Abstract 67: Intervention With Citrus Flavonoids Reverses Existing Metabolic Disorders and Attenuates the Progression of Advanced Atherosclerosis in High Fat--Fed LDLr-/- Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Amy C Burke ◽  
Brian G Sutherland ◽  
Cynthia G Sawyez ◽  
Dawn E Telford ◽  
Joseph Umoh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Caloric Intake ◽  
Atherosclerotic Lesion ◽  
Lesion Size ◽  
High Fat ◽  
Rapid Weight Gain ◽  
Metabolic Dysregulation ◽  
The Metabolic Syndrome ◽  
Citrus Flavonoids

Previous studies demonstrated that addition of the citrus flavonoids naringenin or nobiletin to a high-fat diet prevented the development of many disorders linked to the metabolic syndrome. In the present study, we assessed the ability of intervention with nobiletin or naringenin to reverse pre-established obesity, insulin resistance, hepatic steatosis, dyslipidemia and attenuate atherogenesis. Ldlr-/- mice were fed chow or a high-fat, cholesterol-containing (HFHC) diet for 12 weeks. For an additional 12 weeks, the HFHC-fed mice: (1) continued on the HFHC diet or were transferred to (2) chow, (3) HFHC + 3% naringenin, or (4) HFHC + 0.3% nobiletin. Following rapid weight gain during HFHC-induction, intervention with naringenin or nobiletin stimulated weight loss, while maintaining caloric intake. Micro-CT imaging revealed flavonoid intervention reversed adipose tissue accumulation by 40-60% in both subcutaneous and visceral depots. At 12 weeks, the HFHC-fed mice were hyperinsulinemic (6-fold), which was accompanied by increased fasting plasma glucose. Intervention with either flavonoid normalized plasma insulin and glucose and corrected impaired insulin and glucose tolerance. The HFHC diet increased cholesterol within VLDL (10-fold) and LDL (6-fold), which was reduced (~50%) by either naringenin or nobiletin intervention. HFHC-induction significantly increased hepatic steatosis. Flavonoid intervention reduced hepatic cholesterol (>50%) and triglyceride (~20%) via increased expression of Pgc1a and Cpt1a and reduced expression of Srebp1c. HFHC-induction increased atherosclerotic lesion area (13-fold), which was increased a further 2.5-fold at 24 weeks. Flavonoid intervention modestly retarded lesion size progression (16-20%). As well, intervention with naringenin or nobiletin slowed the accumulation of aortic cholesterol (~30-45%) and reduced lesional necrotic area (~25%), suggesting improved lesion morphology. These studies demonstrate in mice with pre-existing metabolic dysregulation and atherosclerosis that intervention with naringenin or nobiletin reverses obesity, dyslipidemia, hepatic steatosis and insulin resistance, and modestly attenuates the progression of advanced atherosclerosis.

Abstract 686: Intervention with Naringenin Enhances Weight Loss, Potentiates Improvements in Metabolic Dysregulation and Halts Progression of Atherosclerosis Induced by a High-Fat Diet in LDLr-/- Mice.

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Amy C Burke ◽  
Brian G Sutherland ◽  
Julia M Assini ◽  
Murray W Huff
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Plasma Glucose ◽  
High Fat Diet ◽  
Lesion Size ◽  
Chow Diet ◽  
High Fat ◽  
Metabolic Dysregulation ◽  
The Metabolic Syndrome ◽  
Progression Of Atherosclerosis

