IBF-R Regulates IRE1α Post-Translational Modifications and ER Stress in High-Fat Diet-Induced Obese Mice

Obesity is a global health issue linked to the heightened risk of several chronic diseases. Rhus verniciflua (RV) is a traditional food supplement used for a range of pharmacological effects such as antitumor, antioxidant, α-glucosidase inhibitory effects, hepatitis, and arthritis. Despite the traditional medicinal values, scientific evidence for its application in obesity is inadequate and unclear. Thus, this investigation was designed to evaluate the anti-obesity effects of IBF-R, an RV extract, using a high-fat diet (HFD) model. The study has six groups: chow diet group; chow diet with 80 mg/kg IBF-R; HFD group; IBF-R group with 20, 40, and 80 mg/kg. IBF-R supplementation significantly regulated the weight gain than the HFD fed mice. Further, IBF-R supplementation lowered the expressions of adipogenic transcription factors such as SREBP-1c, C/EBPα, FAS, and PPAR-γ in white adipose tissue (WAT) of diet-induced obese mice. In addition, IBF-R supplementation reduced the lipogenic gene expression while enhancing genes was related to fatty acid oxidation. Obesity is linked to redox-based post-translational modifications (PTMs) of IRE1α such as S-nitrosylation, endoplasmic reticulum (ER) stress, and chronic metabolic inflammation. The administration of IBF-R inhibits these PTMs. Notably, IBF-R administration significantly enhanced the expression of AMPK and sirtuin 1 in WAT of HFD-fed mice. Together, these findings reveal the IRE1α S-nitrosylation-inflammation axis as a novel mechanism behind the positive implications of IBF-R on obesity. In addition, it lays a firm foundation for the development of Rhus verniciflua extract as a functional ingredient in the food and pharmaceutical industries.

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Delayed Exercise Training Improves Obesity-Induced Chronic Kidney Disease by Activating AMPK Pathway in High-Fat Diet-Fed Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22010350 ◽

2020 ◽

Vol 22 (1) ◽

pp. 350

Author(s):

Florian Juszczak ◽

Maud Vlassembrouck ◽

Olivia Botton ◽

Thomas Zwakhals ◽

Morgane Decarnoncle ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Exercise Training ◽

High Fat Diet ◽

Interstitial Fibrosis ◽

Calorie Intake ◽

Acid Oxidation ◽

Obese Mice ◽

High Fat ◽

Ampk Pathway

Exercise training is now recognized as an interesting therapeutic strategy in managing obesity and its related disorders. However, there is still a lack of knowledge about its impact on obesity-induced chronic kidney disease (CKD). Here, we investigated the effects of a delayed protocol of endurance exercise training (EET) as well as the underlying mechanism in obese mice presenting CKD. Mice fed a high-fat diet (HFD) or a low-fat diet (LFD) for 12 weeks were subsequently submitted to an 8-weeks EET protocol. Delayed treatment with EET in obese mice prevented body weight gain associated with a reduced calorie intake. EET intervention counteracted obesity-related disorders including glucose intolerance, insulin resistance, dyslipidaemia and hepatic steatosis. Moreover, our data demonstrated for the first time the beneficial effects of EET on obesity-induced CKD as evidenced by an improvement of obesity-related glomerulopathy, tubulo-interstitial fibrosis, inflammation and oxidative stress. EET also prevented renal lipid depositions in the proximal tubule. These results were associated with an improvement of the AMPK pathway by EET in renal tissue. AMPK-mediated phosphorylation of ACC and ULK-1 were particularly enhanced leading to increased fatty acid oxidation and autophagy improvement with EET in obese mice.

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Health Effects of Alternate Day Fasting Versus Pair-Fed Caloric Restriction in Diet-Induced Obese C57Bl/6J Male Mice

Frontiers in Physiology ◽

10.3389/fphys.2021.641532 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chloe G. Henderson ◽

Damian L. Turner ◽

Steven J. Swoap

Keyword(s):

