Liraglutide suppresses obesity and promotes browning of white fat via miR-27b in vivo and in vitro

Objective To investigate the effect of liraglutide on the browning of white fat and the suppression of obesity via regulating microRNA (miR)-27b in vivo and in vitro. Methods Sprague-Dawley rats were fed a high-fat (HF) diet and 3T3-L1 pre-adipocytes were differentiated into mature white adipocytes. Rats and mature adipocytes were then treated with different doses of liraglutide. The mRNA and protein levels of browning-associated proteins, including uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), CCAAT enhancer binding protein β (CEBPβ), cell death-inducing DFFA-like effector A (CIDEA) and peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α), were detected using quantitative real-time polymerase chain reaction and Western blotting. Results Liraglutide decreased body weight and reduced the levels of blood glucose, triglyceride and low-density lipoprotein cholesterol in HF diet-fed rats. Liraglutide increased the levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α in vivo and vitro. The levels of miR-27b were upregulated in HF diet-fed rats, whereas liraglutide reduced the levels of miR-27b. In vitro, overexpression of miR-27b decreased the mRNA and protein levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α. Transfection with the miR-27b mimics attenuated the effect of liraglutide on the browning of white adipocytes. Conclusion Liraglutide induced browning of white adipose through regulation of miR-27b.

Download Full-text

C/EBPα and the Corepressors CtBP1 and CtBP2 Regulate Repression of Select Visceral White Adipose Genes during Induction of the Brown Phenotype in White Adipocytes by Peroxisome Proliferator-Activated Receptor γ Agonists

Molecular and Cellular Biology ◽

10.1128/mcb.01899-08 ◽

2009 ◽

Vol 29 (17) ◽

pp. 4714-4728 ◽

Cited By ~ 125

Author(s):

Cecile Vernochet ◽

Sidney B. Peres ◽

Kathryn E. Davis ◽

Meghan E. McDonald ◽

Li Qiang ◽

...

Keyword(s):

Acute Phase Proteins ◽

Peroxisome Proliferator ◽

Direct Role ◽

Peroxisome Proliferator Activated Receptor ◽

White Adipocyte ◽

White Adipocytes ◽

Carboxy Terminal ◽

White Fat

ABSTRACT White adipose tissue (WAT) stores energy in the form of triglycerides, whereas brown tissue (BAT) expends energy, primarily by oxidizing lipids. WAT also secretes many cytokines and acute-phase proteins that contribute to insulin resistance in obese subjects. In this study, we have investigated the mechanisms by which activation of peroxisome proliferator-activated receptor γ (PPARγ) with synthetic agonists induces a brown phenotype in white adipocytes in vivo and in vitro. We demonstrate that this phenotypic conversion is characterized by repression of a set of white fat genes (“visceral white”), including the resistin, angiotensinogen, and chemerin genes, in addition to induction of brown-specific genes, such as Ucp-1. Importantly, the level of expression of the “visceral white” genes is high in mesenteric and gonadal WAT depots but low in the subcutaneous WAT depot and in BAT. Mutation of critical amino acids within helix 7 of the ligand-binding domain of PPARγ prevents inhibition of visceral white gene expression by the synthetic agonists and therefore shows a direct role for PPARγ in the repression process. Inhibition of the white adipocyte genes also depends on the expression of C/EBPα and the corepressors, carboxy-terminal binding proteins 1 and 2 (CtBP1/2). The data further show that repression of resistin and angiotensinogen expression involves recruitment of CtBP1/2, directed by C/EBPα, to the minimal promoter of the corresponding genes in response to the PPARγ ligand. Developing strategies to enhance the brown phenotype in white adipocytes while reducing secretion of stress-related cytokines from visceral WAT is a means to combat obesity-associated disorders.

Download Full-text

The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00195.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. L881-L891 ◽

Cited By ~ 34

Author(s):

Bum-Yong Kang ◽

Jennifer M. Kleinhenz ◽

Tamara C. Murphy ◽

C. Michael Hart

Keyword(s):

