A High-Fat Diet Attenuates Amp-Activated Protein Kinase α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development in Vivo

Exosomes are important for intercellular communication, but the role of exosomes in the communication between adipose tissue (<a>AT</a>) and the liver remains unknown. The aim of this study is to determine the contribution of AT-derived exosomes in nonalcoholic fatty liver disease (<a>NAFLD</a>). Exosome components, liver fat content, and liver function were monitored in AT in mice fed a <a>high-fat diet </a>(<a>HFD</a>) or treated with metformin- or GW4869 and with AMP-activated protein kinase (AMPKα1) floxed (Prkaα1fl/fl/WT), <a>Prkaα1-/-</a>, liver tissue-specific Prkaα1-/-, or AT-specific Prkaα1-/- modification. In cultured adipocytes and white adipose tissue (WAT), the absence of <a>AMPKα1</a> increased exosome release and exosomal proteins by elevating <a>tumor susceptibility gene 101 (TSG101</a>)-mediated exosome biogenesis. In adipocytes treated with palmitic acid, TSG101 facilitated scavenger receptor class B (CD36) sorting into exosomes. CD36-containing exosomes were then endocytosed by hepatocytes to induce lipid accumulation and inflammation. Consistently, an HFD induced more severe lipid accumulation and cell death in <a>Prkaα1-/- </a>and adipose tissue-specific Prkaα1-/- mice than in WT and liver-specific Prkaα1-/- mice. AMPK activation by metformin reduced adipocyte-mediated exosome release and mitigated fatty liver development in WT and liver specific Prkaα1-/- mice. Moreover, administration of the exosome inhibitor GW4869 blocked exosome secretion and alleviated HFD-induced fatty livers in Prkaα1-/- and adipocyte-specific Prkaα1-/- mice. We conclude that HFD-mediated AMPKα1 inhibition promotes NAFLD by increasing numbers of AT C<a>D36</a>-containing exosomes.

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A High-Fat Diet Attenuates Amp-Activated Protein Kinase α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development in Vivo

10.2337/figshare.13259768 ◽

2020 ◽

Author(s):

Ada Admin ◽

Chenghui Yan ◽

Xiaoxiang Tian ◽

Jiayin Li ◽

Dan Liu ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

Fatty Liver ◽

Lipid Accumulation ◽

High Fat Diet ◽

Liver Development ◽

High Fat ◽

Tissue Specific ◽

Nonalcoholic Fatty Liver ◽

Amp Activated Protein Kinase

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A High-Fat Diet Attenuates Amp-Activated Protein Kinase α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development in Vivo

Diabetes ◽

10.2337/db20-0146 ◽

2020 ◽

pp. db200146

Author(s):

Chenghui Yan ◽

Xiaoxiang Tian ◽

Jiayin Li ◽

Dan Liu ◽

Ding Ye ◽

...

Keyword(s):

Protein Kinase ◽

Fatty Liver ◽

High Fat Diet ◽

Liver Development ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Amp Activated Protein Kinase

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Rheum palmatum L. Attenuates High Fat Diet-Induced Hepatosteatosis by Activating AMP-Activated Protein Kinase

The American Journal of Chinese Medicine ◽

10.1142/s0192415x16500300 ◽

2016 ◽

Vol 44 (03) ◽

pp. 551-564 ◽

Cited By ~ 10

Author(s):

Mingxing Yang ◽

Xiumin Li ◽

Xin Zeng ◽

Zhimin Ou ◽

Mei Xue ◽

...

