scholarly journals Empagliflozin ameliorates obesity-related cardiac dysfunction by regulating Sestrin2-mediated AMPK-mTOR signaling and redox homeostasis in high-fat induced obese mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Xiaodong Sun ◽  
Fang Han ◽  
Qingguo Lu ◽  
Xuan Li ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Redox Homeostasis ◽  
Mtor Signaling ◽  
Whole Body ◽  
Diabetic Patients ◽  
High Fat ◽  
Beneficial Effects ◽  
Reduced Body ◽  
Inducible Protein

Sodium glucose co-transporter-2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in diabetic patients. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mTOR and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction <i>via</i> regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and <i>Sestrin2</i> knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight, whole-body fat, and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function, and reduced cardiac fat accumulation and mitochondria injury. Additionally, EMPA significantly augmented Sestrin2 levels, increased AMPK and eNOS phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed <i>Sestrin2</i> knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction <i>via</i> regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.

scholarly journals Empagliflozin ameliorates obesity-related cardiac dysfunction by regulating Sestrin2-mediated AMPK-mTOR signaling and redox homeostasis in high-fat induced obese mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Xiaodong Sun ◽  
Fang Han ◽  
Qingguo Lu ◽  
Xuan Li ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
Redox Homeostasis ◽  
Mtor Signaling ◽  
Whole Body ◽  
Diabetic Patients ◽  
High Fat ◽  
Beneficial Effects ◽  
Reduced Body ◽  
Inducible Protein

Sodium glucose co-transporter-2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in diabetic patients. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK-mTOR and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction <i>via</i> regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and <i>Sestrin2</i> knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight, whole-body fat, and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function, and reduced cardiac fat accumulation and mitochondria injury. Additionally, EMPA significantly augmented Sestrin2 levels, increased AMPK and eNOS phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed <i>Sestrin2</i> knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1-mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction <i>via</i> regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.

scholarly journals Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance

2012 ◽  
Vol 302 (5) ◽  
pp. E532-E539 ◽  
Author(s):  
Haihong Zong ◽  
Michal Armoni ◽  
Chava Harel ◽  
Eddy Karnieli ◽  
Jeffrey E. Pessin
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Whole Body ◽  
High Fat ◽  
Normal Chow ◽  
Glucose Output ◽  
Fat Diets

Conventional (whole body) CYP2E1 knockout mice displayed protection against high-fat diet-induced weight gain, obesity, and hyperlipidemia with increased energy expenditure despite normal food intake and spontaneous locomotor activity. In addition, the CYP2E1 knockout mice displayed a marked improvement in glucose tolerance on both normal chow and high-fat diets. Euglycemic-hyperinsulinemic clamps demonstrated a marked protection against high-fat diet-induced insulin resistance in CYP2E1 knockout mice, with enhanced adipose tissue glucose uptake and insulin suppression of hepatic glucose output. In parallel, adipose tissue was protected against high-fat diet-induced proinflammatory cytokine production. Taken together, these data demonstrate that the CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo.

scholarly journals Lactiplantibacillusplantarum ATG-K2 Exerts an Anti-Obesity Effect in High-Fat Diet-Induced Obese Mice by Modulating the Gut Microbiome

2021 ◽  
Vol 22 (23) ◽  
pp. 12665
Author(s):  
Young-Sil Lee ◽  
Eun-Jung Park ◽  
Gun-Seok Park ◽  
Seung-Hyun Ko ◽  
Juyi Park ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Obese Mice ◽  
High Fat ◽  
Major Health Problem ◽  
Beneficial Effects ◽  
Reduced Body ◽  
Tnf Α

Obesity is a major health problem. Compelling evidence supports the beneficial effects of probiotics on obesity. However, the anti-obesity effect of probiotics remains unknown. In this study, we investigated the anti-obesity effects and potential mechanisms of Lactiplantibacillus plantarum ATG-K2 using 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. 3T3-L1 cells were incubated to determine the effect of lipid accumulation with lysate of L. plantarum ATG-K2. Mice were fed a normal fat diet or HFD with L. plantarum ATG-K2 and Orlistat for 8 weeks. L. plantarum ATG-K2 inhibited lipid accumulation in 3T3-L1 adipocytes, and reduced body weight gain, WAT weight, and adipocyte size in HFD-induced obese mice, concurrently with the downregulation of PPARγ, SREBP1c, and FAS and upregulation of PPARα, CTP1, UCP1, Prdm16, and ND5. Moreover, L. plantarum ATG-K2 decreased TG, T-CHO, leptin, and TNF-α levels in the serum, with corresponding gene expression levels in the intestine. L. plantarum ATG-K2 modulated the gut microbiome by increasing the abundance of the Lactobacillaceae family, which increased SCFA levels and branched SCFAs in the feces. L. plantarum ATG-K2 exhibited an anti-obesity effect and anti-hyperlipidemic effect in 3T3-L1 adipocytes and HFD-induced obese mice by alleviating the inflammatory response and regulating lipid metabolism, which may be influenced by modulation of the gut microbiome and its metabolites. Therefore, L. plantarum ATG-K2 can be a preventive and therapeutic agent for obesity.

