Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice

Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress.

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Deletion of lysophosphatidylcholine acyltransferase3 in myeloid cells worsens hepatic steatosis after a high fat diet

The Journal of Lipid Research ◽

10.1194/jlr.ra120000737 ◽

2020 ◽

pp. jlr.RA120000737

Author(s):

Thibaut Bourgeois ◽

Antoine Jalil ◽

Charles Thomas ◽

Charlene Magnani ◽

Naig Le Guern ◽

...

Keyword(s):

Hepatic Steatosis ◽

High Fat Diet ◽

Ldl Receptor ◽

Myeloid Cells ◽

Lipid Absorption ◽

High Fat ◽

Triglyceride Accumulation ◽

Pufa Composition

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3’s role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approx. 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.

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Oleacein Prevents High Fat Diet-Induced A Diposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice

Nutrients ◽

10.3390/nu11081829 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1829 ◽

Cited By ~ 8

Author(s):

Lepore ◽

Maggisano ◽

Bulotta ◽

Mignogna ◽

Arcidiacono ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Glucose Transporter ◽

Regulatory Element ◽

Regulatory Elements ◽

High Fat

Oleacein is one of the most abundant polyphenolic compounds of olive oil, which has been shown to play a protective role against several metabolic abnormalities, including dyslipidemia, insulin resistance, and glucose intolerance. Herein, we investigated the effects of oleacein on certain markers of adipogenesis and insulin-resistance in vitro, in 3T3-L1 adipocytes, and in vivo in high-fat diet (HFD)-fed mice. During the differentiation process of 3T3-L1 preadipocytes into adipocytes, oleacein strongly inhibited lipid accumulation, and decreased protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS), while increasing Adiponectin levels. In vivo, treatment with oleacein of C57BL/6JOlaHsd mice fed with HFD for 5 and 13 weeks prevented the increase in adipocyte size and reduced the inflammatory infiltration of macrophages and lymphocytes in adipose tissue. These effects were accompanied by changes in the expression of adipose tissue-specific regulatory elements such as PPARγ, FAS, sterol regulatory element-binding transcription factor-1 (SREBP-1), and Adiponectin, while the expression of insulin-sensitive muscle/fat glucose transporter Glut-4 was restored in HFD-fed mice treated with oleacein. Collectively, our findings indicate that protection against HFD-induced adiposity by oleacein in mice is mediated by the modulation of regulators of adipogenesis. Protection against HFD-induced obesity is effective in improving peripheral insulin sensitivity.

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Anti-adipogenic and anti-obesity activities of purpurin in 3T3-L1 preadipocyte cells and in mice fed a high-fat diet

BMC Complementary and Alternative Medicine ◽

10.1186/s12906-019-2756-5 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 7

Author(s):

Woo Nam ◽

Seok Hyun Nam ◽

Sung Phil Kim ◽

Carol Levin ◽

Mendel Friedman

Keyword(s):

Weight Gain ◽

High Fat Diet ◽

Biological Activities ◽

The Body ◽

High Fat ◽

In Vivo Models ◽

Triglyceride Accumulation ◽

In Cells

Abstract Background The body responds to overnutrition by converting stem cells to adipocytes. In vitro and in vivo studies have shown polyphenols and other natural compounds to be anti-adipogenic, presumably due in part to their antioxidant properties. Purpurin is a highly antioxidative anthraquinone and previous studies on anthraquinones have reported numerous biological activities in cells and animals. Anthraquinones have also been used to stimulate osteoblast differentiation, an inversely-related process to that of adipocyte differentiation. We propose that due to its high antioxidative properties, purpurin administration might attenuate adipogenesis in cells and in mice. Methods Our study will test the effect purpurin has on adipogenesis using both in vitro and in vivo models. The in vitro model consists of tracking with various biomarkers, the differentiation of pre-adipocyte to adipocytes in cell culture. The compound will then be tested in mice fed a high-fat diet. Murine 3T3-L1 preadipocyte cells were stimulated to differentiate in the presence or absence of purpurin. The following cellular parameters were measured: intracellular reactive oxygen species (ROS), membrane potential of the mitochondria, ATP production, activation of AMPK (adenosine 5′-monophosphate-activated protein kinase), insulin-induced lipid accumulation, triglyceride accumulation, and expression of PPARγ (peroxisome proliferator activated receptor-γ) and C/EBPα (CCAAT enhancer binding protein α). In vivo, mice were fed high fat diets supplemented with various levels of purpurin. Data collected from the animals included anthropometric data, glucose tolerance test results, and postmortem plasma glucose, lipid levels, and organ examinations. Results The administration of purpurin at 50 and 100 μM in 3T3-L1 cells, and at 40 and 80 mg/kg in mice proved to be a sensitive range: the lower concentrations affected several measured parameters, whereas at the higher doses purpurin consistently mitigated biomarkers associated with adipogenesis, and weight gain in mice. Purpurin appears to be an effective antiadipogenic compound. Conclusion The anthraquinone purpurin has potent in vitro anti-adipogenic effects in cells and in vivo anti-obesity effects in mice consuming a high-fat diet. Differentiation of 3T3-L1 cells was dose-dependently inhibited by purpurin, apparently by AMPK activation. Mice on a high-fat diet experienced a dose-dependent reduction in induced weight gain of up to 55%.

