scholarly journals GLP-1/GLP-1R Signaling in Regulation of Adipocyte Differentiation and Lipogenesis

2017 ◽  
Vol 42 (3) ◽  
pp. 1165-1176 ◽  
Author(s):  
Jicui Chen ◽  
Huichen Zhao ◽  
Xiaoli Ma ◽  
Yuchao Zhang ◽  
Sumei Lu ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Body Weight Gain ◽  
Mapk Signaling ◽  
Marker Genes ◽  
Down Regulation ◽  
Adipose Tissues ◽  
Oil Red O Staining ◽  
Oil Red O

Background/Aims: The aim of this study was to determine the direct role of liraglutide (LG) in adipogenesis and lipid metabolism. Methods: Lipid accumulation was evaluated by oil red O staining, quantitative real-time PCR (qPCR) was performed to determine glucagon-like peptide 1 receptor (GLP-1R), fatty acid synthase (FASN) and adipose triglyceride lipase (ATGL) expression in 3T3-L1 preadipocytes, differentiated adipocytes and in adipose tissues from mice. The effects of LG on 3T3-L1 adipogenesis and lipid metabolism were analyzed with qPCR, Western Blotting, oil red O staining, immunohistochemistry (IHC) and immunofluorescence (IF). All measurements were performed at least three times. Results: LG increased the expression of differentiation marker genes and lipid accumulation during preadipocyte differentiation. In differentiated adipocytes, LG decreased FASN expression, and simultaneously led to CREB phosphorylation and ERK1/2 activation which were abolished by a GLP-1R antagonist, exendin (9-39). LG induced-FASN down-regulation was partially reversed by PKA and ERK1/2 inhibitors. Consistent with above in vitro findings, LG treatment significantly reduced FASN expression in visceral adipose tissues of ob/ob mice, and reduced body weight gain. Conclusion: LG promotes preadipocytes differentiation, and inhibits FASN expression in adipocytes. LG induced down-regulation of FASN is at least partially mediated by PKA and MAPK signaling pathways.

scholarly journals CMO1 Deficiency Abolishes Vitamin A Production from β-Carotene and Alters Lipid Metabolism in Mice

2007 ◽  
Vol 282 (46) ◽  
pp. 33553-33561 ◽  
Author(s):  
Susanne Hessel ◽  
Anne Eichinger ◽  
Andrea Isken ◽  
Jaume Amengual ◽  
Silke Hunzelmann ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Elevated Serum ◽  
Pcr Analysis ◽  
Marker Genes ◽  
Mouse Mutant ◽  
Adipose Tissues ◽  
Β Carotene

Carotenoids are currently investigated regarding their potential to lower the risk of chronic disease and to combat vitamin A deficiency in humans. These plant-derived compounds must be cleaved and metabolically converted by intrinsic carotenoid oxygenases to support the panoply of vitamin A-dependent physiological processes. Two different carotenoid-cleaving enzymes were identified in mammals, the classical carotenoid-15,15′-oxygenase (CMO1) and a putative carotenoid-9′,10′-oxygenase (CMO2). To analyze the role of CMO1 in mammalian physiology, here we disrupted the corresponding gene by targeted homologous recombination in mice. On a diet providing β-carotene as major vitamin A precursor, vitamin A levels fell dramatically in several tissues examined. Instead, this mouse mutant accumulated the provitamin in large quantities (e.g. as seen by an orange coloring of adipose tissues). Besides impairments in β-carotene metabolism, CMO1 deficiency more generally interfered with lipid homeostasis. Even on a vitamin A-sufficient chow, CMO1-/- mice developed a fatty liver and displayed altered serum lipid levels with elevated serum unesterified fatty acids. Additionally, this mouse mutant was more susceptible to high fat diet-induced impairments in fatty acid metabolism. Quantitative reverse transcription-PCR analysis revealed that the expression of peroxisome proliferator-activated receptor γ-regulated marker genes related to adipogenesis was elevated in visceral adipose tissues. Thus, our study identifies CMO1 as the key enzyme for vitamin A production and provides evidence for a role of carotenoids as more general regulators of lipid metabolism.