Keyword(s):

Liver Disease ◽

Protein Kinase ◽

Glucose Tolerance ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Low Dose ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Amp Activated Protein Kinase

Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disorder characterized by the accumulation of excess fat in the liver. Rheum palmatumL. (RP) decoctions have been reported to ameliorate NAFLD. The aim of the present study was to investigate the effects and underlying mechanisms of RP in fatty liver disease induced by a high-fat diet (HFD) in rats. Low and high doses of aqueous RP extraction were orally administered to HFD-fed rats for six weeks. Body weight, tissue weight, glucose tolerance, insulin tolerance, hepatic morphology, and liver triglyceride (TG) content were assessed. The effects of RP on the expressions of lipogenic and lipolysis genes were measured by quantitative real-time PCR. The phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) was determined by Western blotting. Treatment with low-dose RP significantly reduced liver weight, liver TG content, and improved glucose tolerance in HFD-fed rats. Consistently, RP attenuated excess fat accumulation and downregulated the expression of lipogenic genes in the liver. Further, an increased phosphorylation of AMPK and ACC was observed. These findings suggest that low-dose RP alleviates hepatosteatosis, at least in part, by stimulating AMPK activity.

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Altered expression of transcription factors and genes regulating lipogenesis in liver and adipose tissue of mice with high fat diet-induced obesity and nonalcoholic fatty liver disease

European Journal of Gastroenterology & Hepatology ◽

10.1097/meg.0b013e3282f9b203 ◽

2008 ◽

Vol 20 (9) ◽

pp. 843-854 ◽

Cited By ~ 60

Author(s):

Kengathevy Morgan ◽

Adhemar Uyuni ◽

Ganesh Nandgiri ◽

Lin Mao ◽

Luciano Castaneda ◽

...

Keyword(s):

Adipose Tissue ◽

Transcription Factors ◽

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

High Fat ◽

Altered Expression ◽

Nonalcoholic Fatty Liver ◽

Diet Induced Obesity

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Systemic Overexpression of GDF5 in Adipocytes but Not Hepatocytes Alleviates High-Fat Diet-Induced Nonalcoholic Fatty Liver in Mice

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2021/8894685 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yan Yang ◽

Wenting Zhang ◽

Xiaohui Wu ◽

Jing Wu ◽

Chengjun Sun ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Fatty Liver ◽

High Fat Diet ◽

Lentiviral Vector ◽

Cell Model ◽

Control Group ◽

High Fat ◽

Fatty Acid Binding ◽

Nonalcoholic Fatty Liver

Objective. Our recent study demonstrated that growth differentiation factor 5 (GDF5) could promote white adipose tissue thermogenesis and alleviate high-fat diet- (HFD-) induced obesity in fatty acid-binding protein 4- (Fabp4-) GDF5 transgenic mice (TG). Here, we further investigated the effects of systemic overexpression of the GDF5 gene in adipocytes HFD-induced nonalcoholic fatty liver disease (NAFLD). Methods. Fabp4-GDF5 TG mice were administered an HFD feeding. NAFLD-related indicators associated with lipid metabolism and inflammation were measured. A GDF5 lentiviral vector was constructed, and the LO2 NAFLD cell model was induced by FFA solution (oleic acid and palmitic acid). The alterations in liver function, liver lipid metabolism, and related inflammatory indicators were analyzed. Results. The liver weight was significantly reduced in the TG group, which was in accordance with the significantly downregulated expression of TNFα, MCP1, Aim2, and SREBP-1c and significantly upregulated expression of CPT-1α and ACOX2 in TG mouse livers. Compared to that of cells in the FAA-free control group, LO2 cells with in situ overexpression of GDF5 developed lipid droplets after FFA treatment; the levels of triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were significantly increased in both the GDF5 lentivirus and control lentivirus groups compared with those of the FAA-free group. Additionally, the levels of FAS, SREBP-1, CPT-1α, and inflammation-associated genes, such as ASC and NLRC4, were unaltered despite GDF5 treatment. Conclusion. Systemic overexpression of GDF5 in adipose tissue in vivo significantly reduced HFD-induced NAFLD liver damage in mice. The overexpression of GDF5 in hepatocytes failed to improve lipid accumulation and inflammation-related reactions induced by mixed fatty acids, suggesting that the protective effect of GDF5 in NAFLD was mainly due to the reduction in adipose tissue and improvements in metabolism. Hence, our study suggests that the management of NAFLD should be targeted to reduce the overall amount of body fat and improve metabolic status before the progression to nonalcoholic steatohepatitis occurs.