scholarly journals Angiotensin Receptor Blocker and Neprilysin Inhibitor Suppresses Cardiac Dysfunction by Accelerating Myocardial Angiogenesis in Apolipoprotein E-Knockout Mice Fed a High-Fat Diet

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yasunori Suematsu ◽  
Kohei Tashiro ◽  
Hidetaka Morita ◽  
Akihito Ideishi ◽  
Takashi Kuwano ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Natriuretic Peptide ◽  
Knockout Mice ◽  
Cardiac Dysfunction ◽  
High Fat Diet ◽  
Angiotensin Receptor Blocker ◽  
Left Ventricular ◽  
Angiotensin Receptor ◽  
High Fat ◽  
Apolipoprotein E Knockout Mice

Hypothesis. Myocardial angiogenesis is important for maintaining cardiac contractile function in patients with cardiac hypertrophy. Evidence shows that angiotensin receptor blocker and neprilysin inhibitors (ARNIs) improve heart failure. The present study investigated the myocardial angiogenic effect of valsartan plus sacubitril in early-stage cardiac dysfunction. Materials and Methods. Male apolipoprotein E-knockout mice fed a high-fat diet were divided into control (CTL), valsartan (30 mg/kg) (VAL), sacubitril (30 mg/kg) (SAC), and valsartan plus sacubitril (30 mg/kg each) (VAL/SAC) groups after 4 weeks of prefeeding and were subsequently treated for 12 weeks. Results. The VAL/SAC group exhibited significantly higher serum brain natriuretic peptide levels; more subtle changes in left ventricular systolic diameter, fractional shortening, and ejection fraction, and significantly higher expression levels of natriuretic peptide precursor B and markers of angiogenesis, including clusters of differentiation 34, vascular endothelial growth factor A, and monocyte chemotactic protein 1, than the CTL group. Conclusions. Valsartan plus sacubitril preserved left ventricular systolic function in apolipoprotein E-knockout mice fed a high-fat diet. This result suggests that myocardial angiogenic factors induced by ARNI might provide cardioprotective effects.

scholarly journals Glycemic index differences of high-fat diets modulate primarily lipid metabolism in murine adipose tissue

2011 ◽  
Vol 43 (15) ◽  
pp. 942-949 ◽  
Author(s):  
Evert M. van Schothorst ◽  
Annelies Bunschoten ◽  
Eline Verlinde ◽  
Patrick Schrauwen ◽  
Jaap Keijer
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glycemic Index ◽  
Molecular Mechanisms ◽  
Serum Levels ◽  
Whole Body ◽  
High Fat ◽  
Beneficial Effects ◽  
Ppar Γ

A low vs. high glycemic index of a high-fat (HF) diet (LGI and HGI, respectively) significantly retarded adverse health effects in adult male C57BL/6J mice, as shown recently (Van Schothorst EM, Bunschoten A, Schrauwen P, Mensink RP, Keijer J. FASEB J 23: 1092–1101, 2009). The LGI diet enhanced whole body insulin sensitivity and repressed HF diet-induced body and white adipose tissue (WAT) weight gain, resulting in significantly reduced serum leptin and resistin levels and increased adiponectin levels. We questioned how WAT is modulated and characterized the molecular mechanisms underlying the glycemic index-mediated effects using whole genome microarrays. This showed that the LGI diet mainly exerts its beneficial effects via substrate metabolism, especially fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression, in line with lower WAT mass. An important transcription factor showing enhanced expression is PPAR-γ. Furthermore, serum levels of triglycerides, total cholesterol, and HDL- and LDL-cholesterol were all significantly reduced by LGI diet, and simultaneously muscle insulin sensitivity was significantly increased as analyzed by protein kinase B/Akt phosphorylation. Cumulatively, even though these mice were fed an HF diet, the LGI diet induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones to treat insulin resistance and statins for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans.