scholarly journals Fisetin Protects Against Hepatic Steatosis Through Regulation of the Sirt1/AMPK and Fatty Acid β-Oxidation Signaling Pathway in High-Fat Diet-Induced Obese Mice

2018 ◽  
Vol 49 (5) ◽  
pp. 1870-1884 ◽  
Author(s):  
Chian-Jiun Liou ◽  
Ciao-Han Wei ◽  
Ya-Ling Chen ◽  
Ching-Yi Cheng ◽  
Chia-Ling Wang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
Epididymal Adipose Tissue ◽  
Obese Mice ◽  
High Fat

Background/Aims: Fisetin is a naturally abundant flavonoid isolated from various fruits and vegetables that was recently identified to have potential biological functions in improving allergic airway inflammation, as well as anti-oxidative and anti-tumor properties. Fisetin has also been demonstrated to have anti-obesity properties in mice. However, the effect of fisetin on nonalcoholic fatty liver disease (NAFLD) is still elusive. Thus, the present study evaluated whether fisetin improves hepatic steatosis in high-fat diet (HFD)-induced obese mice and regulates lipid metabolism of FL83B hepatocytes in vitro. Methods: NAFLD was induced by HFD in male C57BL/6 mice. The mice were then injected intraperitoneally with fisetin for 10 weeks. In another experiment, FL83B cells were challenged with oleic acid to induce lipid accumulation and treated with various concentrations of fisetin. Results: NAFLD mice treated with fisetin had decreased body weight and epididymal adipose tissue weight compared to NAFLD mice. Fisetin treatment also reduced liver lipid droplet and hepatocyte steatosis, alleviated serum free fatty acid, and leptin concentrations, significantly decreased fatty acid synthase, and significantly increased phosphorylation of AMPKα and the production of sirt-1 and carnitine palmitoyltransferase I in the liver tissue. In vitro, fisetin decreased lipid accumulation and increased lipolysis and β-oxidation in hepatocytes. Conclusion: This study suggests that fisetin is a potential novel treatment for alleviating hepatic lipid metabolism and improving NAFLD in mice via activation of the sirt1/AMPK and β-oxidation pathway.

scholarly journals LncRNA-H19 promotes hepatic lipogenesis by directly regulating miR-130a/PPARγ axis in non-alcoholic fatty liver disease

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Jun Liu ◽  
Tao Tang ◽  
Guo-Dong Wang ◽  
Bo Liu
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Hepatic Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Oil Red O Staining ◽  
Alcoholic Fatty Liver Disease ◽  
Oil Red O ◽  
Liver Tissues

Abstract Background: As one of the most common liver disorders worldwide, non-alcoholic fatty liver disease (NAFLD) begins with the abnormal accumulation of triglyceride (TG) in the liver. Long non-coding RNA-H19 was reported to modulate hepatic metabolic homeostasis in NAFLD. However, its molecular mechanism of NAFLD was not fully clear. Methods: In vitro and in vivo models of NAFLD were established by free fatty acid (FFA) treatment of hepatocytes and high-fat feeding mice, respectively. Hematoxylin and Eosin (H&E) and Oil-Red O staining detected liver tissue morphology and lipid accumulation. Immunohistochemistry (IHC) staining examined peroxisome proliferator-activated receptor γ (PPARγ) level in liver tissues. ELISA assay assessed TG secretion. Luciferase assay and RNA pull down were used to validate regulatory mechanism among H19, miR-130a and PPARγ. The gene expression in hepatocytes and liver tissues was detected by quantitative real-time PCR (qRT-PCR) and Western blotting. Results: H19 and PPARγ were up-regulated, while miR-130a was down-regulated in NAFLD mouse and cellular model. H&E and Oil-Red O staining indicated an increased lipid accumulation. Knockdown of H19 inhibited steatosis and TG secretion in FFA-induced hepatocytes. H19 could bind to miR-130a, and miR-130a could directly inhibit PPARγ expression. Meanwhile, miR-130a inhibited lipid accumulation by down-regulating NAFLD-related genes PPARγ, SREBP1, SCD1, ACC1 and FASN. Overexpression of miR-130a and PPARγ antagonist GW9662 inhibited lipogenesis and TG secretion, and PPARγ agonist GW1929 reversed this change induced by miR-130a up-regulation. Conclusion: Knockdown of H19 alleviated hepatic lipogenesis via directly regulating miR-130a/PPARγ axis, which is a novel mechanistic role of H19 in the regulation of NAFLD.

