The Farnesoid X Receptor Regulates Adipocyte Differentiation and Function by Promoting Peroxisome Proliferator-activated Receptor-γ and Interfering with the Wnt/β-Catenin Pathways

Abstract The serum and glucocorticoid-inducible kinase 1 (SGK1) is an inducible kinase the physiological function of which has been characterized primarily in the kidney. Here we show that SGK1 is expressed in white adipose tissue and that its levels are induced in the conversion of preadipocytes into fat cells. Adipocyte differentiation is significantly diminished via small interfering RNA inhibition of endogenous SGK1 expression, whereas ectopic expression of SGK1 in mesenchymal precursor cells promotes adipogenesis. The SGK1-mediated phenotypic effects on differentiation parallel changes in the mRNA levels for critical regulators and markers of adipogenesis, such as peroxisome proliferator-activated receptor γ, CCAAT enhancer binding protein α, and fatty acid binding protein aP2. We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1−/− cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone. Together these results show that SGK1 influences adipocyte differentiation by regulating Foxo1 phosphorylation and reveal a potentially important function for this kinase in the control of fat mass and function.

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PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer

Oncogene ◽

10.1038/s41388-021-01707-7 ◽

2021 ◽

Vol 40 (13) ◽

pp. 2355-2366

Author(s):

Laura C. A. Galbraith ◽

Ernest Mui ◽

Colin Nixon ◽

Ann Hedley ◽

David Strachan ◽

...

Keyword(s):

Prostate Cancer ◽

Mitochondrial Biogenesis ◽

Nuclear Export ◽

Epithelial To Mesenchymal Transition ◽

Ppar Gamma ◽

Peroxisome Proliferator ◽

Serine Threonine Kinase ◽

Peroxisome Proliferator Activated Receptor ◽

Mesenchymal Transition ◽

And Function

AbstractPeroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.

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The Potential Applications of Peroxisome Proliferator-Activated ReceptorδLigands in Assisted Reproductive Technology

PPAR Research ◽

10.1155/2008/794814 ◽

2008 ◽

Vol 2008 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Jaou-Chen Huang

Keyword(s):

Assisted Reproductive Technology ◽

Reproductive Function ◽

Reproductive Technology ◽

Embryonic Cell ◽

Preimplantation Embryos ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Potential Applications ◽

And Function

Peroxisome proliferator-activated receptorδ(PPARδ, also known as PPARβ) has ubiquitous distribution and extensive biological functions. The reproductive function of PPARδwas first revealed in the uterus at the implantation site. Since then, PPARδand its ligand have been discovered in all reproductive tissues, including the gametes and the preimplantation embryos. PPARδin preimplantation embryos is normally activated by oviduct-derived PPARδligand. PPARδactivation is associated with an increase in embryonic cell proliferation and a decrease in programmed cell death (apoptosis). On the other hand, the role of PPARδand its ligand in gamete formation and function is less well understood. This review will summarize the reproductive functions of PPARδand project its potential applications in assisted reproductive technology.

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Licochalcone A Prevents Adipocyte Differentiation and Lipogenesis via Suppression of Peroxisome Proliferator-Activated Receptor γ and Sterol Regulatory Element-Binding Protein Pathways

Journal of Agricultural and Food Chemistry ◽

10.1021/jf2050763 ◽

2012 ◽

Vol 60 (20) ◽

pp. 5112-5120 ◽

Cited By ~ 16

Author(s):

Hai-Yan Quan ◽

Nam In Baek ◽

Sung Hyun Chung

Keyword(s):

Adipocyte Differentiation ◽

Binding Protein ◽

Regulatory Element ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Licochalcone A ◽

Element Binding Protein ◽

Sterol Regulatory Element

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Lysophosphatidic Acid Inhibits Adipocyte Differentiation via Lysophosphatidic Acid 1 Receptor-dependent Down-regulation of Peroxisome Proliferator-activated Receptor γ2

Journal of Biological Chemistry ◽

10.1074/jbc.m412585200 ◽

2005 ◽

Vol 280 (15) ◽

pp. 14656-14662 ◽

Cited By ~ 107

Author(s):

Marie Françoise Simon ◽

Danièle Daviaud ◽

Jean Philippe Pradère ◽

Sandra Grès ◽

Charlotte Guigné ◽

...

Keyword(s):

Lysophosphatidic Acid ◽

Adipocyte Differentiation ◽

Peroxisome Proliferator ◽

Down Regulation ◽

Peroxisome Proliferator Activated Receptor

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Adipocyte differentiation of 3T3-L1 preadipocytes is dependent on lipoxygenase activity during the initial stages of the differentiation process

Biochemical Journal ◽

10.1042/bj20030503 ◽

2003 ◽

Vol 375 (3) ◽

pp. 539-549 ◽

Cited By ~ 98

Author(s):

Lise MADSEN ◽

Rasmus K. PETERSEN ◽

Morten B. SØRENSEN ◽

Claus JØRGENSEN ◽

Philip HALLENBORG ◽

...

