이 있음이 보고되어 있고 최근 들어 감귤박의 비만을 억제하는 효능이 밝혀져 항비만 효과가 입증되었다. 본 연구에서는 고지방식으로 유도한 비만모델 ICR 생쥐에서 Aspergillus oryzae로 발효한 감귤박의 증강된 항비만 효과를 확인하고자 하였다. 항비만 효과를 확인하기 위해 생쥐의 체중변화와 조직의 무게변화를 관찰하였고, 그룹별 혈청 지질 농도, 간 지질농도 및 동맥경화지수를 관찰하였다. 그 결과, 고지방식이 투여군(HFD)에 비해 감귤박 추출물 투여군(CP)과 감귤박 발효 추출물 투여군(CPA)은 체중 증가량과 증체율이 감소하였고, 혈청과 간의 total cholesterol (TG), triglyceride (TC) 함량이 현저히 감소하였다. 한편, 유익한 cholesterol로 알려진 high density lipoprotein cholesterol (HDL-C) 함량은 일반식이 투여군(NFD)과 CPA 투여군이 비슷하였다. CP 투여군과 CPA 투여군의 조직 무게에서도 HFD 투여군보다 감소하여, 전체적으로 CPA 투여군에서 특히 유의적으로 감소하였다. There is a rising trend in obesity due to various factors, including changes in eating habits, lack of exercise, and genetic and psychological factors. Citrus peel has been reported to prevent obesity via antioxidative, antihypertensive, and LDL cholesterol-lowering effects. This study investigated the effects of citrus peel extract fermented with or without Aspergillus oryzae in a mouse model of diet-induced obesity. The animals were divided into four groups: a high-fat diet group (HFD), a normal fat diet (NFD) group, a citrus peel extract (CP) group, and a citrus peel extract fermented with A. oryzae (CPA) group. The citrus peel extract improved lipid metabolism and weight loss in the high-fat diet-induced obese mouse model. As expected, the body weight was higher in the HFD group compared with the NFD, CP, and CPA groups. However, the concentrations of total cholesterol (TG) and triglyceride (TC) in the serum and liver of the CP and CPA groups were lower than in the HFD group. There were no significant differences in the HDL cholesterol concentration among the groups. Taken together, our results suggest that extract of citrus peel biotransformed with A. oryzae had more antiobesity activity than citrus peel not transformed by A. oryzae through the fermentation of metabolites.

Lipase Inhibition and Antiobesity Effect of Atractylodes lancea

The ethanol extract of Atractylodes lancea rhizome displayed significant lipase inhibition with an IC50 value of 9.06 µg/mL in a human pancreatic lipase assay from high-throughput screening. Bioassay-guided isolation led to the identification of one new polyacetylene, syn-(5E,11E)-3-acetoxy-4-O-(3-methylbutanoyl)-1,5,11-tridecatriene-7,9-diyne-3,4-diol (7), along with six known compounds (1-6). The structure of compound 7 was determined based on the analysis of NMR and MS data. Among these seven lipase inhibitors, the major compound atractylodin (1) showed the highest lipase inhibitory activity (IC50 = 39.12 µM). The antiobesity effect of the ethanol extract of Atractylodes lancea rhizome was evaluated in a high-fat diet-induced obesity mice model at daily dosages of 250 mg/kg and 500 mg/kg body weight for 4 weeks, and treatment with this extract demonstrated a moderate efficacy at the 500 mg/kg dose level.

Central Inflammation and Leptin Resistance Are Attenuated by Ginsenoside Rb1 Treatment in Obese Mice Fed a High-Fat Diet

A low-grade pro-inflammatory state is at the pathogenic core of obesity and type 2 diabetes. We tested the hypothesis that the plant terpenoid compound ginsenoside Rb1 (Rb1), known to exert anti-inflammatory effects, would ameliorate obesity, obesity-associated inflammation and glucose intolerance in the high-fat diet-induced obese mouse model. Furthermore, we examined the effect of Rb1 treatment on central leptin sensitivity and the leptin signaling pathway in the hypothalamus. We found that intraperitoneal injections of Rb1 (14 mg/kg, daily) for 21 days significantly reduced body weight gain, fat mass accumulation, and improved glucose tolerance in obese mice on a HF diet compared to vehicle treatment. Importantly, Rb1 treatment also reduced levels of pro-inflammatory cytokines (TNF-α, IL-6 and/or IL-1β) and NF-κB pathway molecules (p-IKK and p-IκBα) in adipose tissue and liver. In the hypothalamus, Rb1 treatment decreased the expression of inflammatory markers (IL-6, IL-1β and p-IKK) and negative regulators of leptin signaling (SOCS3 and PTP1B). Furthermore, Rb1 treatment also restored the anorexic effect of leptin in high-fat fed mice as well as leptin pSTAT3 signaling in the hypothalamus. Ginsenoside Rb1 has potential for use as an anti-obesity therapeutic agent that modulates obesity-induced inflammation and improves central leptin sensitivity in HF diet-induced obesity.