scholarly journals Korean Traditional Fermented Soybean Paste (Doenjang) Regulate Renin-Angiotensin System (RAS) in 3T3-L1 Adipocytes

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 791-791
Author(s):  
Hayoung Woo ◽  
Jung Eun Park ◽  
Youn-Soo Cha
Keyword(s):  
Blood Pressure ◽  
Lipid Accumulation ◽  
Lipid Droplets ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Fermented Soybean ◽  
Soybean Paste ◽  
Oil Red O Staining ◽  
Oil Red O

Abstract Objectives Doenjang, the Korean traditional fermented soybean paste, contains much salt. There is a concern that cardiovascular disease may occur due to such high salinity. Nevertheless, previous studies have demonstrated functional properties of doenjang anti-obesity and anti-cancer effects. Furthermore, in our recent studies, we showed that the anti-hypertensive effect of doenjang through renin-angiotensin system (RAS) regulation. Doenjang regulated the RAS to improve lipid metabolism in adipose tissue, which had a positive effect on blood pressure control. Therefore, we expected to find the exact mechanism of action or target point of doenjang in adipocyte using 3T3-L1 cells. Methods In this study, 3T3-L1 cells were treated with doenjang and RAS blockers, Losartan (10−4 M), and Captopril (10−4 M), were treated as positive control which suppresses AT1R and ACE, respectively. Non-cytotoxic concentrations of samples were selected as per MTT assay and added with induction media, harvested after 4 days for RNA extraction. Lipid droplets were detected by Oil Red O staining. Results Doenjang downregulated mRNA levels of peroxisome proliferator-activated receptor-γ (Pparg), RAS related genes such as angiotensinogen (Agt), Renin (Ren), and aldosterone-releasing factors (P < 0.05). Especially, angiotensin convert enzyme (Ace) and angiotensin II receptor 2 (Agtr2) levels were decreased by doenjang treatment. Doenjang reduced the lipid accumulation, which was confirmed from the Oil Red O staining of lipid droplets. As a result, it is revealed that doenjang not only inhibits lipid accumulation in adipocytes but also may inhibit ACE in 3T3-L1 adipocytes through a mechanism similar to the effect of Captopril. Conclusions These data are consistent with our animal study. It have been shown to regulate blood pressure through lipid improvement and ACE inhibition despite high salt content in doenjang. Funding Sources This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) (No. 2018R1A2B6006477).

scholarly journals Mechanism of lncRNA H19 in the Regulation of Lipid Accumulation and Inflammatory Response in Macrophages

2020 ◽  
Author(s):  
Xue-Mei Wang ◽  
Xiao-Ming Gao ◽  
Fen Liu ◽  
Ying Cao ◽  
Jie-Ying Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Lipid Accumulation ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Cholesterol Concentration ◽  
Abca1 Expression ◽  
Intracellular Lipid Accumulation ◽  
Oil Red O Staining ◽  
Oil Red O

Abstract Background and aims: Lipid accumulation of macrophages caused by oxidative stress is the key reason for the early pathological changes of atherosclerosis. LncRNA H19 repression downregulated NF-κB activation, upregulated ABCA1 expression, intracellular lipid accumulation increased, but the role of lncRNA H19 in atherogenesis and the molecular mechanisms have not been defined. We aimed to explore if and how lncRNA H19 affects lipid accumulation of macrophages by regulating lipid metabolism and inflammatory response.Methods and results: THP-1 macrophages were cultured with ox-LDL to form foam cells. THP-1-derived macrophages were incubated with H19 siRNA or not. Oil Red O staining was used for the determination lipid accumulation in macrophages. Enzymatic methods were performed to analyze cholesterol concentration. Both western blot and qRT-PCR were applied to detect target gene expression. ELISA was used to examine the levels of oxidative and inflammatory mediators. We found that lncRNA H19 repression reduced lipid accumulation by elevating efficiency of RCT and via upregulation of ABCA1 and PPARα expression in THP-1 derived macrophages. Further, lncRNA H19 repression upregulated PGC-1α and downregulated NF-κB signaling pathway.Conclusion: These results suggest that lncRNA H19 repression inhibits atherosclerosis by promoting RCT process and reducing inflammatory response via PGC-1α and NF-κB pathways, respectively.