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Activation of AMP-Activated Protein Kinase-Sirtuin 1 Pathway Contributes to Salvianolic Acid A-Induced Browning of White Adipose Tissue in High-Fat Diet Fed Male Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.614406 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jianfei Lai ◽

Qianyu Qian ◽

Qinchao Ding ◽

Li Zhou ◽

Ai Fu ◽

...

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

White Adipose Tissue ◽

High Fat Diet ◽

Sirtuin 1 ◽

Male Mice ◽

High Fat ◽

Sirt1 Expression ◽

Salvianolic Acid ◽

Amp Activated Protein Kinase

Background: Salvianolic acid A (Sal A), a natural polyphenolic compound extracted from Radix Salvia miltiorrhiza (Danshen), exhibits exceptional pharmacological activities against cardiovascular diseases. While a few studies have reported anti-obesity properties of Sal A, the underlying mechanisms are largely unknown. Given the prevalence of obesity and promising potential of browning of white adipose tissue to combat obesity, recent research has focused on herbal ingredients that may promote browning and increase energy expenditure.Purpose: The present study was designed to investigate the protective antiobesity mechanisms of Sal A, in part through white adipose browning.Methods: Both high-fat diet (HFD)-induced obese (DIO) male mice model and fully differentiated C3H10T1/2 adipocytes from mouse embryo fibroblasts were employed in this study. Sal A (20 and 40 mg/kg) was administrated to DIO mice by intraperitoneal injection for 13-weeks. Molecular mechanisms mediating effects of Sal A were evaluated.Resluts: Sal A treatment significantly attenuated HFD-induced weight gain and lipid accumulation in epididymal fat pad. Uncoupling protein 1 (UCP-1), a specialized thermogenic protein and marker for white adipocyte browning, was significantly induced by Sal A treatment in both white adipose tissues and cultured adipocytes. Further mechanistic investigations revealed that Sal A robustly reversed HFD-decreased AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) expression in mice. Genetically silencing either AMPK or SIRT1 using siRNA abolished UCP-1 upregulation by Sal A. AMPK silencing significantly blocked Sal A-increased SIRT1 expression, while SIRT1 silencing did not affect Sal A-upregulated phosphorylated-AMPK. These findings indicate that AMPK was involved in Sal A-increased SIRT1.Conclusion: Sal A increases white adipose tissue browning in HFD-fed male mice and in cultured adipocytes. Thus, Sal is a potential natural therapeutic compound for treating and/or preventing obesity.

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Niacin Ameliorates Hepatic Steatosis by Inhibiting De Novo Lipogenesis Via a GPR109A-Mediated PKC–ERK1/2–AMPK Signaling Pathway in C57BL/6 Mice Fed a High-Fat Diet

Journal of Nutrition ◽

10.1093/jn/nxz303 ◽

2019 ◽

Vol 150 (4) ◽

pp. 672-684 ◽

Cited By ~ 3

Author(s):

Lingyan Ye ◽

Zheng Cao ◽

Xiangru Lai ◽

Ying Shi ◽

Naiming Zhou

Keyword(s):

