Abstract 18792: Beclin-1 Haploinsufficiency Protects Against Obesity-induced Cardiac Dysfunction Through Compensatory Mitophagy and Alternative Autophagy

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Xiangwei Liu ◽  
Xihui Xu ◽  
Yingmei Zhang ◽  
Jun Ren
Keyword(s):  
Beneficial Effect ◽  
High Fat Diet ◽  
Heart Function ◽  
Body Weight Gain ◽  
Beclin 1 ◽  
Pronounced Effect ◽  
Low Fat Diet ◽  
Cardiac Contractile ◽  
Coupling Protein ◽  
The Impact

Background: Though autophagy including the selective mitophagy is essential for cellular homeostasis, its role in obese heart function remains controversial. Beclin-1 plays a cardinal role in conventional autophagy and has recently been implicated in alternative autophagy and mitophagy. This study was designed to examine the impact of Beclin-1 haploinsufficiency using heterozygous deletion of Beclin-1 (BCN-KO) on high fat diet (HFD)-induced cardiac anomalies. Methods and Results: Adult wild type (WT) and BCN-KO mice were fed low fat diet (LFD) or HFD for 12 weeks. HFD triggered comparable body weight gain in WT and BCN-KO mice. However, BCN-KO improved HFD-induced glucose intolerance and countered against HFD-induced cardiomyocyte contractile dysfunction manifested as decreased peak shortening, +dL/dt, -dL/dt and prolonged TR 90 . Levels of Beclin-1 were downregulated following HFD feeding although such effect was masked by BCN haploinsufficiency. Levels of autophagy markers LC3B-II/I and Atg5 were downregulated in a comparable manner in both HFD groups. Interestingly, Rab9, an essential regulator for alternative autophagy, was upregulated in HFD groups with a more pronounced effect in BCN-KO mice. Level of p62 was increased by HFD in WT but not BCN-KO group. Furthermore, the mitochondrial coupling protein for LC3B Bnip3 (also a key molecule for alternative autophagy-induced mitophagy) was upregulated in HFD groups with a more pronounced effect in BCN-KO mice. Moreover, Pink1 and AMPK phosphorylation, two key regulators in mitophagy were decreased by HFD in WT but not BCN-KO group. In line with these results, PGC-1 a (a marker of mitochondrial biogenesis) was downregulated by HFD, the effect of which was rescued by BCN-KO. Conclusion: Taken together, our data revealed that HFD led to cardiac contractile defect accompanied with dampened conventional autophagy and facilitated alternative autophagy. Our data suggested that adaptive mitophagy may play a pivotal role in BCN haploinsufficiency-induced beneficial effect. Such as beneficial effect was achieved through promoting HFD-induced alternative autophagy, which may contribute to increased mitophagy under HFD intake possibly via AMPK, Rab9 and Bnip3-mediated signaling pathways.

scholarly journals Sex modulates hepatic mitochondrial adaptations to high-fat diet and physical activity

2019 ◽  
Vol 317 (2) ◽  
pp. E298-E311 ◽  
Author(s):  
Colin S. McCoin ◽  
Alex Von Schulze ◽  
Julie Allen ◽  
Kelly N. Z. Fuller ◽  
Qing Xia ◽  
...  
Keyword(s):  
Physical Activity ◽  
High Fat Diet ◽  
Wheel Running ◽  
Transcriptional Coactivator ◽  
High Fat ◽  
Respiratory Capacity ◽  
Interacting Protein ◽  
Low Fat Diet ◽  
The Impact ◽  
Mitochondrial Adaptations

The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific peroxisome proliferative activated-receptor-γ coactivator-1α (PGC-1α), a transcriptional coactivator of biogenesis, and BCL-2/ADENOVIRUS EIB 19-kDa interacting protein (BNIP3), a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild-type (WT), liver-specific PGC-1α heterozygote (LPGC-1α), and BNIP3 null mice were thermoneutral housed (29–31°C) and divided into three groups: sedentary-low-fat diet (LFD), 16 wk of (HFD), or 16 wk of HFD with VWR for the final 8 wk (HFD + VWR) ( n = 5–7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group; however, HFD + VWR significantly increased maximal respiratory capacity only in WT and PGC-1α females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling control and reduced H2O2production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1α and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD + VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1α or BNIP3.

scholarly journals It’s the fiber, not the fat: Significant effects of dietary challenge on the gut microbiome