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Bixin Attenuates High-Fat Diet-Caused Liver Steatosis and Inflammatory Injury through Nrf2/PPARα Signals

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6610124 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Shasha Tao ◽

Youjing Yang ◽

Jianzhong Li ◽

Hongyan Wang ◽

Yu Ma

Keyword(s):

Liver Disease ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Fatty Liver Disease ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Cytoprotective Activity ◽

Inflammatory Damage

Nonalcoholic fatty liver disease is the most common liver disease worldwide. Hepatic steatosis and oxidative stress are the main characteristics of NAFLD (nonalcoholic fatty liver disease), which also affect its prognosis. Bixin acts as novel Nrf2 (NF-E2 p45-related factor 2) activator with the cytoprotection against oxidative stress and inflammation; this study mainly focused on the mechanism of Nrf2 activation by bixin and explored its potential feasibilities in long-term high-fat diet- (HFD-) caused hepatic steatosis and inflammatory response in vitro and in vivo. Bixin was found to activate Nrf2 signals by the modification of critical Keap1 (Kelch-like ECH-associated protein 1) cystine and competitive interaction with Keap1 with upregulating P62 mRNA and protein expression. In human liver cells exposed to FFA (free fatty acid), bixin displayed a pronounced cytoprotective activity with upregulation of Nrf2-mediated gene expression, such as PPARα and its targets related with fatty acid oxidation. In HFD-fed mice, systemic administration of bixin attenuated lipid accumulation, decreased oxidant inflammatory damage in the liver, and reduced circulating lipid levels through Nrf2. Different from most of other established inducers, bixin activated Nrf2 signals through two different mechanisms with safe administration for protection of oxidant inflammatory damage and attenuation of lipid accumulation in the in vivo long-term HFD-fed mice. Bixin represents a prototype Nrf2 activator that displays cytoprotective activity upon system administration targeting hepatic steatosis and oxidant inflammation originating from long-term HFD-fed mice. And bixin-based Nrf2-directed systemic intervention may also provide therapeutic benefit in protecting other organs in the process of metabolic syndrome.

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Muscular G9a regulates muscle-liver-fat axis by musclin under overnutrition in female mice

10.2337/figshare.12990842.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Wenquan Zhang ◽

Dong Yang ◽

Yangmian Yuan ◽

Chong Liu ◽

...

Keyword(s):

Hepatic Steatosis ◽

High Fat Diet ◽

Critical Role ◽

Liver Fat ◽

High Fat ◽

Core Domain ◽

Female Mice ◽

Methylase Activity

Crosstalk among different tissues and organs is a hotspot in metabolic research. Recent studies have revealed the regulatory roles of a number of myokines in metabolism. Here, we report that female mice muscle-specific lacking histone methylase G9a (Ehmt2Ckmm KO or Ehmt2HSA KO) are resistant to high-fat-diet (HFD) induced obesity and hepatic steatosis. Furthermore, we identified significantly upregulated circulating level of musclin, a myokine, in HFD-fed Ehmt2Ckmm KO or Ehmt2HSA KO female mice. Similarly, upregulated musclin was observed in mice injected with two structurally different inhibitors for G9a methylase activity, BIX01294 and A366. Moreover, injection of recombinant full-length musclin or its functional core domain, inhibited the HFD-induced obesity and hepatic steatosis in wildtype female and male mice. Mechanistically, G9a methylase activity-dependently regulated muscular musclin level by binding to its promoter, also by regulating p-Foxo1/Foxo1 level in vivo and in vitro. Collectively, these data suggested a critical role for G9a in the ‘muscle-liver-fat’ metabolic axis, at least for female mice. Musclin may serve as a potential therapeutic candidate for obesity and associated diseases.