scholarly journals Embryonic cardiospecific knockout of α-E-catenin gene leads to alteration of energy metabolism in adult heart

2017 ◽  
Vol 23 (2) ◽  
pp. 65-69
Author(s):  
V. Balatskyy ◽  
L. Macewicz ◽  
O. Piven
Keyword(s):  
Lipid Metabolism ◽  
Energy Metabolism ◽  
Transgenic Mice ◽  
Lipid Droplets ◽  
Metabolic Disorders ◽  
Conditional Knockout ◽  
Heart Hypertrophy ◽  
Oil Red O Staining ◽  
Oil Red O

Previously we have shown that the α-E-catenin knockout in the embryonic heart leads to hypertrophy in adult and activation of canonical Wntsignaling. Heart hypertrophy is also accompanied by metabolic disorders, but role of the α-E-catenin in these processes is not known. Aim of our work is to study the effect of α-E-catenin deletion on the lipid metabolism in the heart. Methods. In our experiment we have used α-Е-catenin conditional knockout and αMHC-Cre transgenic mice. We have utilized histological (Oil Red O staining) and molecular biological (Western blot) methods. Results. α-Е-catenin deletion leads to accumulation of lipid droplets in myocardium, and to violation of expression and phosphorylation of key regulators of lipid metabolism (Ampk, Pparα, Acc, Hsl). Conclusions. Ous results suggest that α-Е-catenin deletion leads to inhibition of lipid metabolism in the heart.

scholarly journals Inhibitory Effects of Pinostilbene on Adipogenesis in 3T3-L1 Adipocytes: A Study of Possible Mechanisms

2021 ◽  
Vol 22 (24) ◽  
pp. 13446
Author(s):  
You Chul Chung ◽  
Chang-Gu Hyun
Keyword(s):  
Fatty Acid Synthase ◽  
Structural Instability ◽  
Inhibitory Effects ◽  
Ampk Signaling ◽  
Anticancer Effects ◽  
Effects Of Ph ◽  
Insulin Dependent ◽  
Oil Red O Staining ◽  
Resveratrol Derivative ◽  
Oil Red O

Resveratrol is a phytoalexin with multiple bioactive properties, including antioxidative, neuroprotective, cardioprotective, and anticancer effects. However, resveratrol exhibits structural instability in response to UV irradiation, alkaline pH, and oxygen exposure. Thus, resveratrol derivatives have attracted considerable research interest. In this study, we aimed to evaluate the anti-adipogenic effects of pinostilbene hydrate (PH), a methylated resveratrol derivative, in 3T3-L1 cells. We also evaluated the mechanisms underlying the effects of PH on adipogenesis in 3T3-L1 adipocytes. Oil Red O staining, lipid accumulation assay, and triglyceride (TG) content assay revealed that PH significantly inhibited lipid and TG accumulation without cytotoxicity. In addition, we determined that PH decreased the expression of adipogenesis-related transcription factors, such as PPARγ, C/EBPα, SREBP-1c, and FABP4, and the phosphorylation of MAPK and protein kinase B (AKT). Moreover, PH attenuated the expression of CREB and C/EBPβ, while increasing the phosphorylation of AMPK and ACC, and decreasing the expression of fatty acid synthase and FABP4. Based on these results, we suggest that PH suppresses adipogenesis in 3T3-L1 cells via the activation of the AMPK signaling pathway and the inhibition of the MAPK and AKT insulin-dependent signaling pathways.

scholarly journals Inhibition of lipogenesis and induction of apoptosis by valproic acid in prostate cancer cells via the C/EBPα/SREBP-1 pathway