2019 ◽  
Author(s):  
Kathleen E. Morrison ◽  
Eldin Jašarević ◽  
Christopher D. Howard ◽  
Tracy L. Bale
Keyword(s):  
Body Weight ◽  
Gut Microbiota ◽  
Dietary Fat ◽  
Gut Microbiome ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Chow Diet ◽  
Soluble Fiber ◽  
High Fat ◽  
The Impact

AbstractBackgroundDietary effects on the gut microbiome has been shown to play a key role in the pathophysiology of behavioral dysregulation, inflammatory disorders, metabolic syndrome, and obesity. Often overlooked is that experimental diets vary significantly in the proportion and source of dietary fiber. Commonly, treatment comparisons are made between animals that are fed refined diets that lack soluble fiber and animals fed vivarium-provided chow diet that contain a rich source of soluble fiber. Despite the well-established role of soluble fiber on metabolism, immunity, and behavior via the gut microbiome, the extent to which measured outcomes may be driven by differences in dietary fiber is unclear. Further, the significant impact of sex and age in response to dietary challenge is likely important and should also be considered.ResultsWe compared the impact of transitioning young and aged male and female mice from a chow diet to a refined low soluble fiber diet on body weight and gut microbiota. Then, to determine the contribution of dietary fat, we examined the impact of transitioning a subset of animals from refined low fat to refined high fat diet. Serial tracking of body weights revealed that consumption of low fat or high fat refined diet increased body weight in young and aged adult male mice. Young adult females showed resistance to body weight gain, while high fat diet-fed aged females had significant body weight gain. Transition from a chow diet to low soluble fiber refined diet accounted for most of the variance in community structure and composition across all groups. This dietary transition was characterized by a loss of taxa within the phylum Bacteroidetes and a concurrent bloom of Clostridia and Proteobacteria in a sex- and age-specific manner. Most notably, no changes to gut microbiota community structure and composition were observed between mice consuming either low- or high-fat diet, suggesting that transition to the refined diet that lacks soluble fiber is the primary driver of gut microbiota alterations, with limited additional impact of dietary fat on gut microbiota.ConclusionCollectively, our results show that the choice of control diet has a significant impact on outcomes and interpretation related to body weight and gut microbiota. These data also have broad implications for rodent studies that draw comparisons between refined high fat diets and chow diets to examine dietary fat effects on metabolic, immune, behavioral, and neurobiological outcomes.

scholarly journals Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

2013 ◽  
Vol 219 (2) ◽  
pp. 131-143 ◽  
Author(s):  
Zhiguo Liu ◽  
Chun Yan Lim ◽  
Michelle Yu-Fah Su ◽  
Stephanie Li Ying Soh ◽  
Guanghou Shui ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Milk Composition ◽  
High Fat ◽  
Low Fat Diet ◽  
Metabolic Defects ◽  
The Difference ◽  
Stomach Weight

Neonatal overnutrition results in accelerated development of high-fat diet (HFD)-induced metabolic defects in adulthood. To understand whether the increased susceptibility was associated with aggravated inflammation and dysregulated lipid metabolism, we studied metabolic changes and insulin signaling in a chronic postnatal overnutrition (CPO) mouse model. Male Swiss Webster pups were raised with either three pups per litter to induce CPO or ten pups per litter as control (CTR) and weaned to either low-fat diet (LFD) or HFD. All animals were killed on the postnatal day 150 (P150) except for a subset of mice killed on P15 for the measurement of stomach weight and milk composition. CPO mice exhibited accelerated body weight gain and increased body fat mass prior to weaning and the difference persisted into adulthood under conditions of both LFD and HFD. As adults, insulin signaling was more severely impaired in epididymal white adipose tissue (WAT) from HFD-fed CPO (CPO–HFD) mice. In addition, HFD-induced upregulation of pro-inflammatory cytokines was exaggerated in CPO–HFD mice. Consistent with greater inflammation, CPO–HFD mice showed more severe macrophage infiltration than HFD-fed CTR (CTR–HFD) mice. Furthermore, when compared with CTR–HFD mice, CPO–HFD mice exhibited reduced levels of several lipogenic enzymes in WAT and excess intramyocellular lipid accumulation. These data indicate that neonatal overnutrition accelerates the development of insulin resistance and exacerbates HFD-induced metabolic defects, possibly by worsening HFD-induced inflammatory response and impaired lipid metabolism.