T Cell ◽

Caloric Restriction ◽

High Fat Diet ◽

Chow Diet ◽

Obese Mice ◽

High Fat ◽

Mesenteric Lymph Nodes ◽

Fasting Period ◽

Alternate Day Fasting ◽

Ad Libitum

Alternate day fasting (ADF) induces weight loss and improves various markers of health in rodents and humans. However, it is unclear whether the benefits of ADF are derived from the lower caloric intake of ADF or from the 24-h fasting period. Therefore, this study directly compared selected markers for health – such as glucose control, body weight, liver triglycerides, T cell frequencies, and others – in high-fat (60% calories from fat) diet-induced obese mice subjected to either ADF or caloric restriction (CR). Obese mice were randomly assigned to one of four groups: (1) ADF: remained on the high-fat diet, but fed on alternate days (n = 5), (2) PF: remained on the high-fat diet, but pair-fed to the ADF group (n = 5), (3) LF: moved to a chow ad libitum diet (n = 5; 17% calories from fat), and (4) HF: remained on the high-fat ad libitum diet (n = 5). An additional group of non-obese mice maintained on a chow diet since weaning were used as controls (CON: n = 5). After 10 weeks, ADF, PF, and LF mice ate fewer kcals, had a lower body mass, had smaller epididymal fat pads, improved glucose tolerance, and had a lower hepatic triglyceride content relative to HF mice (p < 0.05), but none reached that of CON mice in these measures. T cell frequencies of the spleen, blood, and mesenteric lymph nodes were reduced in ADF, PF, and HF compared to the CON group. Importantly, there were no significant differences between the ADF and PF groups in any of the measurements made in the current study. These data suggest that ADF, PF, and LF diets each lead to improved markers of health relative to high-fat diet-induced obese mice, and that the caloric restriction associated with ADF is the major factor for the noted improvements.

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Omega-3 Phospholipids from Krill Oil Enhance Intestinal Fatty Acid Oxidation More Effectively than Omega-3 Triacylglycerols in High-Fat Diet-Fed Obese Mice

Nutrients ◽

10.3390/nu12072037 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2037 ◽

Cited By ~ 1

Author(s):

Petra Kroupova ◽

Evert M. van Schothorst ◽

Jaap Keijer ◽

Annelies Bunschoten ◽

Martin Vodicka ◽

...

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

High Fat Diet ◽

Body Weight Gain ◽

Acid Oxidation ◽

Obese Mice ◽

Krill Oil ◽

Omega 3 ◽

High Fat ◽

Lower Body Weight

Antisteatotic effects of omega-3 fatty acids (Omega-3) in obese rodents seem to vary depending on the lipid form of their administration. Whether these effects could reflect changes in intestinal metabolism is unknown. Here, we compare Omega-3-containing phospholipids (krill oil; ω3PL-H) and triacylglycerols (ω3TG) in terms of their effects on morphology, gene expression and fatty acid (FA) oxidation in the small intestine. Male C57BL/6N mice were fed for 8 weeks with a high-fat diet (HFD) alone or supplemented with 30 mg/g diet of ω3TG or ω3PL-H. Omega-3 index, reflecting the bioavailability of Omega-3, reached 12.5% and 7.5% in the ω3PL-H and ω3TG groups, respectively. Compared to HFD mice, ω3PL-H but not ω3TG animals had lower body weight gain (−40%), mesenteric adipose tissue (−43%), and hepatic lipid content (−64%). The highest number and expression level of regulated intestinal genes was observed in ω3PL-H mice. The expression of FA ω-oxidation genes was enhanced in both Omega-3-supplemented groups, but gene expression within the FA β-oxidation pathway and functional palmitate oxidation in the proximal ileum was significantly increased only in ω3PL-H mice. In conclusion, enhanced intestinal FA oxidation could contribute to the strong antisteatotic effects of Omega-3 when administered as phospholipids to dietary obese mice.

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Selective overexpression of Toll-like receptor-4 in skeletal muscle impairs metabolic adaptation to high-fat feeding

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00139.2015 ◽

2015 ◽

Vol 309 (3) ◽

pp. R304-R313 ◽

Cited By ~ 8

Author(s):

Ryan P. McMillan ◽

Yaru Wu ◽

Kevin Voelker ◽

Gabrielle Fundaro ◽

John Kavanaugh ◽

...