2020 ◽  
Author(s):  
Bo Pang ◽  
Juanjuan Zhang ◽  
Jihong Yuan ◽  
Yanan Shi ◽  
Ling Qiao
Keyword(s):  
Prostate Cancer ◽  
Valproic Acid ◽  
Lipid Metabolism ◽  
Cell Viability ◽  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Statistical Significance ◽  
Analytical Data ◽  
B Cell Lymphoma

Abstract Background Lipid metabolism reprogramming is now accepted as a new hallmark of cancer. Hence, targeting the lipogenesis pathway may be a promising avenue for cancer treatment. Valproic acid (VPA) emerges as a promising drug for cancer therapy, however, the underlying mechanisms are not yet fully understood. This study aimed to investigate the effects and mechanism of VPA on cell viability, lipogenesis, and apoptosis in human prostate cancer PC-3 cells.Methods The effects of VPA on the viability of PC-3 cells were investigated using MTT assay and wound-healing assay. Oil Red O staining was used to examine lipid droplets, and DAPI staining assay and Annexin V-PI staining assay were used to measure the extent of cell apoptosis. Quantitative real-time PCR and Western blotting were used to determine the expression of lipogenesis and apoptosis genes. Statistical and analytical data with SPSS 17.0 Software, statistical significance was set at *P < 0.05, **P < 0.01, and ***P < 0.001 levels.Results The results showed that VPA significantly reduced lipid accumulation and induced apoptosis of PC-3 cells. Moreover, the expression of CCAAT/enhancer-binding protein α (C/EBPα), as well as sterol regulatory element-binding protein 1 (SREBP-1) and its downstream effectors, including fatty acid synthase (FASN), acetyl CoA carboxylase 1 (ACC1), and antiapoptotic B cell lymphoma 2 (Bcl-2), markedly decreased in PC-3 cells after VPA administration. Mechanistically, the overexpression of C/EBPα rescued the levels of SREBP-1, FASN, ACC1, and Bcl-2, enhanced lipid accumulation and attenuated apoptosis of VPA-treated PC-3 cells. Conversely, C/EBPα knockdown by siRNA further decreased the levels of SREBP-1, FASN, ACC1, and Bcl-2 and lipid accumulation and enhanced apoptosis. In addition, SREBP-1a and 1c enhanced the expression of FASN and ACC1, but only SREBP-1a had a significant effect on Bcl-2 expression in VPA-treated PC-3 cells.ConclusionsOn the whole, it is concluded that VPA significantly inhibits cell viability via inhibiting lipogenesis and inducing apoptosis by the C/EBPα/SREBP-1 pathway in PC-3 cells. Hence, VPA, which targets lipid metabolism and apoptosis, is a promising candidate for PCa chemotherapy.

scholarly journals PSXI-27 Association of an increased marbling score by dietary glycerol supplementation with lipid metabolism gene expression in Korean cattle steers

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 383-384
Author(s):  
Seon Pil Yoo ◽  
Dilla Fassah ◽  
Myunggi Baik ◽  
sang Weon Na ◽  
Inhyuk Jeong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Mrna Levels ◽  
Lipid Uptake ◽  
Marbling Score ◽  
Adipose Tissues ◽  
Korean Cattle ◽  
Subcutaneous Adipose

