Project description:Obesity increases plasma renin activity and angiotensin II levels, leading to vascular damage, elevated blood pressure, diabetes mellitus, and renal damage. Because genetic deletion of crucial parts of the renin-angiotensin system protect against obesity-related cardiovascular defects, we hypothesized that Dahl salt-sensitive (SS) rats, a model of chronically low plasma renin activity and angiotensin II levels, would be protected against vascular defects during diet-induced obesity compared with SS.13(BN) consomic rats showing normal renin-angiotensin system regulation. We evaluated vascular function in middle cerebral arteries of SS or SS.13(BN) rats fed high-fat (45% kcal from fat) versus normal-fat diet for 15 to 20 weeks from weaning. Endothelium-dependent relaxation in response to acetylcholine (10(-8) to 10(-4) mol/L) was restored in middle cerebral arteries of high-fat SS rats versus normal-fat diet controls, whereas vasodilation to acetylcholine was dramatically reduced in high-fat SS 13(BN) rats versus normal-fat diet controls. These findings support the hypothesis that physiological levels of angiotensin II play an important role in maintaining normal vascular relaxation in cerebral arteries and suggest that the cerebral vasculature of the SS rat model is genetically protected against endothelial dysfunction in diet-induced obesity.
Project description:OBJECTIVE:The induction of beige/brite adipose cells in white adipose tissue (WAT) is associated with protection against high fat diet-induced obesity and insulin resistance in animals. The helix-loop-helix transcription factor Early B-Cell Factor-2 (EBF2) regulates brown adipose tissue development. Here, we asked if EBF2 regulates beige fat cell biogenesis and protects animals against obesity. METHODS:In addition to primary cell culture studies, we used ?Ebf2 knockout mice and mice overexpressing EBF2 in the adipose tissue to study the necessity and sufficiency of EBF2 to induce beiging in vivo. RESULTS:We found that EBF2 is required for beige adipocyte development in mice. Subcutaneous WAT or primary adipose cell cultures from Ebf2 knockout mice did not induce Uncoupling Protein 1 (UCP1) or a thermogenic program following adrenergic stimulation. Conversely, over-expression of EBF2 in adipocyte cultures induced UCP1 expression and a brown-like/beige fat-selective differentiation program. Transgenic expression of Ebf2 in adipose tissues robustly stimulated beige adipocyte development in the WAT of mice, even while housed at thermoneutrality. EBF2 overexpression was sufficient to increase mitochondrial function in WAT and protect animals against high fat diet-induced weight gain. CONCLUSIONS:Taken together, our results demonstrate that EBF2 controls the beiging process and suggest that activation of EBF2 in WAT could be used to reduce obesity.
Project description:The aim of the present study was to investigate the anti-obesity effect of a mixture composed of Garcinia cambogia extract, soypeptide, and L: -carnitine (1.2:0.3:0.02, w/w/w) in rats rendered obese by a high-fat diet (HFD). Sprague-Dawley rats were fed either the high-fat control diet (CD) or the 0.38% mixture-supplemented HFD (CD + M) for 9 weeks. The mixture significantly reduced body weight gain and the accumulation of visceral fat mass in a rat model of HFD-induced obesity. Moreover, the mixture effectively lowered blood and hepatic lipid concentrations and serum glucose, insulin, c-peptide, and leptin levels in rats with HFD-induced obesity. Results from real-time reverse transcription-polymerase chain reaction analyses indicated that the expression levels of leptin, tumor necrosis factor-alpha (TNF-alpha), and sterol regulatory element binding protein 1c (SREBP1c) genes in the epididymal fat tissue of rats fed the CD + M diet were 0.4-, 0.6-, and 0.48-fold, respectively, of those found in the CD rats (P < 0.05), while expression of the uncoupling protein 2 (UCP2) gene in epididymal adipose tissue was 1.25-fold (P < 0.05) of that found in CD rats. In conclusion, a mixture composed of G. cambogia extract, soy peptide, and L: -carnitine attenuated visceral fat accumulation and improved dyslipidemia in a rat model with HFD-induced obesity.