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

Whole Body ◽

Metabolic Adaptation ◽

Acid Oxidation ◽

Chow Diet ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4 ◽

Fat Feeding

Toll-like receptor-4 (TLR-4) is elevated in skeletal muscle of obese humans, and data from our laboratory have shown that activation of TLR-4 in skeletal muscle via LPS results in decreased fatty acid oxidation (FAO). The purpose of this study was to determine whether overexpression of TLR-4 in skeletal muscle alters mitochondrial function and whole body metabolism in the context of a chow and high-fat diet. C57BL/6J mice (males, 6–8 mo of age) with skeletal muscle-specific overexpression of the TLR-4 (mTLR-4) gene were created and used for this study. Isolated mitochondria and whole muscle homogenates from rodent skeletal muscle (gastrocnemius and quadriceps) were investigated. TLR-4 overexpression resulted in a significant reduction in FAO in muscle homogenates; however, mitochondrial respiration and reactive oxygen species (ROS) production did not appear to be affected on a standard chow diet. To determine the role of TLR-4 overexpression in skeletal muscle in response to high-fat feeding, mTLR-4 mice and WT control mice were fed low- and high-fat diets for 16 wk. The high-fat diet significantly decreased FAO in mTLR-4 mice, which was observed in concert with elevated body weight and fat, greater glucose intolerance, and increase in production of ROS and cellular oxidative damage compared with WT littermates. These findings suggest that TLR-4 plays an important role in the metabolic response in skeletal muscle to high-fat feeding.

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Tetragonia tetragonoides (Pall.) Kuntze (New Zealand Spinach) Prevents Obesity and Hyperuricemia in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu10081087 ◽

2018 ◽

Vol 10 (8) ◽

pp. 1087 ◽

Cited By ~ 9

Author(s):

Young-Sil Lee ◽

Seung-Hyung Kim ◽

Heung Yuk ◽

Geung-Joo Lee ◽

Dong-Seon Kim

Keyword(s):

Uric Acid ◽

New Zealand ◽

High Fat Diet ◽

Body Weight Gain ◽

Gastrointestinal Diseases ◽

Acid Oxidation ◽

Obese Mice ◽

High Fat ◽

Edible Plant ◽

Garcinia Cambogia

Tetragonia tetragonoides (Pall.) Kuntze, called New Zealand spinach (NZS), is an edible plant used in salad in Western countries and has been used to treat gastrointestinal diseases in traditional medicine. We examined the anti-obesity and anti-hyperuricemic effects of NZS and the underlying mechanisms in high-fat diet (HFD)-induced obese mice. Mice were fed a normal-fat diet (NFD); high-fat diet (HFD); HFD with 75, 150, or 300 mg/kg NZS extract; or 245 mg/kg Garcinia cambogia (GC) extract. NZS decreased body weight gain, total white adipose tissue (WAT), liver weight, and size of adipocytes and improved hepatic and plasma lipid profiles. With NZS, the plasma levels of the leptin and uric acid were significantly decreased while the levels of the adiponectin were increased. Furthermore, NZS decreased the expression levels of adipogenesis-related genes and xanthine oxidoreductase (XOR), which is involved in uric acid production, while increasing that of proteins associated with fatty acid oxidation. UPLC analysis revealed that NZS contained 6-methoxykaempferol-3-O-β-d-glucosyl(1′′′→2′′)-β-d-glucopyranoside, 6-methoxykaempferol-3-O-β-d-glucosyl(1′′′→2′′)-β-d-glucopyranosyl-(6′′′′-caffeoyl)-7-O-β-d-glucopyranoside, and 6,4′-dimethoxykaempferol-3-O-β-d-glucosyl(1′′′→2′′)-β-d-glucopyranosyl-(6′′′′-caffeoyl)-7-O-β-d-glucopyranoside. These results suggest that NZS exerts anti-obesity, anti-hyperlipidemia, and anti-hyperuricemic effects in HFD-induced obese mice, which are partly explained by regulation of lipid-metabolism-related genes and proteins and decreased expression of XOR.

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Green Tea Extract Supplementation Induces the Lipolytic Pathway, Attenuates Obesity, and Reduces Low-Grade Inflammation in Mice Fed a High-Fat Diet

Mediators of Inflammation ◽

10.1155/2013/635470 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 48

Author(s):

Cláudio A. Cunha ◽

Fábio S. Lira ◽

José C. Rosa Neto ◽

Gustavo D. Pimentel ◽

Gabriel I. H. Souza ◽

...