scholarly journals Effect of diet and intestinal AhR expression on fecal microbiome and metabolomic profiles

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Fang Yang ◽  
Jennifer A. A. DeLuca ◽  
Rani Menon ◽  
Erika Garcia-Vilarato ◽  
Evelyn Callaway ◽  
...  
Keyword(s):  
Metabolite Profile ◽  
Fecal Microbiota ◽  
Pronounced Effect ◽  
Intestinal Epithelial ◽  
Microbiota Composition ◽  
Fecal Microbiome ◽  
Aryl Hydrocarbon ◽  
Low Fat Diet ◽  
Tryptophan Metabolites ◽  
The Impact

Abstract Background Diet, loss of aryl hydrocarbon receptor (AhR) expression and their modification of the gut microbiota community composition and its metabolites affect the development of colorectal cancer (CRC). However, the concordance between fecal microbiota composition and the fecal metabolome is poorly understood. Mice with specific AhR deletion (AhRKO) in intestinal epithelial cell and their wild-type littermates were fed a low-fat diet or a high-fat diet. Shifts in the fecal microbiome and metabolome associated with diet and loss of AhR expression were assessed. Microbiome and metabolome data were integrated to identify specific microbial taxa that contributed to the observed metabolite shifts. Results Our analysis shows that diet has a more pronounced effect on mouse fecal microbiota composition than the impact of the loss of AhR. In contrast, metabolomic analysis showed that the loss of AhR in intestinal epithelial cells had a more pronounced effect on metabolite profile compared to diet. Integration analysis of microbiome and metabolome identified unclassified Clostridiales, unclassified Desulfovibrionaceae, and Akkermansia as key contributors to the synthesis and/or utilization of tryptophan metabolites. Conclusions Akkermansia are likely to contribute to the synthesis and/or degradation of tryptophan metabolites. Our study highlights the use of multi-omic analysis to investigate the relationship between the microbiome and metabolome and identifies possible taxa that can be targeted to manipulate the microbiome for CRC treatment.

scholarly journals Blackberry and Blueberry Anthocyanin Supplementation Counteract High-Fat-Diet-Induced Obesity by Alleviating Oxidative Stress and Inflammation and Accelerating Energy Expenditure

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Tao Wu ◽  
Yufang Gao ◽  
Xueqi Guo ◽  
Min Zhang ◽  
Lingxiao Gong
Keyword(s):  
Oxidative Stress ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Glutathione Metabolism ◽  
High Fat ◽  
Hepatic Lipid ◽  
Beneficial Effects ◽  
Low Fat Diet ◽  
Diet Induced Obesity

Many studies indicate that an anthocyanin-rich diet has beneficial effects preventing metabolic disease. In the present study, the molecular mechanism underlying the antiobesity effect of consuming blackberry anthocyanins (BLA) and blueberry anthocyanins (BBA) was investigated in high-fat-diet- (HFD-) fed C57BL/6 mice. Sixty mice were administered a low-fat diet (LFD), a HFD, or a HFD plus orlistat, and BLA or BBA in their daily food for 12 weeks. As a result, the consumption of BLA and BBA inhibited body weight gain by 40.5% and 55.4%, respectively, in HFD-fed mice. The BLA and BBA treatments markedly reduced serum and hepatic lipid levels and significantly increased hepatic superoxide dismutase and glutathione peroxidase activities. In addition, the treatments effectively increased fecal acetate and butyrate levels and significantly attenuated expression of tumor necrosis factor TNF-α, interleukin-6, and nuclear factor-kappaB genes. Moreover, gas chromatography time-of-flight mass spectroscopy results suggested that BLA and BBA significantly affected the hepatic lipid and glucose metabolic pathways, including glycerophospholipid metabolism, glutathione metabolism, and the insulin-signaling pathway. Therefore, BLA and BBA ameliorated diet-induced obesity by alleviating oxidative stress and inflammation and accelerating energy expenditure.

scholarly journals Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis

2021 ◽  
Vol 22 (2) ◽  
pp. 818
Author(s):  
Narjes Nasiri-Ansari ◽  
Chrysa Nikolopoulou ◽  
Katerina Papoutsi ◽  
Ioannis Kyrou ◽  
Christos S. Mantzoros ◽  
...  
Keyword(s):  
Er Stress ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Beclin 1 ◽  
Control Group ◽  
Caspase 8 ◽  
Mrna Levels ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
The Impact