Abstract This study investigated effects of dietary glycerol supplementation on liver, muscle, and adipose gene expression related with gluconeogenesis and lipid metabolism and association of gene expression levels with marbling score in Korean cattle steers. Fourteen Korean cattle steers (average age 28.4 months; average body weight 733 kg) were equally assigned to two groups (0 and 5% glycerol supplementation). Glycerol was provided with glycerol (63%)-adsorbed ground wheat bran (37%, DM) by top dressing during roughage feeding. A concentrate (1.2% of body weight) and 1.0 kg of ryegrass were individually fed twice daily. After four months of study, steers were slaughtered, and marbling score was evaluated. Longissimus thoracis (LT) and subcutaneous adipose tissue at the 13th thoracic vertebra area and liver were collected and analyzed for mRNA levels by quantitative real-time PCR. Statistical significance was analyzed by analysis of variance. Correlations were analyzed using Pearson’s correlation analysis. Glycerol supplementation increased (P = 0.01) marbling score. In the LT, glycerol supplementation tended to increase (0.05 &lt; P ≤ 0.10) lipid uptake CD36 and lipoprotein lipase (LPL) mRNA levels. In subcutaneous adipose tissues, glycerol supplementation increased (P ≤ 0.05) LPL, adipogenic sterol regulatory element binding protein 1 (SREBP1), and lipogenic acetyl CoA carboxylase (ACC) mRNA levels and tended to increase (0.05 &lt; P &lt; 0.10) CD36, adipogenic peroxisome proliferator-activated gamma (PPARG), and lipogenic fatty acid synthase (FASN) expression. It did not affect (P &gt; 0.05) mRNA levels of hepatic gluconeogenesis genes. Marbling score showed significant positive correlations (0.57 &lt; r &lt; 0.68; P &lt; 0.05) with mRNA levels of several genes including LPL, PPARG, SREBP1, and ACC in adipose tissues, but not with any genes examined in the LT. Our study demonstrates that lipid uptake, adipogenesis and lipogenesis may mainly contribute to the increased marbling score by glycerol supplementation.

Abstract 13671: GSK-3α Directly Regulates Lipid Metabolism Through Obesity-linked Phosphorylation of PPARα

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Michinari Nakamura ◽  
Peiyong Zhai ◽  
Tong Liu ◽  
Hong Li ◽  
Junichi Sadoshima
Keyword(s):  
Lipid Metabolism ◽  
Cardiac Dysfunction ◽  
Lipid Accumulation ◽  
Glycogen Synthase ◽  
Body Weight Gain ◽  
Glycogen Synthesis ◽  
Mass Spectrometry Analysis ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Peroxisome Proliferator Activated Receptor

Obesity impairs lipid metabolism and leads to cardiac dysfunction, where peroxisome proliferator-activated receptor α (PPARα) serves as a key regulator of lipid metabolism. Glycogen synthase kinase-3α (GSK-3α), a serine-threonine kinase, is markedly upregulated in the heart of obese mice, suppressing glycogen synthesis. However, the functional significance of upregulated GSK-3α in lipid metabolism remains unknown. Here we show that GSK-3α directly upregulates lipid metabolism and aggravates cardiac lipotoxicity in obesity. GSK-3α activity was enhanced by palmitic acid (PA) in the nucleus in cardiomyocytes (CMs), and knockdown of GSK-3α suppressed PA-induced activation of PPARα. GSK-3α, but not GSK-3β, directly interacted with PPARα. Mass spectrometry analysis revealed that GSK-3α phosphorylates PPARα at Ser280, located in the ligand binding domain. A PPARα phospho-mimicking mutant (PPARα-S280D) exhibited an increase in both the interaction of PPARα with RXR and its DNA binding, enhancing PPARα activity and stimulating expression of lipid metabolism-related genes, including Cpt1b, CD36 and PDHK4, in CMs. High-fat diet (HFD)-fed mice displayed increased GSK-3α activity and PPARα phosphorylation in the heart. Cardiac-specific haploinsufficiency of GSK-3α normalized HFD-induced lipid accumulation (Oil Red O staining), abnormally enhanced palmitate oxidation (0.82 fold, p<0.05), cardiac hypertrophy and diastolic dysfunction (0.36 fold in EDPVR, p<0.05) without affecting body weight gain or food intake. While adenovirus-mediated overexpression of PPARα in the heart exacerbated HFD-induced lipid dysregulation and cardiac dysfunction, that of PPARα phospho-resistant mutant (PPARα-S280A) failed to facilitate lipid metabolism and cardiac dysfunction in the presence of a HFD. Notably, a PPARα ligand, fenofibrate, allosterically inhibited PPARα phosphorylation in obese mice by interfering with the interaction between GSK-3α and PPARα, and improved HFD-induced lipid accumulation and cardiac dysfunction. These data show that GSK-3α directly regulates lipid metabolism through Ser280 phosphorylation of PPARα, and that its phosphorylation could be a novel therapeutic target for obesity-related cardiac dysfunction.

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