Keyword(s):

Adipose Tissue ◽

Green Tea ◽

High Fat Diet ◽

Green Tea Extract ◽

Chow Diet ◽

Low Grade ◽

Obese Mice ◽

High Fat ◽

Tea Extract ◽

Low Grade Inflammation

The aim of this study was to evaluate the effects of green teaCamellia sinensisextract on proinflammatory molecules and lipolytic protein levels in adipose tissue of diet-induced obese mice. Animals were randomized into four groups: CW (chow diet and water); CG (chow diet and water + green tea extract); HW (high-fat diet and water); HG (high-fat diet and water + green tea extract). The mice were fedad libitumwith chow or high-fat diet and concomitantly supplemented (oral gavage) with 400 mg/kg body weight/day of green tea extract (CG and HG, resp.). The treatments were performed for eight weeks. UPLC showed that in 10 mg/mL green tea extract, there were 15 μg/mg epigallocatechin, 95 μg/mg epigallocatechin gallate, 20.8 μg/mg epicatechin gallate, and 4.9 μg/mg gallocatechin gallate. Green tea administered concomitantly with a high-fat diet increased HSL, ABHD5, and perilipin in mesenteric adipose tissue, and this was associated with reduced body weight and adipose tissue gain. Further, we observed that green tea supplementation reduced inflammatory cytokine TNFαlevels, as well as TLR4, MYD88, and TRAF6 proinflammatory signalling. Our results show that green tea increases the lipolytic pathway and reduces adipose tissue, and this may explain the attenuation of low-grade inflammation in obese mice.

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Reduced Number of Adipose Lineage and Endothelial Cells in Epididymal fat in Response to Omega-3 PUFA in Mice Fed High-Fat Diet

Marine Drugs ◽

10.3390/md16120515 ◽

2018 ◽

Vol 16 (12) ◽

pp. 515 ◽

Cited By ~ 7

Author(s):

Katerina Adamcova ◽

Olga Horakova ◽

Kristina Bardova ◽

Petra Janovska ◽

Marie Brezinova ◽

...

Keyword(s):

Endothelial Cells ◽

Dna Content ◽

High Fat Diet ◽

Macrophage Polarization ◽

Chow Diet ◽

Obese Mice ◽

Omega 3 ◽

High Fat ◽

Pufa Supplementation ◽

Inflammatory Status

We found previously that white adipose tissue (WAT) hyperplasia in obese mice was limited by dietary omega-3 polyunsaturated fatty acids (omega-3 PUFA). Here we aimed to characterize the underlying mechanism. C57BL/6N mice were fed a high-fat diet supplemented or not with omega-3 PUFA for one week or eight weeks; mice fed a standard chow diet were also used. In epididymal WAT (eWAT), DNA content was quantified, immunohistochemical analysis was used to reveal the size of adipocytes and macrophage content, and lipidomic analysis and a gene expression screen were performed to assess inflammatory status. The stromal-vascular fraction of eWAT, which contained most of the eWAT cells, except for adipocytes, was characterized using flow cytometry. Omega-3 PUFA supplementation limited the high-fat diet-induced increase in eWAT weight, cell number (DNA content), inflammation, and adipocyte growth. eWAT hyperplasia was compromised due to the limited increase in the number of preadipocytes and a decrease in the number of endothelial cells. The number of leukocytes and macrophages was unaffected, but a shift in macrophage polarization towards a less inflammatory phenotype was observed. Our results document that the counteraction of eWAT hyperplasia by omega-3 PUFA in dietary-obese mice reflects an effect on the number of adipose lineage and endothelial cells.

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Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet

BioMed Research International ◽

10.1155/2018/5045182 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Xiaoqing Ma ◽

Wenhua Du ◽

Shanshan Shao ◽

Chunxiao Yu ◽

Lingyan Zhou ◽

...

Keyword(s):

Er Stress ◽

High Fat Diet ◽

Hepg2 Cells ◽

Liver Weight ◽

Chow Diet ◽

High Fat ◽

Western Blots ◽

Nonalcoholic Fatty Liver ◽

Expression Levels

Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD), high fat diet (HFD), and HFD administered with vildagliptin (50 mg/Kg) (V-HFD). After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission electron microscopy, real-time PCR for gene expression levels, and western blots for protein expression levels. ER stress was induced in HepG2 cells with palmitic acid and the effects of vildagliptin were investigated. Results. HFD mice showed increased liver weight/body weight (20.27%) and liver triglycerides (314.75%) compared to CD mice, but these decreased by 9.27% and 21.83%, respectively, in V-HFD mice. In the liver, HFD induced the expression of ER stress indicators significantly, which were obviously decreased by vildagliptin. In vitro, the expressions of molecular indicators of ER stress were reduced in HepG2 when vildagliptin was administered. Conclusions. Vildagliptin alleviates hepatic ER stress in a mouse high fat diet model. In HepG2 cells, vildagliptin directly reduced ER stress. Therefore, vildagliptin may be a potential agent for nonalcoholic fatty liver disease.