Aims/hypothesis: SGLT-2 inhibitors (SGLT-2i) have been studied as potential treatments against NAFLD, showing varying beneficial effects. The molecular mechanisms mediating these effects have not been fully clarified. Herein, we investigated the impact of empagliflozin on NAFLD, focusing particularly on ER stress, autophagy and apoptosis. Methods: Five-week old ApoE(-/-) mice were switched from normal to a high-fat diet (HFD). After five weeks, mice were randomly allocated into a control group (HFD + vehicle) and Empa group (HFD + empagliflozin 10 mg/kg/day) for five weeks. At the end of treatment, histomorphometric analysis was performed in liver, mRNA levels of Fasn, Screbp-1, Scd-1, Ppar-γ, Pck-1, Mcp-1, Tnf-α, Il-6, F4/80, Atf4, Elf2α, Chop, Grp78, Grp94, Χbp1, Ire1α, Atf6, mTor, Lc3b, Beclin-1, P62, Bcl-2 and Bax were measured by qRT-PCR, and protein levels of p-EIF2α, EIF2a, CHOP, LC3II, P62, BECLIN-1 and cleaved CASPASE-8 were assessed by immunoblotting. Results: Empagliflozin-treated mice exhibited reduced fasting glucose, total cholesterol and triglyceride serum levels, as well as decreased NAFLD activity score, decreased expression of lipogenic enzymes (Fasn, Screbp-1c and Pck-1) and inflammatory molecules (Mcp-1 and F4/80), compared to the Control group. Empagliflozin significantly decreased the expression of ER stress molecules Grp78, Ire1α, Xbp1, Elf2α, Atf4, Atf6, Chop, P62(Sqstm1) and Grp94; whilst activating autophagy via increased AMPK phosphorylation, decreased mTOR and increased LC3B expression. Finally, empagliflozin increased the Bcl2/Bax ratio and inhibited CASPASE-8 cleavage, reducing liver cell apoptosis. Immunoblotting analysis confirmed the qPCR results. Conclusion: These novel findings indicate that empagliflozin treatment for five weeks attenuates NAFLD progression in ApoE(-/-) mice by promoting autophagy, reducing ER stress and inhibiting hepatic apoptosis.

Abstract 15583: Toll-Like Receptor 4 Knockout Preserves Cardiac Function in High Fat Diet-Induced Obesity

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nan Hu ◽  
Yingmei Zhang ◽  
Jun Ren
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Ros Generation ◽  
Myocardial Inflammation ◽  
Toll Like Receptor ◽  
High Fat ◽  
Toll Like Receptor 4 ◽  
Major Pathway ◽  
The Impact

Background: Toll-like receptor 4 (TLR4) is an innate proinflammatory mediator found in a wide variety of cell types including cardiomyocytes. The autophagy-lysosome pathway, a major pathway governing protein and organelle degradation and recycling, plays a pivotal role in maintaining cardiac homeostasis under physiological and pathological conditions. The aim of this study was to evaluate the impact of TLR4 knockout (TLR4 -/- ) on high fat diet (HFD)-induced cardiomyopathy and the underlying mechanisms involved, with a focus on inflammation and autophagy pathways. Methods: Wild type (WT) and TLR4 -/- mice were fed on low fat diet (LFD) or HFD for 12 weeks. Metabolic rate and glucose tolerance were measured in WT and TLR4 -/- mice at the end of fat diet intake. Echocardiographic, cardiomyocyte mechanical function, morphological feature, aconitase activity, ROS generation and immunoblotting were assessed. Results: TLR4 -/- did not prevent HFD-induced obesity and insulin resistance, as evidenced by body weight gain and glucose intolerance. In addition, there was little difference in metabolic parameters (V O2 , V CO2 , RER, energy expenditure and physical activity) between WT and TLR4 -/- mice fed with HFD. However, TLR4 -/- alleviated HFD-elicited cardiac hypertrophy and contractile dysfunction. HFD-feeding caused extensive mitochondrial injury and ROS generation, which were alleviated by TLR4 -/- . TLR4 -/- dramatically attenuated inflammation signaling (up-regulated p-IKβ, NF-κB and p-JNK) in the face of HFD intake. Cardiac autophagy was significantly suppressed by HFD, as evidenced by up-regulated p-mTOR, down-regulated p-AMPK, Atg5, Atg12, LC3BII, and up-regulated P62 in HFD-induced cardiomyopathy. Furthermore, in vitro study revealed that the TLR4 inhibitor-TAK-242 reconciled palmitic acid-induced cardiomyocyte autophagy and contractile anomalies. Conclusions: Our results suggested that TLR4 -/- does not prevent HFD-induced obesity and insulin resistance. However, TLR4 is a culprit factor for cardiac dysfunction following HFD intake. The cardioprotective effect of TLR4 -/- against HFD-induced cardiomyopathy is associated with attenuation of myocardial inflammation and recovery of cardiac autophagy activity.