scholarly journals MGAT2 deficiency and vertical sleeve gastrectomy have independent metabolic effects in the mouse

2014 ◽  
Vol 307 (11) ◽  
pp. E1065-E1072 ◽  
Author(s):  
Joram D. Mul ◽  
Denovan P. Begg ◽  
April M. Haller ◽  
Josh W. Pressler ◽  
Joyce Sorrell ◽  
...  
Keyword(s):  
Body Weight ◽  
Sleeve Gastrectomy ◽  
Glucose Metabolism ◽  
Energy Expenditure ◽  
Lipid Synthesis ◽  
Metabolic Effects ◽  
Whole Body ◽  
Vertical Sleeve Gastrectomy ◽  
Beneficial Effects ◽  
Reduced Body

Vertical sleeve gastrectomy (VSG) is currently one of the most effective treatments for obesity. Despite recent developments, the underlying mechanisms that contribute to the metabolic improvements following bariatric surgery remain unresolved. VSG reduces postprandial intestinal triglyceride (TG) production, but whether the effects of VSG on intestinal metabolism are related to metabolic outcomes has yet to be established. The lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 ( Mogat2; MGAT2) plays a crucial role in the assimilation of dietary fat in the intestine and in regulation of adiposity stores as well. Given the phenotypic similarities between VSG-operated and MGAT2-deficient animals, we reasoned that this enzyme could also have a key role in mediating the metabolic benefits of VSG. However, VSG reduced body weight and fat mass and improved glucose metabolism similarly in whole body MGAT2-deficient ( Mogat2−/−) mice and wild-type littermates. Furthermore, along with an increase in energy expenditure, surgically naive Mogat2−/− mice had altered macronutrient preference, shifting preference away from fat and toward carbohydrates, and increased locomotor activity. Collectively, these data suggest that the beneficial effects of VSG on body weight and glucose metabolism are independent of MGAT2 activity and rather that they are separate from the effects of MGAT2 deficiency. Because MGAT2 inhibitors are proposed as a pharmacotherapeutic option for obesity, our data suggest that, in addition to increasing energy expenditure, shifting macronutrient preference away from fat could be another important mechanism by which these compounds could contribute to weight loss.

Hypertriglyceridemia in experimental diabetes: relationship to cardiac dysfunction

1994 ◽  
Vol 72 (5) ◽  
pp. 447-455 ◽  
Author(s):  
Brian Rodrigues ◽  
Paul F. Grassby ◽  
Mary L. Battell ◽  
Stephanie Y. N. Lee ◽  
John H. McNeill
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Plasma Triglyceride ◽  
Diabetic Rat ◽  
Diabetic Patients ◽  
Beneficial Effects ◽  
Rate Of Increase

The incidence of mortality from cardiovascular disease is higher in diabetic patients. The objective of the present investigation was to test die hypothesis that the diabetes-induced depression in cardiac function may be due to hypertriglyceridemia. Hyperlipidemia and a depressed left ventricular developed pressure and rate of increase and decrease of ventricular pressure (±dP/dt) were produced in isolated hearts from rats made diabetic with streptozotocin compared with hearts from control animals. This depressed cardiac performance was successfully prevented by hydralazine treatment (for 3 weeks), which also lowered plasma triglyceride levels and suggested that hyperlipidemia may be important in altering cardiac function in experimental diabetic rats. The beneficial effects of clofibrate, verapamil, prazosin, enalapril, and benazepril administration were then studied in diabetic rats. The treatments (with die exception of enalapril) significantly reduced plasma triglyceride levels but did not prevent die onset of heart dysfunction in chronically diabetic rats. These studies suggest that in the chronically diabetic rat, hypertriglyceridemia may not be as important as previously suggested, in the development of cardiac dysfunction. Since acute dichloroacetate perfusion improves cardiac function in 6 week (but not 24 week) diabetic rats, it appears more likely that improving myocardial glycose utilization is more critical than triglyceride lowering, in preventing cardiac dysfunction in die diabetic rat at this time point.Key words: diabetes, triglycerides, heart function, glucose oxidation.

scholarly journals SAT-299 Chronic Treatment Of Juvenile Hypothalamic Pomc-deficient Mice With RM-493 Prevents The Development Of Obesity

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Zoe Thompson ◽  
Bhavik P Shah ◽  
Malcolm J Low
Keyword(s):  
Energy Expenditure ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Preclinical Study ◽  
Vehicle Group ◽  
High Fat ◽  
Ambulatory Activity ◽  
Entire Study ◽  
Beneficial Effects ◽  
Obesity Syndrome