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Jianpi Qinghua Formula Reduced Intramyocellular Lipids (IMCLs) by Inhibiting Excessive Activation of mTORC1

10.21203/rs.3.rs-136215/v1 ◽

2021 ◽

Author(s):

Xv Han ◽

Qingguang Chen ◽

Yahua Liu ◽

Junfei Xv ◽

Hao Lu

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Palmitic Acid ◽

High Fat Diet ◽

C2c12 Cells ◽

Akt Pathway ◽

High Fat ◽

Akt Phosphorylation

Abstract Background:IMCLs are an important factor in skeletal muscle insulin resistance. This study aimed to explore the effect of Jianpi Qinghua formula (JPQHF) on IMCLs and its mechanism, as well as the relationship between IMCLs and other skeletal muscle insulin sensitivity factors, thereby elucidating the mechanism by which JPQHF improves insulin sensitivity.Methods: In an in vivo experiment, JPQHF and pioglitazone (PIO) were individually used to treat C57 mice with high-fat diet-induced obesity. In an in vitro experiment, JPQHF and rapamycin in serum were individually used to treat C2C12 cells induced with palmitic acid. The IMCLs of tissue and cells were subjected to oil red O staining. The RNA and protein expression of PPARγ, myogenin, mTORC1 and members of the PI3K/AKT pathway in skeletal muscle tissue and C2C12 cells was examined. Differences between the different intervention groups were determined.Results: IMCLs were significantly increased in mice with obesity induced by a high-fat diet and the C2C12 cell line treated with palmitic acid compared to the corresponding controls. mTORC1 phosphorylation and PPARγ levels were also increased, and AKT phosphorylation and myogenin levels were decreased. Intervention with JPQHF reversed the above changes. In addition, the PPARγ level in C2C12 cells was reduced after intervention with rapamycin, an inhibitor of mTORC1. However, AKT phosphorylation and myogenin levels did not recover after rapamycin intervention.Conclusion: IMCLs were significantly increased in obese C57 mice and palmitic acid-treated C2C12 cells. JPQHF reduced IMCLs both in vivo and in vitro. Mechanistically, this effect likely occurred through JPQHF-mediated inhibition of the overactivation of mTORC1 and a subsequent reduction in the expression of PPARγ. However, the function of JPQHF in elevating myogenin levels and the PI3K/AKT pathway may not be entirely dependent on mTORC1.

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Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ

eLife ◽

10.7554/elife.66398 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Zhang ◽

Gerd Bobe ◽

Cristobal L Miranda ◽

Malcolm B Lowry ◽

Victor L Hsu ◽

...

Keyword(s):

Hepatic Steatosis ◽

High Fat Diet ◽

Caloric Intake ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Competitive Binding Assay ◽

Docking Simulations ◽

Synthetic Derivative

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8–10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.

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Chrysanthemum indicum Inhibits Adipogenesis and Activates the AMPK Pathway in High-Fat-Diet-Induced Obese Mice

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500076 ◽

2018 ◽

Vol 46 (01) ◽

pp. 119-136 ◽

Cited By ~ 12

Author(s):

Sarmila Nepali ◽

Ji-Yun Cha ◽

Hyeon-Hui Ki ◽

Hoon-Yeon Lee ◽

Young-Ho Kim ◽

...

Keyword(s):

High Fat Diet ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Obese Mice ◽

High Fat ◽

In Vivo Models ◽

Garcinia Cambogia ◽

Chrysanthemum Indicum

Chrysanthemum indicum (CI) is widely distributed in China and many parts of the tropical world, and has been reported to have antibacterial, antiviral, anti-oxidant and immunomodulatory effects, but no information is available on its effects on high fat diet (HFD)-induced obesity. This was undertaken to investigate the mechanism responsible for the effect of ethyl acetate fraction of CI (CIEA) on adipogenesis, in vitro and in vivo models of obesity. In the in vitro study, differentiating 3T3-L1 cells were treated with media to initiate differentiation (MDI) in the presence or absence of CIEA with different concentrations, and in the in vivo study, C57BL/6 mice were fed with HFD and administered CIEA daily for six weeks. Garcinia cambogia (GC) was used as the positive control, and was administered in the same manner as CIEA. Results showed CIEA reduced HFD-induced body weight gain, epididymal white adipose tissue (eWAT), and liver weight. In addition, CIEA significantly decreased serum lipid profiles, including total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterol (LDLc) and increased high density lipoprotein cholesterol (HDLc) levels. Furthermore, CIEA also reduced leptin levels and increased adiponectin levels in serum, and significantly decreased peroxisome proliferator-activated receptor [Formula: see text] (PPAR[Formula: see text]) and CCAAT/enhancer-binding protein (C/EPBs) levels, but increased PPAR[Formula: see text] level and the phosphorylation of AMP-activated protein kinase (AMPK) in eWATs and in the liver tissues of HFD fed obese mice. Taken together, these results indicate CIEA might be beneficial for preventing obesity.

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Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00203.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E1063-E1069 ◽

Cited By ~ 1

Author(s):

Weidong Chai ◽

Kevin Aylor ◽

Zhenqi Liu ◽

Li-Ming Gan ◽

Erik Michaëlsson ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Disease Risk ◽

Therapeutic Potential ◽

Cardiovascular Disease Risk ◽

Sprague Dawley ◽

High Fat

A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-mediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD’s microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.

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