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Anti-Obesity Effects of the Flower of Prunus persica in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu11092176 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2176 ◽

Cited By ~ 6

Author(s):

Jungbin Song ◽

Young-Sik Kim ◽

Linae Kim ◽

Hyo Jin Park ◽

Donghun Lee ◽

...

Keyword(s):

Fatty Acid ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Prunus Persica ◽

Quantitative Polymerase Chain Reaction ◽

Water Extract ◽

Control Group ◽

Acid Oxidation ◽

Obese Mice ◽

High Fat

Prunus persica (L.) Batsch is a deciduous fruit tree cultivated worldwide. The flower of P. persica (PPF), commonly called the peach blossom, is currently consumed as a tea for weight loss in East Asia; however, its anti-obesity effects have yet to be demonstrated in vitro or in vivo. Since PPF is rich in phytochemicals with anti-obesity properties, we aimed to investigate the effects of PPF on obesity and its underlying mechanism using a diet-induced obesity model. Male C57BL/6 mice were fed either normal diet, high-fat diet (HFD), or HFD containing 0.2% or 0.6% PPF water extract for 8 weeks. PPF significantly reduced body weight, abdominal fat mass, serum glucose, alanine transaminase and aspartate aminotransferase levels, and liver and spleen weights compared to the HFD control group. Real-time quantitative polymerase chain reaction analysis revealed that PPF suppressed lipogenic gene expression, including stearoyl-CoA desaturase-1 and -2 and fatty acid synthase, and up-regulated the fatty acid β-oxidation gene, carnitine palmitoyltransferase-1, in the liver. Our results suggest that PPF exerts anti-obesity effects in obese mice and these beneficial effects might be mediated through improved hepatic lipid metabolism by reducing lipogenesis and increasing fatty acid oxidation.

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Rhus verniciflua and Eucommia ulmoides Protects Against High-Fat Diet-Induced Hepatic Steatosis by Enhancing Anti-Oxidation and AMPK Activation

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500642 ◽

2019 ◽

Vol 47 (06) ◽

pp. 1253-1270

Author(s):

Hwa-Young Lee ◽

Geum-Hwa Lee ◽

Young Yoon ◽

Han-Jung Chae

Keyword(s):

Protein Folding ◽

Er Stress ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Liver Disorder ◽

Eucommia Ulmoides ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Rhus Verniciflua ◽

Anti Oxidant

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder associated with features of metabolic syndrome and oxidative stress. We examined the mechanism by which the combined extracts of Rhus verniciflua and Eucommia ulmoides extracts (ILF-RE) regulate hepatic dyslipidemia in an established NAFLD model, high-fat diet (HFD)-induced lipid dysmetabolism in rats. ILF-RE attenuated alanine aminotransferase (ALT) by 1.5% [Formula: see text], aspartate aminotransferase (AST) by 1.5% [Formula: see text], triglycerides by 1.5% [Formula: see text], cholesterol by 2.0% [Formula: see text], and lipid peroxidation by 1.5% [Formula: see text] in the NAFLD model. ILF-RE, recently shown to have anti-oxidant properties, also inhibited hepatic ROS accumulation by 1.68% [Formula: see text] and regulated ER-redox imbalance, a key phenomenon of ER stress. Due to nutrient overload stress-associated protein folding, ER stress and downstream SREBP-lipogenic transcription signaling were highly activated, and the mTORC1-AMPK axis was also disturbed, leading to hepatic steatosis. ILF-RE results in recovery from hepatic conditions induced by nutrient-based protein folding stress signaling and the ER stress-SREBP and AMPK-mTORC1-SREBP1 axes. Based on these results, ILF-RE is suggested to be a potential therapeutic strategy for hepatic steatosis and may represent a promising novel agent for the prevention and treatment of NAFLD.

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