Transcription Factors ◽

Hypoxia Inducible Factor ◽

Cell Counting ◽

Mouse Lung ◽

Therapeutic Effects ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels

Peroxisome proliferator-activated receptor (PPAR) γ activation attenuates hypoxia-induced pulmonary hypertension (PH) in mice. The current study examined the hypothesis that PPARγ attenuates hypoxia-induced endothelin-1 (ET-1) signaling to mediate these therapeutic effects. To test this hypothesis, human pulmonary artery endothelial cells (HPAECs) were exposed to normoxia or hypoxia (1% O2) for 72 h and treated with or without the PPARγ ligand rosiglitazone (RSG, 10 μM) during the final 24 h of exposure. HPAEC proliferation was measured with MTT assays or cell counting, and mRNA and protein levels of ET-1 signaling components were determined. To explore the role of hypoxia-activated transcription factors, selected HPAECs were treated with inhibitors of hypoxia-inducible factor (HIF)-1α (chetomin) or nuclear factor (NF)-κB (caffeic acid phenethyl ester, CAPE). In parallel studies, male C57BL/6 mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 wk with or without gavage with RSG (10 mg·kg−1·day−1) for the final 10 days of exposure. Hypoxia increased ET-1, endothelin-converting enzyme-1, and endothelin receptor A and B levels in mouse lung and in HPAECs and increased HPAEC proliferation. Treatment with RSG attenuated hypoxia-induced activation of HIF-1α, NF-κB activation, and ET-1 signaling pathway components. Similarly, treatment with chetomin or CAPE prevented hypoxia-induced increases in HPAEC ET-1 mRNA and protein levels. These findings indicate that PPARγ activation attenuates a program of hypoxia-induced ET-1 signaling by inhibiting activation of hypoxia-responsive transcription factors. Targeting PPARγ represents a novel therapeutic strategy to inhibit enhanced ET-1 signaling in PH pathogenesis.

Download Full-text

A Study on the Anti-obesity Effect of Caffeoylquinic Acids From the Cell Culture of Saussurea Involucrata

10.21203/rs.3.rs-406894/v1 ◽

2021 ◽

Author(s):

Changjie Bao ◽

Jupeng Gao ◽

Yonghong Zhang ◽

Peng Wang ◽

Guang Chen ◽

...

Keyword(s):

Fatty Acid Synthase ◽

Digestive Enzyme ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Peroxisome Proliferator Activated Receptor ◽

Saussurea Involucrata ◽

Caffeoylquinic Acids

Abstract Backgroud: Saussurea involucrata Kar. et Kir. (Compositae) (CCSauI) cells are rich in caffeoylquinic acids (CQAs), which have plasma lipid reducing properties and anti-obesity effects, although the mechanisms remain unclear. Clarify CQA’s anti-obesity mechanism and provide new treatments for obesity. Methods: Sprague Dawley (SD) rat were fed a high-fat diet (HFD), then CQAs was intragastric administrated (0.1, 0.5 or 1 mg/mL). Rats were randomly divided into five groups (n=30): NC, MC, TPL (0.1 mg/mL), TPM (0.5 mg/mL) and TPH (1 mg/mL). Digestive enzyme inhibition was obtained by measuring the inhibition rate of α-amylase, α-glucosidase, and pancreatic lipase in vitro. Anti-obesity function was detected by determining the content of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), malondialdehyde (MDA) superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). To analyze the related mechanisms qRT-PCR was employed. Results: From in vitro enzyme activity assays, the IC50 values of the CQAs extract for α-amylase, α-glucosidase, and lipase were 0.631, 0.31, and 0.438 mg/mL, respectively. CQAs administration for 8 weeks decreased retroperitoneal fat and serum and liver TC, TG, LDL-C, and MDA. Comparatively, levels of HDL-C, SOD, and GSH-Px were increased. Real-time fluorescent quantitative PCR showed inhibited expression of fatty acid synthase and 3-hydroxy-3-methyl glutaryl and coenzyme A reductase, peroxisome proliferator-activated receptor-α activation, and 7α-hydroxylase promotion. Conclusion: This study explored the role of CQAs in inhibiting digestive enzyme activities and up-regulating the expression of lipase, significant for prevention and treatment of diabetes and obesity.

Download Full-text

Fruit of Gardenia jasminoides Induces Mitochondrial Activation and Non-Shivering Thermogenesis through Regulation of PPARγ

Antioxidants ◽

10.3390/antiox10091418 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1418

Author(s):

Woo Yong Park ◽

Gahee Song ◽

Ja Yeon Park ◽

Kwan-Il Kim ◽

Kwang Seok Ahn ◽

...

Keyword(s):

Uncoupling Protein ◽

Exposure Model ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Gardenia Jasminoides ◽