Antiobesity potential of ursolic acid stearoyl glucoside by inhibiting pancreatic lipase

The present study was designed to evaluate the hypolipidemic effect of ursolic acid stearoyl glucoside (UASG) in high-fat diet-induced obesity. Two in vivo experiments such as high-fat diet-induced obesity mice model and lipid emulsion tolerance test in normal rats were performed. In vitro inhibition of pancreatic lipase activity was further measured to substantiate the results. In high-fat diet-induced obesity mice model, female Swiss mice were fed a high fat diet (HFD; 40% fat) with or without 1 or 2% of UASG or 0.012% orlistat for nine weeks. In lipid emulsion tolerance test male Wister rats were orally administered, lipid emulsion with or without 500 or 1000mg/kg of UASG and the plasma triglycerides were measured from 0.5 to 5h. Consumption of HFD containing UASG to mice for nine weeks exhibited significant reduction in lipid parameters, body weight, parametrial adipose tissue weight, liver triglyceride (TG) and different organ weight compared to HFD fed control. Further it was noted the improvement in insulin resistance induced by the HFD alone group. Furthermore, consumption of an HFD containing 1 or 2% of UASG significantly increased the fecal content and fecal triglyceride compared with the HFD group. Pre-treatment with UASG inhibited the elevated plasma triglyceride level after the oral administration of the lipid emulsion to rats. Further, UASG significantly inhibits activity of pancreatic lipase at a concentration of 2.5mg/ml. Data obtained from the results indicated that UASG prevent high-fat diet-induced obesity in mice possibly by inhibiting pancreatic lipase activity.

Effect of moderate exercise training and low-fat diet on peritoneal macrophage immunocompetence in high-fat diet-induced obese mice model

This study investigated the effect of moderate exercise training on macrophage immunocompetence in high fat diet-induced obese mice. To determine the differential effects of exercise training and low fat diet on macrophage, C57BL/6 male mice (4 week old, n=32) were fed high-fat diet for 5 weeks to induce obese. The high fat-induced obese mice were then divided into four groups and differently treated by high/low fat diet and exercise training for a further 8 weeks; HHC (13 weeks high-fat diet), HHE (13 weeks high-fat diet with 8 weeks Exercise training) and HLC (5 weeks high-fat diet and 8 weeks low-fat diet), HLE (5 weeks high-fat diet and 8 weeks low-fat diet with exercise training). The exercise groups were performed on a motorized treadmill, running for 30-60 min/day at 10-22 m/min, 0% grade for 8wks. Body weight was significantly decreased for those with a low-fat diet and exercise training (HLE). Macrophage phagocytosis was significantly increased by low-fat diet and exercise training (HLE). The percentage of stimulation of NO release induced by LPS was higher in HLE than in other groups. The percentage of stimulation of IL-1β release induced by LPS was higher in HHE and HLE than in other groups. The percentage of stimulation of IFN-γ release induced by LPS was higher in HLE than in other groups. These findings suggest that moderate exercise and low-fat diet have beneficial effects on macrophage immunocompetence in high fat diet-induced obese mice.

Effects of cationic hydroxyethyl cellulose on glucose metabolism and obesity in a diet‐induced obesity mouse model

To investigate the effect of a new soluble fiber, namely cationic hydroxyethyl cellulose (cHEC), on weight loss and metabolic disorders associated with obesity using a high-fat diet-induced obese mouse model. Obese male C57BL/6J (B6) mice were fed high-fat (60% kcal) diets supplemented with cHEC for 5 weeks. Body weight, energy intake, mesenteric adipose and liver weights, plasma cholesterol, plasma insulin, glucose, adiponectin, and leptin were assessed to determine the effects of cHEC. Hepatic and fecal lipids were also analyzed to investigate the effect of cHEC on lipid absorption and metabolism. Supplementation of the high-fat diet with cHEC resulted in significant weight loss in obese mice. In addition, significant decreases were seen in mesenteric adipose and liver weights, as well as concentrations of plasma cholesterol and hepatic lipids. A significant improvement in glucose homeostasis, insulin sensitivity, and leptin concentrations were observed at 4% cHEC. Moreover, increases in fecal excretion of total bile acids, sterols, and fats indicated altered fat absorption when cHEC was supplemented in the diet. We have shown in the present study that cHEC reduces body weight, improves insulin sensitivity, and prevents the development of metabolic syndrome. Furthermore, the effects of cHEC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption.