Previous studies demonstrate that the addition of naringenin, a grapefruit flavonoid, to a high-fat diet prevents the development of many disorders of the metabolic syndrome and atherosclerosis in Ldlr-/- mice. Furthermore, in intervention studies, the addition of naringenin to a high-fat, high cholesterol (HFHC) diet reversed pre-established obesity, hyperlipidemia, hepatic steatosis, insulin resistance and improved atherosclerotic lesion pathology, but not lesion size. In the present intervention study, we tested the hypothesis that addition of naringenin to a chow diet would further improve pre-established metabolic dysregulation and attenuate lesion development, compared to chow alone. Ldlr-/- mice were fed a HFHC diet for 12 weeks to induce metabolic dysregulation. Subsequently, mice received one of 3 diets for another 12 weeks: 1) continuation of the HFHC diet, 2) an isoflavone-free chow diet or 3) isoflavone-free chow with 3% naringenin. At 12 weeks, the HFHC diet induced significant weight gain and increased adiposity. Intervention with chow alone reduced the weight gained during induction by 22%, whereas the addition of naringenin to chow induced a weight loss of 71%. Specifically, the reduction in adiposity was 2.75-times greater in naringenin-treated mice, compared to chow alone. The HFHC diet increased VLDL cholesterol 20-fold and LDL cholesterol 5-fold, which were reduced by intervention with both chow (>60%) and chow supplemented with naringenin (>80%). The HFHC diet induced insulin resistance and glucose intolerance. Naringenin improved insulin tolerance (plasma glucose AUC -38%) and glucose tolerance (plasma glucose AUC -58%), which was accompanied by normalization of plasma insulin and glucose. HFHC-induction promoted the development of intermediate atherosclerotic lesions. Continuation of the HFHC diet doubled lesion size. Intervention with chow alone attenuated lesion size progression by 65%. The addition of naringenin to chow slowed lesion progression by 90%, resulting in smaller lesions compared to chow intervention alone (P=0.042). We conclude that intervention with naringenin-supplemented chow enhances weight loss, improves metabolic dysregulation and halts the progression of atherosclerosis.

Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet

2010 ◽  
Vol 119 (6) ◽  
pp. 239-250 ◽  
Author(s):  
Vanessa Souza-Mello ◽  
Bianca M. Gregório ◽  
Fernando S. Cardoso-de-Lemos ◽  
Laís de Carvalho ◽  
Márcia B. Aguila ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Glucose Transporter ◽  
Oral Glucose ◽  
Free Access ◽  
High Fat ◽  
The Metabolic Syndrome ◽  
Glucose Transporter 2 ◽  
Drug Treatments

The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg·kg−1 of body weight·day−1), HF-S (HF diet treated with sitagliptin; 1.08 g·kg−1 of body weight·day−1), HF-M (HF diet treated with metformin; 310.0 mg·kg−1 of body weight·day−1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-α (peroxisome-proliferator-activated receptor-α) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-α immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-α (tumour necrosis factor-α) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-γ agonism and PPAR-α activation in the liver with extended incretin action.

scholarly journals Deepure Tea Improves High Fat Diet-Induced Insulin Resistance and Nonalcoholic Fatty Liver Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Jing-Na Deng ◽  
Juan Li ◽  
Hong-Na Mu ◽  
Yu-Ying Liu ◽  
Ming-Xia Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Synthesis ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
High Fat ◽  
The Metabolic Syndrome

This study was to explore the protective effects of Deepure tea against insulin resistance and hepatic steatosis and elucidate the potential underlying molecular mechanisms. C57BL/6 mice were fed with a high fat diet (HFD) for 8 weeks to induce the metabolic syndrome. In the Deepure tea group, HFD mice were administrated with Deepure tea at 160 mg/kg/day by gavage for 14 days. The mice in HFD group received water in the same way over the same period. The age-matched C57BL/6 mice fed with standard chow were used as normal control. Compared to the mice in HFD group, mice that received Deepure tea showed significantly reduced plasma insulin and improved insulin sensitivity. Deepure tea increased the expression of insulin receptor substrate 2 (IRS-2), which plays an important role in hepatic insulin signaling pathway. Deepure tea also led to a decrease in hepatic fatty acid synthesis and lipid accumulation, which were mediated by the downregulation of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthesis (FAS), and acetyl-CoA carboxylase (ACC) proteins that are involved in liver lipogenesis. These results suggest that Deepure tea may be effective for protecting against insulin resistance and hepatic steatosis via modulating IRS-2 and downstream signaling SREBP-1c, FAS, and ACC.