White Adipocytes ◽

Beige Adipocytes ◽

Underlying Mechanisms ◽

Induced Changes

The extract of the Gardenia jasminoides fruit (GJFE) can been consumed as an herbal tea or used as a yellow dye. Recently, studies report that GFJE exerts inhibitory effects on lipid accumulation and adipogenesis in white adipocytes. We evaluated the thermogenic actions of GJFE by focusing on mitochondrial activation and studying the underlying mechanisms. To investigate the role of GJFE on thermogenesis in mice, we used an acute cold exposure model. After 2 weeks of feeding, the cold tolerance of GJFE-fed mice was notably increased compared to PBS-fed mice. This was due to an increase in thermogenic proteins in the inguinal white adipose tissue of the cold-exposed mice. Moreover, GJFE significantly increased thermogenic factors such as peroxisome proliferator-activated receptor gamma (PPARγ), uncoupling protein 1 (UCP1), and PPARγ coactivator 1 alpha (PGC1α) in vitro as well. Factors related to mitochondrial abundance and functions were also induced by GJFE in white and beige adipocytes. However, the treatment of PPARγ inhibitor abolished the GJFE-induced changes, indicating that activation of PPARγ is critical for the thermogenic effect of GJFE. In conclusion, GJFE induces thermogenic action by activating mitochondrial function via PPARγ activation. Through these findings, we suggest GJFE as a potential anti-obesity agent with a novel mechanism involving thermogenic action in white adipocytes.

Download Full-text

Ultrasound-targeted simvastatin-loaded microbubble destruction promotes OA cartilage repair by modulating the cholesterol efflux pathway mediated by PPARγ in rabbits

Bone and Joint Research ◽

10.1302/2046-3758.1010.bjr-2021-0162.r3 ◽

2021 ◽

Vol 10 (10) ◽

pp. 693-703

Author(s):

Xinwei Wang ◽

Danbi Wang ◽

Peng Xia ◽

Kai Cheng ◽

Qi Wang ◽

...

Keyword(s):

Cholesterol Efflux ◽

Density Lipoprotein ◽

Peroxisome Proliferator ◽

Efflux Rate ◽

Peroxisome Proliferator Activated Receptor ◽

Oa Chondrocytes ◽

Collagen Ii ◽

Efflux Pathway

Aims To evaluate the effect of ultrasound-targeted simvastatin-loaded microbubble destruction (UTMD SV ) for alleviation of the progression of osteoarthritis (OA) in rabbits through modulation of the peroxisome proliferator-activated receptor (PPARγ). Methods In vitro, OA chondrocytes were treated with ultrasound (US), US-targeted microbubble destruction (UTMD), simvastatin (SV), and UTMD SV on alternate days for four weeks. Chondrocytes were also treated with PPARγ inhibitor, PPARγ inhibitor+ UTMD SV , and UTMD SV . The cholesterol efflux rate and triglyceride levels were measured using an assay kit and oil red O staining, respectively. In vivo, the OA rabbits were treated with a single intra-articular injection of UTMD, SV, and UTMD SV every seven days for four weeks. Cartilage histopathology was assessed by safranin-O staining and the Mankin score. Total cholesterol (TC) and high-density lipoprotein-cholesterol (HDL-C) in rabbit knee synovial fluid were detected by enzyme-marker assay. Aggrecan, collagen II, and PPARγ expression levels were analyzed by Western blotting (WB). Results In vitro, UTMD SV significantly increased the cholesterol efflux rate and aggrecan, collagen II, and PPARγ levels in OA chondrocytes; these effects were blocked by the PPARγ inhibitor. In vivo, UTMD SV significantly increased aggrecan, collagen II, PPARγ, and HDL-C levels, while TC levels and Mankin scores were decreased compared with the UTMD, SV, OA, and control groups. Conclusion UTMD SV promotes cartilage extracellular matrix synthesis by modulating the PPARγ-mediated cholesterol efflux pathway in OA rabbits. Cite this article: Bone Joint Res 2021;10(10):693–703.

Download Full-text

Effects and Mechanism of Chlorogenic Acid on Weight Loss

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200318124922 ◽

2020 ◽

Vol 21 (11) ◽

pp. 1099-1106 ◽

Cited By ~ 1

Author(s):

Yanchun Zhong ◽

Yueling Ding ◽

Laiqing Li ◽

Meina Ge ◽

Guangguo Ban ◽

...

Keyword(s):

Mouse Model ◽

Chlorogenic Acid ◽

Hepg2 Cells ◽

Uncoupling Protein ◽

Monosodium Glutamate ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Fat Reduction

Background: Chlorogenic Acid (CA) has diverse, recognized health effects. Objective: This study aimed to explore the effects of CA on fat reduction and the underlying mechanism of these effects. Materials and Methods: First, we established a Monosodium Glutamate (MSG)-induced obesity mouse model and subjected the mice to 4 weeks of CA gavage. Then, we established an oleic acidinduced model of human fatty liver in HepG2 cells, and administered a CA intervention to the cells for 48 h. Finally, we used Oil red O staining, biochemical detection kits, RT-PCR and Western blot analysis to evaluate the effects of CA on fat reduction and on related pathways. Results: The CA treatment could reduce fat accumulation in the liver and reduce blood lipid levels. In addition, CA decreased the mRNA and protein levels of peroxisome proliferator-activated receptor gamma, coactivator 1 α (PGC-1α) and Uncoupling Protein 1 (UCP1) in the MSG-induced obesity mouse model and the oleic acid-induced HepG2 cells. Conclusion: Based on the above results, we deduced that CA could reduce body weight and fat deposition in vitro and in vivo and that the mechanism may be related to the PGC-1α/UCP-1 pathway. CA can be developed as a drug to lower blood lipids and to treat obesity.