Project description:Red pitaya (Hylocereus polyrhizus) or known as buah naga merah in Malay belongs to the cactus family, Cactaceae. Red pitaya has been shown to give protection against liver damage and may reduce the stiffness of the heart. Besides, the beneficial effects of red pitaya against obesity have been reported; however, the mechanism of this protection is not clear. Therefore, in the present study, we have investigated the red pitaya-targeted genes in obesity using high-carbohydrate, high-fat diet-induced metabolic syndrome rat model.A total of four groups were tested: corn-starch (CS), corn-starch?+?red pitaya juice (CRP), high-carbohydrate, high-fat (HCHF) and high-carbohydrate, high-fat?+?red pitaya juice (HRP). The intervention with 5 % red pitaya juice was continued for 8 weeks after 8 weeks initiation of the diet. Retroperitoneal, epididymal and omental fat pads were collected and weighed. Plasma concentration of IL-6 and TNF-? were measured using commercial kits. Gene expression analysis was conducted using RNA extracted from liver samples. A total of eighty-four genes related to obesity were analyzed using PCR array.The rats fed HCHF-diet for 16 weeks increased body weight, developed excess abdominal fat deposition and down-regulated the expression level of IL-1?, IL-1r1, and Cntfr as compared to the control group. Supplementation of red pitaya juice for 8 weeks increased omental and epididymal fat but no change in retroperitoneal fat was observed. Red pitaya juice reversed the changes in energy balance homeostasis in liver tissues by regulation of the expression levels of Pomc and Insr. The increased protein expression levels of IL-6 and TNF-? in HCHF group and red pitaya treated rats confirmed the results of gene expression.Collectively, this study revealed the usefulness of this diet-induced rat model and the beneficial effects of red pitaya on energy balance homeostasis by modulating the anorectic, orexigenic and energy expenditure related genes.
Project description:The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERB?, CRY, PER) and metabolic (PPAR?, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPAR? mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPAR? transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPAR? transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPAR? expression prior to obesity development.
Project description:Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined.Male wild-type (WT), AhR null (AhR(-/-)) and AhR heterozygote (AhR(+/-)) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed.AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared with WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial ?-oxidation genes in muscle were significantly higher in AhR(-/-) and AhR(+/-) mice compared with WT.This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders.
Project description:Mitochondrial oxidative and thermogenic functions in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensates for partial deficiencies in this tissue and protects against obesity. Here, we show that the transcription factor Yin Yang 1 (YY1) in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins, including fibroblast growth factor 21 (FGF21), bone morphogenetic protein 8b (BMP8b), growth differentiation factor 15 (GDF15), angiopoietin-like 6 (Angptl6), neuromedin B, and nesfatin, linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity and exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight.
Project description:The effects of obesity on different musculoskeletal tissues are not well understood. The glycolytic quadriceps muscles are compromised with obesity, but due to its high oxidative capacity, the soleus muscle may be protected against obesity-induced muscle damage. To determine the time-course relationship between a high-fat/high-sucrose (HFS) metabolic challenge and soleus muscle integrity, defined as intramuscular fat invasion, fibrosis and molecular alterations over six time points. Male Sprague-Dawley rats were fed a HFS diet (n = 64) and killed at serial short-term (3 days, 1 week, 2 weeks, 4 weeks) and long-term (12 weeks, 28 weeks) time points. Chow-fed controls (n = 21) were killed at 4, 12, and 28 weeks. At sacrifice, animals were weighed, body composition was calculated (DXA), and soleus muscles were harvested and flash-frozen. Cytokine and adipokine mRNA levels for soleus muscles were assessed, using RT-qPCR Histological assessment of muscle fibrosis and intramuscular fat was conducted, CD68+ cell number was determined using immunohistochemistry, and fiber typing was assessed using myosin heavy chain protein analysis. HFS animals demonstrated significant increases in body fat by 1 week, and this increase in body fat was sustained through 28 weeks on the HFS diet. Short-term time-point soleus muscles demonstrated up-regulated mRNA levels for inflammation, atrophy, and oxidative stress molecules. However, intramuscular fat, fibrosis, and CD68+ cell number were similar to their respective control group at all time points evaluated. Therefore, the oxidative capacity of the soleus may be protective against diet-induced alterations to muscle integrity. Increasing oxidative capacity of muscles using aerobic exercise may be a beneficial strategy for mitigating obesity-induced muscle damage, and its consequences.