Inhibitory Effects ofChung Hun Wha Dam Tang(CHWDT) on High-Fat Diet-Induced Obesity via AMP-Activated Protein Kinase Activation

The Chung Hun Wha Dam Tang (CHWDT) herbal combination was reported to cease dizziness and phlegm. However, the effect of CHWDT in obesity has not yet been known mechanically. Therefore, we investigated whether this CHWDT could protect the cells from lipogenesis, gluconeogenesis, and inflammation in both in vivo and in vitro. CHWDT significantly decreased body weight, epididymal and perirenal fat content without affecting feed intake in high-fat diet-induced obese mice model. Additionally, CHWDT inhibited obesity-induced SREBP1, FAS, PGC1α, G6Pase, PEPCK and increased CPT1, ACO, and LCAD genes expression in vivo and in vitro. Proinflammatory cytokines like TNF-α and iNOS expression were reduced by CHWDT in both Raw264.7 macrophages and HepG2 cells. In addition, NO production was also significantly decreased by CHWDT in LPS-stimulated macrophages. Furthermore, AMPKα activation by CHWDT was involved in inhibition of obesity by reducing triglycerides production and increasing CPT1 expression. Based on all of the results, we suggest that CHWDT has inhibitory effects on obesity-induced lipogenesis, gluconeogenesis, and inflammation via AMPKα activation.

Functional Polymorphism of IL-1 Alpha and Its Potential Role in Obesity in Humans and Mice

Proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. IL-1α is one of the proinflammatory cytokines; however, it has not been clarified whether IL-1α may also cause obesity. In this study, we investigated whether polymorphisms in IL-1α contribute to human obesity. A total of 260 obese subjects were genotyped for IL-1α C-889T (rs1800587) and IL-1α G+4845T (rs17561). Analyses of genotype distributions revealed that both IL-1α polymorphisms C-889T (rs1800587) and G+4845T (rs17561) were associated with an increase in body mass index in obese healthy women. In addition, the effect of rs1800587 on the transcriptional activity of IL-1α was explored in pre-adipocyte 3T3-L1 cells. Significant difference was found between the rs1800587 polymorphism in the regulatory region of the IL-1α gene and transcriptional activity. We extended these observations in vivo to a high-fat diet-induced obese mouse model and in vitro to pre-adipocyte 3T3-L1 cells. IL-1α levels were dramatically augmented in obese mice, and triglyceride was increased 12 hours after IL-1α injection. Taken together, IL-1α treatment regulated the differentiation of preadipocytes. IL-1α C-889T (rs1800587) is a functional polymorphism of IL-1α associated with obesity. IL-1α may have a critical function in the development of obesity.

Effect of hydroxypropyl methylcellulose on obesity and glucose metabolism in a diet-induced obesity mouse model

To investigate the effect of hydroxypropyl methylcellulose (HPMC) on weight loss and metabolic disorders associated with obesity using a high-fat diet-induced obese mouse model under a high-fat diet regimen. Obese male C57BL/6J (B6) mice were fed either a high-fat (60% kcal), low-fat (10% kcal), or high-fat diet plus HPMC (4% and 8%) for 5 weeks. Body, mesenteric adipose, and liver weights were determined at the end of the study. In addition, plasma cholesterol, insulin, glucose, adiponectin, and leptin were analyzed to determine the effects of HPMC. Hepatic and fecal lipids were measured to determine the effect of HPMC on lipid absorption and metabolism. Supplementation of the high-fat diet with 4% and 8% HPMC resulted in significant weight loss in obese B6 mice. Furthermore, significant decreases were seen in adipose (30%-40%), liver weights (15%-26%), and concentrations of plasma cholesterol (13%-20%) and hepatic lipids (13%-36%). Supplementation with 8% HPMC led to significant improvements in glucose homeostasis and leptin concentrations. Reductions in plasma cholesterol, glucose, and insulin levels were strongly correlated with reduced leptin concentrations. Moreover, increases in fecal secretion of total bile acids, sterols, and fats indicated altered fat absorption when HPMC was incorporated in the diet. The data indicate that HPMC not only reduces body weight, but also normalizes the metabolic abnormalities associated with obesity and suggest that the effects of HPMC on glucose and lipid homeostasis in B6 mice are mediated by improvements in leptin sensitivity resulting from reduced fat absorption.