Liver Disease ◽

Protein Kinase ◽

Fatty Liver ◽

Signaling Pathway ◽

Lipid Accumulation ◽

High Fat Diet ◽

Hepg2 Cells ◽

De Novo ◽

De Novo Lipogenesis ◽

High Fat

ABSTRACT Background Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Hepatic de novo lipogenesis (DNL) has been suggested to contribute to the pathogenesis of NAFLD. Recent studies have demonstrated that niacin (NA) modulates hepatic DNL through GPR109A. However, the underlying mechanism remains largely unknown. Objectives This study aims to elucidate the potential molecular mechanism by which GPR109A inhibits hepatic DNL. Methods C57BL/6 wild-type (WT) and Gpr109a knockout (KO) mice (male, 5 wk old) were fed a high-fat diet (60% energy from fat) firstly for 6 wk to generate a diet-induced obese model. Subsequently, they were randomly divided into 4 groups for the next 8–9 wk: WT mice with oral water [WT + vehile (VE)], WT mice with oral NA (50 mM, dissolved in water) (WT + NA), KO mice with oral water (KO + VE), and KO mice with oral NA (50 mM) (KO + NA). Mechanisms were examined in HepG2 cells. Body composition, liver histology, biomarkers of hepatic function, lipid accumulation, and lipid synthesis signals in HepG2 cells were measured. Results Upon activation, GPR109A apparently protected against obesity and hepatic steatosis (P < 0.05). The concentrations of hepatic Tnf-α in the WT + NA group were about 50% of those in the WT + VE group (P < 0.05). The activities of serum alanine transaminase and aspartate transaminase were 26.7% and 53.5% lower in the WT + NA group than in the WT + VE group, respectively (P < 0.05). In HepG2 cells, activation of GPR109A resulted in remarkable inhibition of oleic acid–induced lipid accumulation via a protein kinase C–extracellular signal-regulated kinase-1/2–AMP-activated protein kinase signaling pathway. Conclusions NA inhibits hepatic lipogenesis in C57BL/6 mice through a GPR109A-mediated signaling pathway, consistent with the mechanistic studies in HepG2 cells, suggesting its potential for treatment of NAFLD and other fatty liver diseases.

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Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00249.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. G634-G642 ◽

Cited By ~ 85

Author(s):

Zhigang Wang ◽

Tong Yao ◽

Maria Pini ◽

Zhanxiang Zhou ◽

Giamila Fantuzzi ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Control Diet ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Betaine Supplementation

Adipose tissue dysfunction, featured by insulin resistance and/or dysregulated adipokine production, plays a central role not only in disease initiation but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Promising beneficial effects of betaine supplementation on nonalcoholic fatty liver disease (NAFLD) have been reported in both clinical investigations and experimental studies; however, data related to betaine therapy in NAFLD are still limited. In this study, we examined the effects of betaine supplementation on hepatic fat accumulation and injury in mice fed a high-fat diet and evaluated mechanisms underlying its hepatoprotective effects. Male C57BL/6 mice weighing 25 ± 0.5 (SE) g were divided into four groups (8 mice/group) and started on one of four treatments: control diet, control diet supplemented with betaine, high-fat diet, and high-fat diet supplemented with betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Our results showed that long-term high-fat feeding caused NAFLD in mice, which was manifested by excessive neutral fat accumulation in the liver and elevated plasma alanine aminotransferase levels. Betaine supplementation alleviated hepatic pathological changes, which were concomitant with attenuated insulin resistance as shown by improved homeostasis model assessment of basal insulin resistance values and glucose tolerance test, and corrected abnormal adipokine (adiponectin, resistin, and leptin) productions. Specifically, betaine supplementation enhanced insulin sensitivity in adipose tissue as shown by improved extracellular signal-regulated kinases 1/2 and protein kinase B activations. In adipocytes freshly isolated from mice fed a high-fat diet, pretreatment of betaine enhanced the insulin signaling pathway and improved adipokine productions. Further investigation using whole liver tissues revealed that betaine supplementation alleviated the high-fat diet-induced endoplasmic reticulum stress response in adipose tissue as shown by attenuated glucose-regulated protein 78/C/EBP homologous protein (CHOP) protein abundance and c-Jun NH2-terminal kinase activation. Our findings suggest that betaine might serve as a safe and efficacious therapeutic tool for NAFLD by improving adipose tissue function.

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