Abstract Arc-Pomc knockout mice have a disruption of the two neural enhancers for the Pomc (proopiomelanocortin) gene, resulting in selective loss of Pomc gene expression in the arcuate nucleus of the hypothalamus. This gene targeting strategy leaves pituitary Pomc expression unaffected. These mice are hyperphagic starting at weaning, and develop progressive obesity, infertility and insulin resistance over their lifetime. RM-493 (setmelanotide) is a melanocortin-4 receptor agonist that has shown promise in treating humans with Pomc null mutations. In this preclinical study, we investigated the effects of chronic RM-493 treatment using subcutaneously implanted osmotic minipumps in two groups of male mice: Arc-Pomc knockout mice, fed regular chow throughout the study period, and their wildtype counterparts, fed a 45% high-fat diet. Each of these groups of mice was randomized into three treatment cohorts at weaning: one that was given RM-493 throughout the entire study period (4–24 weeks of age, “RM-493” group), one that was given RM-493 only for the first 4 weeks of the study (4–8 weeks of age, “switch” group) and then switched to vehicle, and one cohort that received vehicle for the entire study (“vehicle” group). We serially measured body weight, food intake, body composition, glucose tolerance, insulin tolerance, and several measures of metabolism using the Comprehensive Lab Animal Monitoring System, including oxygen consumption, energy expenditure, ambulatory activity and lipid and glucose oxidation. Among other results, at the end of the study (24 weeks of age), Arc-Pomc knockout mice in the RM-493 group weighed significantly less than either the switch or vehicle groups (p&lt;0.05). Arc-Pomc knockout mice on RM-493 also had higher energy expenditure when compared to the switch and vehicle groups (p&lt;0.05). In addition, RM-493 improved the glucose-insulin index for Arc-Pomc knockout mice (p&lt;0.05). According to our preliminary results, wildtype mice on high-fat diet, treated chronically with RM-493, did not differ in any of these measurements from their switch and vehicle groups. We conclude that the obesity syndrome caused by a loss of hypothalamic Pomc expression was completely blocked by RM-493 treatment started before the onset of obesity, with no apparent desensitization to the drug’s action over 20 weeks. However, the beneficial effects of a single month’s treatment were steadily reversed within one month after switching to vehicle treatment. In contrast to the dramatic effects of RM-493 in the genetic obesity syndrome, at this time, there does not appear to be any phenotypic changes in wild-type mice with RM-493 administration on the development of obesity or secondary metabolic disruptions in response to high-fat diet consumption.

scholarly journals Vertical sleeve gastrectomy confers metabolic improvements by reducing intestinal bile acids and lipid absorption in mice

2021 ◽  
Vol 118 (6) ◽  
pp. e2019388118
Author(s):  
Lili Ding ◽  
Eryun Zhang ◽  
Qiaoling Yang ◽  
Lihua Jin ◽  
Kyle M. Sousa ◽  
...  
Keyword(s):  
Sleeve Gastrectomy ◽  
Bile Acids ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Lipid Absorption ◽  
Metabolic Effects ◽  
Fat Absorption ◽  
Vertical Sleeve Gastrectomy ◽  
High Fat ◽  
Beneficial Effects

Vertical sleeve gastrectomy (VSG) is one of the most effective and durable therapies for morbid obesity and its related complications. Although bile acids (BAs) have been implicated as downstream mediators of VSG, the specific mechanisms through which BA changes contribute to the metabolic effects of VSG remain poorly understood. Here, we confirm that high fat diet-fed global farnesoid X receptor (Fxr) knockout mice are resistant to the beneficial metabolic effects of VSG. However, the beneficial effects of VSG were retained in high fat diet-fed intestine- or liver-specific Fxr knockouts, and VSG did not result in Fxr activation in the liver or intestine of control mice. Instead, VSG decreased expression of positive hepatic Fxr target genes, including the bile salt export pump (Bsep) that delivers BAs to the biliary pathway. This reduced small intestine BA levels in mice, leading to lower intestinal fat absorption. These findings were verified in sterol 27-hydroxylase (Cyp27a1) knockout mice, which exhibited low intestinal BAs and fat absorption and did not show metabolic improvements following VSG. In addition, restoring small intestinal BA levels by dietary supplementation with taurocholic acid (TCA) partially blocked the beneficial effects of VSG. Altogether, these findings suggest that reductions in intestinal BAs and lipid absorption contribute to the metabolic benefits of VSG.

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