B56α/Protein Phosphatase 2A Inhibits Adipose Lipolysis in High-Fat Diet-Induced Obese Mice

Lipolysis and lipogenesis are two opposite processes that control lipid storage in adipocytes. Impaired adipose lipolysis has been observed in both obese human subjects and animal models. This study investigated the mechanisms underlying impaired adipose lipolysis in a high-fat diet-induced obese (DIO) mouse model. DIO models were created using male C57BL/6 mice. Our results show that beta3 adrenergic receptor-specific agonist BRL37344 induced adipose lipolysis was significantly blunted in DIO mice. The levels of Ser660 phosphorylation of hormone-sensitive lipase (HSL) were significantly decreased in the epididymal fat of DIO mice. However, protein levels of HSL, adipose triglyceride lipase and its coactivator comparative gene identification-58 were similar between DIO and control mice. It is known that upon lipolytic hormone stimulation, protein kinase A phosphorylates HSL Ser660 and activates HSL, whereas protein phosphatase 2A (PP2A) dephosphorylates and inactivates HSL. Interestingly, our study shows that high-fat feeding did not alter epididymal fat cAMP and protein kinase A protein levels but significantly increased the expression of the alpha-isoform of PP2A regulatory subunit B' (B56alpha). To study the role of B56alpha in obesity-associated lipolytic defect, B56alpha was overexpressed or knocked down by adenovirus-mediated gene transduction in cultured 3T3-L1CARDelta1 adipocytes. Overexpression of B56alpha significantly decreased HSL Ser660 phosphorylation. In contrast, knocking down B56alpha increased hormone-stimulated HSL activation and lipolysis in mature 3T3-L1CARDelta1 adipocytes. These results strongly suggest that elevated B56alpha/PP2A inhibits HSL and lipolysis in white adipose tissue of DIO mice.

The “Good Cholesterol”

Atherosclerosis is an insidious and dangerous disease: a progressive chemical and structural injury to the blood vessels in such critical organs as the heart, brain, and kidney. The hallmark feature of atherosclerosis is the buildup of cholesterol into lesions called plaques that can reduce the flow of blood. When the delivery of blood to heart muscle drops enough, this can result in the development of chest pain or angina. Angina indicates that the heart muscle is not receiving enough oxygen to carry out its pumping functions. Atherosclerotic plaques can also suddenly rupture, develop a blood clot on their surface, and completely choke off a portion of heart muscle. This chain of events frequently results in heart attack or sudden death without warning. Atherosclerotic disease also predisposes people to stroke, peripheral vascular disease, lower-extremity amputation, and loss of kidney function, among other devastating outcomes. Despite all that we have learned in the past 50 years, atherosclerosis remains the No. 1 killer of men and women and the chief reason for loss of quality of life in Western countries. We are, however, gaining ground. Considerable research has revealed the importance of factors that increase an individual’s risk for developing this disease. Among the most important of these risk factors are elevated blood pressure, diabetes mellitus, obesity, inactivity, smoking, and cholesterol levels. When your physician measures your cholesterol level, he or she is looking at your lipid profile, which comprises low-density lipoprotein cholesterol (LDL-C, or the “bad” cholesterol), triglycerides (blood fats), and high-density lipoprotein cholesterol (HDL-C, or the “good” cholesterol). In a general way, when it comes to measurement of your LDL-C and triglyceride values, a lower value is better because these lipids drive the development and progression of atherosclerosis. In sharp contrast, when it …

Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model

To understand the molecular mechanisms underlying alterations in the pathophysiologic status of dietary obesity, we examined hepatic genes differentially expressed in a long-term high-fat intake-induced obesity mouse model. C57BL/6J male mice were fed with two kinds of diets for 12 weeks; a low-fat diet (LFD), a high-fat diet (HFD; n=8), and the expression levels of ∼10,000 transcripts in liver tissues from the two groups were assessed using cDNA microarray analysis. Twelve-week feeding with the HFD resulted in significant increase in body weight, visceral fat accumulation and circulating cholesterol concentration, compared with the LFD group. The cDNA microarray analysis revealed marked differences in the expressions of 97 hepatic genes. These genes were categorized into seven groups: 1. metabolism; 2. defense, stress, and inflammation responses; 3. signal transduction, apoptosis, and cell cycle; 4. transcription regulation; 5. protein synthesis and modification; 6. transport; and 7. cellular adhesion, cytoskeleton and trafficking. The expression of genes involved in fatty acid catabolism and ketone body synthesis, such as acyl–CoA oxidase1 ( Acox1) and HMG–CoA lyase ( Hmgcl), was significantly increased, and expression of genes involved in lipogenesis and cholesterol synthesis, such as acetyl–CoA synthetase2 ( Acs2), fatty acid synthase ( Fasn), and squalene epoxidase ( Sqle), was drastically decreased in the HFD group. Interestingly, the genes implicated in defense and stress responses, such as glutathione S-transferases ( GSTs) and heat shock proteins ( Hsps), were also highly represented in the HFD group. Besides, a number of previously unappreciated regulatory molecules were changed by the HFD. These results revealed a transcriptional adaptation to long-term HFD and provided interesting information about the molecules involved in the development and maintenance of the obesity phenotype in vivo.