Download Full-text

Labisia pumilaUpregulates Peroxisome Proliferator-Activated Receptor Gamma Expression in Rat Adipose Tissues and 3T3-L1 Adipocytes

Advances in Pharmacological Sciences ◽

10.1155/2013/808914 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7

Author(s):

Fazliana Mansor ◽

Harvest F. Gu ◽

Claes-Göran Östenson ◽

Louise Mannerås-Holm ◽

Elisabet Stener-Victorin ◽

...

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary ◽

Mrna Level ◽

Water Extract ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that regulates lipid and glucose metabolism. We investigated the effects ofLabisia pumila(LP) standardized water extract on PPARgamma transcriptional activity in adipocytesin vitroandin vivo. We used a rat model of dihydrotestosterone- (DHT-) induced polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance. At 9 weeks of age, the PCOS rats were randomly subdivided into two groups: PCOS-LP (50 mg/kg/day of LP) and PCOS-control (1 mL of deionised water) for 4-5 weeks on the same schedule. Real-time RT-PCR was performed to determine the PPARgamma mRNA levels. LP upregulated PPARgamma mRNA level by 40% in the PCOS rats. Western blot analysis further demonstrated the increased PPARgamma protein levels in parallel with upregulation in mRNA. These observations were further proven by adipocytes culture. Differentiated 3T3-L1 adipocytes were treated with final concentration of 100 μg/mL LP and compared to untreated control and 10 μM of rosiglitazone (in type of thiazolidinediones). LP increased PPARgamma expressions at both mRNA and protein levels and enhanced the effect of glucose uptake in the insulin-resistant cells. The data suggest that LP may ameliorate insulin resistance in adipocytes via the upregulation of PPARgamma pathway.

Download Full-text

Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0300317 ◽

2003 ◽

Vol 30 (3) ◽

pp. 317-329 ◽

Cited By ~ 27

Author(s):

KS Frederiksen ◽

EM Wulf ◽

K Wassermann ◽

P Sauerberg ◽

J Fleckner

Keyword(s):

Insulin Resistance ◽

Tyrosine Phosphatase ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

High Fat ◽

Transcriptional Responses ◽

Ppar Alpha ◽

Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor (PPAR)-alpha controls the expression of multiple genes involved in lipid metabolism, and activators of PPAR-alpha, such as fibrates, are commonly used drugs in the treatment of hypertriglyceridemia and other dyslipidemic states. Recent data have also suggested a role for PPAR-alpha in insulin resistance and glucose homeostasis. In the present study, we have assessed the transcriptional and physiological responses to PPAR-alpha activation in a diet-induced rat model of insulin resistance. The two PPAR-alpha activators, fenofibrate and Wy-14643, were dosed at different concentrations in high-fat fed Sprague-Dawley rats, and the transcriptional responses were examined in liver using cDNA microarrays. In these analyses, 98 genes were identified as being regulated by both compounds. From this pool of genes, 27 correlated to the observed effect on plasma insulin, including PPAR-alpha itself and the leukocyte antigen-related protein tyrosine phosphatase (PTP-LAR). PTP-LAR was downregulated by both compounds, and showed upregulation as a result of the high-fat feeding. This regulation was also observed at the protein level. Furthermore, downregulation of PTP-LAR by fenofibric acid was demonstrated in rat FaO hepatoma cells in vitro, indicating that the observed regulation of PTP-LAR by fenofibrate and Wy-14643 in vivo is mediated as a direct effect of the PPAR agonists on the hepatocytes. PTP-LAR is one of the first genes involved in insulin receptor signaling to be shown to be regulated by PPAR-alpha agonists. These data suggest that factors apart from skeletal muscle lipid supply may influence PPAR-alpha-mediated amelioration of insulin resistance.

Download Full-text

Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

Download Full-text

The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽

10.1186/s12885-021-08417-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei Zhu ◽

Hongyang Zhao ◽

Fenfen Xu ◽

Bin Huang ◽

Xiaojing Dai ◽

...

Keyword(s):

Noncoding Rna ◽

Glioma Cells ◽

Lipid Lowering ◽

Fibric Acid Derivative ◽

Peroxisome Proliferator ◽

Glioma Invasion ◽

Peroxisome Proliferator Activated Receptor ◽

Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

Download Full-text