scholarly journals Differential effects of high fat diet-induced obesity on oocyte mitochondrial functions in inbred and outbred mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Waleed F. A. Marei ◽  
Anouk Smits ◽  
Omnia Mohey-Elsaeed ◽  
Isabel Pintelon ◽  
Daisy Ginneberge ◽  
...  
Keyword(s):  
Mouse Models ◽  
High Fat Diet ◽  
Genetic Background ◽  
Maternal Obesity ◽  
Body Weight Gain ◽  
Inbred Mouse ◽  
Oocyte Quality ◽  
High Fat ◽  
Mitochondrial Functions ◽  
The Impact

Abstract Maternal obesity can cause reduced oocyte quality and subfertility. Mitochondrial dysfunction plays a central role here, and most often inbred mouse models are used to study these pathways. We hypothesized that the mouse genetic background can influence the impact of high fat diet (HFD)-induced obesity on oocyte quality. We compared the inbred C57BL/6 (B6) and the outbred Swiss strains after feeding a HFD for 13w. HFD-mice had increased body weight gain, hypercholesterolemia, and increased oocyte lipid droplet (LD) accumulation in both strains. LD distribution was strain-dependent. In Swiss mouse oocytes, HFD significantly increased mitochondrial inner membrane potential (MMP), reactive oxygen species concentrations, mitochondrial ultrastructural abnormalities (by 46.4%), and endoplasmic reticulum (ER) swelling, and decreased mtDNA copy numbers compared with Swiss controls (P < 0.05). Surprisingly, B6-control oocytes exhibited signs of cellular stress compared to the Swiss controls (P < 0.05); upregulated gene expression of ER- and oxidative stress markers, high mitochondrial ultrastructural abnormalities (48.6%) and ER swelling. Consequently, the HFD impact on B6 oocyte quality was less obvious, with 9% higher mitochondrial abnormalities, and no additive effect on MMP and stress marks compared to B6 control (P > 0.1). Interestingly, mtDNA in B6-HFD oocytes was increased suggesting defective mitophagy. In conclusion, we show evidence that the genetic background or inbreeding can affect mitochondrial functions in oocytes and may influence the impact of HFD on oocyte quality. These results should create awareness when choosing and interpreting data obtained from different mouse models before extrapolating to human applications.

Non-Fasting Factor VII Coagulant Activity (FVII:C) Increased by High-Fat Diet

1994 ◽  
Vol 71 (06) ◽  
pp. 755-758 ◽  
Author(s):  
E M Bladbjerg ◽  
P Marckmann ◽  
B Sandström ◽  
J Jespersen
Keyword(s):  
High Fat Diet ◽  
Fat Content ◽  
Factor Vii ◽  
Amidolytic Activity ◽  
High Fat ◽  
Low Fat Diet ◽  
Increased Risk ◽  
Coagulant Activity ◽  
High Fat Diets ◽  
Fat Diets

SummaryPreliminary observations have suggested that non-fasting factor VII coagulant activity (FVII:C) may be related to the dietary fat content. To confirm this, we performed a randomised cross-over study. Seventeen young volunteers were served 2 controlled isoenergetic diets differing in fat content (20% or 50% of energy). The 2 diets were served on 2 consecutive days. Blood samples were collected at 8.00 h, 16.30 h and 19.30 h, and analysed for triglycerides, FVII coagulant activity using human (FVII:C) or bovine thromboplastin (FVII:Bt), and FVII amidolytic activity (FVIPAm). The ratio FVII:Bt/FVII:Am (a measure of FVII activation) increased from fasting levels on both diets, but most markedly on the high-fat diet. In contrast, FVII: Am (a measure of FVII protein) tended to decrease from fasting levels on both diets. FVII:C rose from fasting levels on the high-fat diet, but not on the low-fat diet. The findings suggest that high-fat diets increase non-fasting FVII:C, and consequently may be associated with increased risk of thrombosis.

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