scholarly journals Luteolin-Enriched Artichoke Leaf Extract Alleviates the Metabolic Syndrome in Mice with High-Fat Diet-Induced Obesity

Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 979 ◽  
Author(s):  
Eun-Young Kwon ◽  
So Kim ◽  
Myung-Sook Choi
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Acid Oxidation ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome

This current study aimed to elucidate the effects and possible underlying mechanisms of long-term supplementation with dietary luteolin (LU)-enriched artichoke leaf (AR) in high-fat diet (HFD)-induced obesity and its complications (e.g., dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease) in C57BL/6N mice. The mice were fed a normal diet, an HFD, or an HFD plus AR or LU for 16 weeks. In the HFD-fed mice, AR decreased the adiposity and dyslipidemia by decreasing lipogenesis while increasing fatty acid oxidation, which contributed to better hepatic steatosis. LU also prevented adiposity and hepatic steatosis by suppressing lipogenesis while increasing biliary sterol excretion. Moreover, AR and LU prevented insulin sensitivity by decreasing the level of plasma gastric inhibitory polypeptide and activity of hepatic glucogenic enzymes, which may be linked to the lowering of inflammation as evidenced by the reduced plasma interleukin (IL)-6, IL-1β, and plasminogen activator inhibitor-1 levels. Although the anti-metabolic syndrome effects of AR and LU were similar, the anti-adiposity and anti-dyslipidemic effects of AR were more pronounced. These results in mice with diet-induced obesity suggest that long-term supplementation with AR can prevent adiposity and related metabolic disorders such as dyslipidemia, hepatic steatosis, insulin resistance, and inflammation.

scholarly journals Insulin signaling in AgRP neurons regulates meal size to limit glucose excursions and insulin resistance

2021 ◽  
Vol 7 (9) ◽  
pp. eabf4100
Author(s):  
Garron T. Dodd ◽  
Seung Jae Kim ◽  
Mathieu Méquinion ◽  
Chrysovalantou E. Xirouchaki ◽  
Jens C. Brüning ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Insulin Signaling ◽  
Caloric Intake ◽  
Postprandial Glucose ◽  
Meal Size ◽  
High Fat ◽  
Genetic Ablation ◽  
The Metabolic Syndrome ◽  
Food Seeking

The importance of hypothalamic insulin signaling on feeding and glucose metabolism remains unclear. We report that insulin acts on AgRP neurons to acutely decrease meal size and thereby limit postprandial glucose and insulin excursions. The promotion of insulin signaling in AgRP neurons decreased meal size without altering total caloric intake, whereas the genetic ablation of the insulin receptor had the opposite effect. The promotion of insulin signaling also decreased the intake of sucrose-sweetened water or high-fat food over standard chow, without influencing food-seeking and hedonic behaviors. The ability of heightened insulin signaling to override the hedonistic consumption of highly palatable high-fat food attenuated the development of systemic insulin resistance, without affecting body weight. Our findings define an unprecedented mechanism by which insulin acutely influences glucose metabolism. Approaches that enhance insulin signaling in AgRP neurons may provide a means for altering feeding behavior in a nutrient-dense environment to combat the metabolic syndrome.

Black rice anthocyanins alleviate hyperlipidemia, liver steatosis and insulin resistance by regulating lipid metabolism and gut microbiota in obese mice

2021 ◽  
Author(s):  
Haizhao Song ◽  
Xinchun Shen ◽  
Yang Zhou ◽  
Xiaodong Zheng
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Gut Microbiota ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Liver Steatosis ◽  
Obese Mice ◽  
Black Rice ◽  
High Fat ◽  
Diet Induced Obesity

Supplementation of black rice anthocyanins (BRAN) alleviated high fat diet-induced obesity, insulin resistance and hepatic steatosis by improvement of lipid metabolism and modification of the gut microbiota.