Project description:Beneficial effects of green tea polyphenols (GTP) against obesity have been reported, however, the mechanism of this protection is not clear. Therefore, the objective of this study was to identify GTP-targeted genes in obesity using the high-fat-diet-induced obese rat model. A total of three groups (n?=?12/group) of Sprague Dawley (SD) female rats were tested, including the control group (rats fed with low-fat diet), the HF group (rats fed with high-fat diet), and the HF+GTP group (rats fed with high-fat diet and GTP in drinking water). The HF group increased body weight as compared to the control group. Supplementation of GTP in the drinking water in the HF+GTP group reduced body weight as compared to the HF group. RNA from liver samples was extracted for gene expression analysis. A total of eighty-four genes related to obesity were analyzed using PCR array. Compared to the rats in the control group, the rats in the HF group had the expression levels of 12 genes with significant changes, including 3 orexigenic genes (Agrp, Ghrl, and Nr3c1); 7 anorectic genes (Apoa4, Cntf, Ghr, IL-1?, Ins1, Lepr, and Sort); and 2 genes that relate to energy expenditure (Adcyap1r1 and Adrb1). Intriguingly, the HF+GTP group restored the expression levels of these genes in the high-fat-induced obese rats. The protein expression levels of IL-1? and IL-6 in the serum samples from the control, HF, and HF+GTP groups confirmed the results of gene expression. Furthermore, the protein expression levels of superoxide dismutase-1 (SOD1) and catechol-O-methyltransferase (COMT) also showed GTP-regulated protective changes in this obese rat model. Collectively, this study revealed the beneficial effects of GTP on body weight via regulating obesity-related genes, anti-inflammation, anti-oxidant capacity, and estrogen-related actions in high-fat-induced obese rats.
Project description:We characterized the hypolipidemic effects of alpha-lipoic acid (LA, R-form) and examined the associated molecular mechanisms in a high fat fed Zucker rat model. Rats (n?=?8) were assigned to a high fat (HF) diet or the HF diet with 0.25% LA (HF-LA) for 30 days and pair fed to remove confounding effects associated with the anorectic properties of LA. Compared with the HF controls, the HF-LA group was protected against diet-induced obesity (102.5±3.1 vs. 121.5±3.6,% change BW) and hypercholesterolemia with a reduction in total-C (-21%), non-HDL-C (-25%), LDL-C (-16%), and total LDL particle number (-46%) and an increase in total HDL particles (?22%). This cholesterol-lowering response was associated with a reduction in plasma PCSK9 concentration (-70%) and an increase in hepatic LDLr receptor protein abundance (2 fold of HF). Compared with the HF-fed animals, livers of LA-supplemented animals were protected against TG accumulation (-46%), likely through multiple mechanisms including: a suppressed lipogenic response (down-regulation of hepatic acetyl-CoA carboxylase and fatty acid synthase expression); enhanced hepatic fat oxidation (increased carnitine palmitoyltransferase I? expression); and enhanced VLDL export (increased hepatic diacylglycerol acyltransferase and microsomal triglyceride transfer protein expression and elevated plasma VLDL particle number). Study results also support an enhanced fatty acid uptake (2.8 fold increase in total lipase activity) and oxidation (increased CPT1? protein abundance) in muscle tissue in LA-supplemented animals compared with the HF group. In summary, in the absence of a change in caloric intake, LA was effective in protecting against hypercholesterolemia and hepatic fat accumulation under conditions of strong genetic and dietary predisposition toward obesity and dyslipidemia.