scholarly journals Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

2011 ◽  
Vol 43 (8) ◽  
pp. 408-416 ◽  
Author(s):  
Isabel Rubio-Aliaga ◽  
Baukje de Roos ◽  
Manuela Sailer ◽  
Gerard A. McLoughlin ◽  
Mark V. Boekschoten ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Carbon Metabolism ◽  
Dietary Intervention ◽  
Liver Steatosis ◽  
Oxidative Capacity ◽  
Blood Cholesterol ◽  
High Fat ◽  
One Carbon Metabolism ◽  
Fat Feeding

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

scholarly journals Effect of the Hepatocyte-Specific Deletion of SND1 in Mice on the Liver Insulin Resistance and Acute Liver Failure

2020 ◽  
Author(s):  
Chunyan Zhao ◽  
Xiaoteng Cui ◽  
Baoxin Qian ◽  
Nan Zhang ◽  
Lingbiao Xin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Cholesterol Level ◽  
Hepatic Steatosis ◽  
Glucose Homeostasis ◽  
Hepatic Failure ◽  
High Fat Diet ◽  
High Fat ◽  
Specific Deletion

Abstract Background: The multifunctional protein SND1 was reported to be involved in a variety of biological processes, such as cell cycle, proliferation or lipogenesis. We previously proposed that global-expressed SND1 in vivo is likely to be a key regulator for ameliorating HFD-induced hepatic steatosis and systemic insulin resistance. Herein, we are very interested in investigating further whether the hepatocyte-specific deletion of SND1 affects the insulin resistance or acute liver failure (ALF) of mice.Methods: By using Cre-loxP technique, we constructed conditional knockout (LKO) mice of SND1 driven by albumin in hepatocytes and analyze the changes of glucose homeostasis, cholesterol level, hepatic steatosis and hepatic failure under the treatment of high-fat diet (HFD) or upon the simulation of Lipopolysaccharide/galactosamine (LPS/GalN).Results: No difference for the body weight, liver weight, and cholesterol level was detected. Furthermore, we did not observe the alteration of glucose homeostasis in SND1 hepatic knockout mice on either chow diet or high-fat diet. Besides, hepatocyte-specific deletion of SND1 failed to influence the hepatic failure of mice induced by LPS/GalN.Conclusions: These findings suggest that hepatic SND1, independently, is insufficient for changing glucose homeostasis, hepatic lipid accumulation and inflammation. The synergistic action of multiple organs may contribute to the role of SND1 in insulin sensitivity or inflammatory response.

scholarly journals WDR76 mediates obesity and hepatic steatosis via HRas destabilization

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jong-Chan Park ◽  
Woo-Jeong Jeong ◽  
Seol Hwa Seo ◽  
Kang-Yell Choi
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Regulation ◽  
Adipocyte Differentiation ◽  
High Fat ◽  
Active Protein ◽  
Wd40 Repeat ◽  
Ras Protein ◽  
Protein Kinase Signaling

AbstractRas/MAPK (mitogen active protein kinase) signaling plays contradictory roles in adipocyte differentiation and is tightly regulated during adipogenesis. However, mechanisms regulating adipocyte differentiation involving Ras protein stability regulation are unknown. Here, we show that WD40 repeat protein 76 (WDR76), a novel Ras regulating E3 linker protein, controls 3T3-L1 adipocyte differentiation through HRas stability regulation. The roles of WDR76 in obesity and metabolic regulation were characterized using a high-fat diet (HFD)-induced obesity model using Wdr76−/− mice and liver-specific Wdr76 transgenic mice (Wdr76Li−TG). Wdr76−/− mice are resistant to HFD-induced obesity, insulin resistance and hyperlipidemia with an increment of HRas levels. In contrast, Wdr76Li-TG mice showed increased HFD-induced obesity, insulin resistance with reduced HRas levels. Our findings suggest that WDR76 controls HFD-induced obesity and hepatic steatosis via HRas destabilization. These data provide insights into the links between WDR76, HRas, and obesity.

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