Keyword(s):

Adipocyte Differentiation ◽

Critical Evaluation ◽

Nordihydroguaiaretic Acid ◽

Whole Body ◽

Transcriptional Networks ◽

Peroxisome Proliferator ◽

The Novel ◽

Differentiation Process ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

Adipocytes play a central role in whole-body energy homoeostasis. Complex regulatory transcriptional networks control adipogensis, with ligand-dependent activation of PPARγ (peroxisome proliferator-activated receptor γ) being a decisive factor. Yet the identity of endogenous ligands promoting adipocyte differentiation has not been established. Here we present a critical evaluation of the role of LOXs (lipoxygenases) during adipocyte differentiation of 3T3-L1 cells. We show that adipocyte differentiation of 3T3-L1 preadipocytes is inhibited by the general LOX inhibitor NDGA (nordihydroguaiaretic acid) and the 12/15-LOX selective inhibitor baicalein. Baicalein-mediated inhibition of adipocyte differentiation was rescued by administration of rosiglitazone. Treatment with baicalein during the first 4 days of the differentiation process prevented adipocyte differentiation; supplementation with rosiglitazone during the same period was sufficient to rescue adipogenesis. Accordingly, we demonstrate that adipogenic conversion of 3T3-L1 cells requires PPARγ ligands only during the first 4 days of the differentiation process. We show that the baicalein-sensitive synthesis of endogenous PPARγ ligand(s) increases rapidly upon induction of differentiation and reaches a maximum on days 3–4 of the adipocyte differentiation programme. The conventional platelet- and leucocyte-type 12(S)-LOXs and the novel eLOX-3 (epidermis-type LOX-3) are expressed in white and brown adipose tissue, whereas only eLOX-3 is clearly expressed in 3T3-L1 cells. We suggest that endogenous PPARγ ligand(s) promoting adipocyte differentiation are generated via a baicalein-sensitive pathway involving the novel eLOX-3.

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Evidence for the Regulatory Role of Lipocalin 2 in High-Fat Diet-Induced Adipose Tissue Remodeling in Male Mice

Endocrinology ◽

10.1210/en.2013-1289 ◽

2013 ◽

Vol 154 (10) ◽

pp. 3525-3538 ◽

Cited By ~ 33

Author(s):

Hong Guo ◽

Merlijn Bazuine ◽

Daozhong Jin ◽

Merry M. Huang ◽

Samuel W. Cushman ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Adipocyte Differentiation ◽

Tissue Remodeling ◽

Peroxisome Proliferator ◽

Lipocalin 2 ◽

Peroxisome Proliferator Activated Receptor ◽

Adipose Tissue Remodeling ◽

Fat Depot

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

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The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

Journal of Clinical Medicine ◽

10.3390/jcm10081763 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1763

Author(s):

Marta Mazzetti ◽

Giulia Marconi ◽

Martina Mancinelli ◽

Antonio Benedetti ◽

Marco Marzioni ◽

...

Keyword(s):

Liver Diseases ◽

Immunosuppressive Drugs ◽

Farnesoid X Receptor ◽

New Drugs ◽

Primary Biliary Cholangitis ◽

Peroxisome Proliferator ◽

Biliary Cirrhosis ◽

Peroxisome Proliferator Activated Receptor ◽

Multiple Drugs ◽

New Treatments

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.

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Abstract 126: Peroxisomal Proliferator Activated Receptor Alpha Overexpression in Hypertrophied Cardiomyocytes Restores Mitochondrial Integrity and Function

Circulation Research ◽

10.1161/res.121.suppl_1.126 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Sagartirtha Sarkar ◽

Santanu Rana

Keyword(s):

Energy Demand ◽

Cardiac Tissue ◽

Structural Integrity ◽

Heart Function ◽

Ros Generation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Atp Production ◽

Receptor Alpha ◽

And Function

Cardiac tissue engineering is an interdisciplinary field that engineers modulation of viable molecular milieu to restore, maintain or improve heart function. Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux to maintain specialized cellular processes, yet the heart has a limited capacity for substrate storage and utilization during pathophysiological conditions. Damage to heart muscle, acute or chronic, leads to dysregulation of cardiac metabolic processes associated with gradual but progressive decline in mitochondrial respiratory pathways resulting in diminished ATP production. The Peroxisome Proliferator Activated Receptor Alpha ( PPARα ) is known to regulate fatty acid to glucose metabolic balance as well as mitochondrial structural integrity. In this study, a non-canonical pathway of PPARα was analyzed by cardiomyocyte targeted PPARα overexpression during cardiac hypertrophy that showed significant downregulation in p53 acetylation as well as GSK3β activation levels. Targeted PPARα overexpression during hypertrophy resulted in restoration of mitochondrial structure and function along with significantly improved mitochondrial ROS generation and membrane potential. This is the first report of myocyte targeted PPARα overexpression in hypertrophied myocardium that results in an engineered heart with significantly improved function with increased muscle mitochondrial endurance and reduced mitochondrial apoptotic load, thus conferring a greater resistance to pathological stimuli within cardiac microenvironment.

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Abstract 12555: The Dual PPAR-α/γ Agonist Aleglitazar Enhances Arteriogenesis, Angiogenesis and Endothelial Function

Circulation ◽

10.1161/circ.130.suppl_2.12555 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Christian Werner ◽

Stephan H Schirmer ◽

Valerie Pavlickova ◽

Michael Böhm ◽

Ulrich Laufs

Keyword(s):

Endothelial Function ◽

Vascular Function ◽

Daily Injection ◽

Peroxisome Proliferator ◽

Fluorescent Microspheres ◽

Artery Ligation ◽

Peroxisome Proliferator Activated Receptor ◽

Beneficial Effects ◽

And Function

Objective: Peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists modify lipid and glucose metabolism. The aim of the study was to characterize the effects of the dual PPAR-α/γ agonist aleglitazar on endothelial function, neoangiogenesis and arteriogenesis in mice and on human endothelial progenitor cells (EPC). Methods and Results: Male C57Bl/6 wild-type (WT, normal chow) and apolipoprotein E-deficient (apoE-/-) mice on Western-type diet (WTD) were treated with aleglitazar (10 mg/kg i.p.) or vehicle by daily injection. Hindlimb ischemia was induced by right femoral artery ligation (FAL). ApoE-/- mice on WTD treated with aleglitazar before FAL were characterized by an improvement of endothelial-dependent laser Doppler perfusion (right/left foot ratio 0.40±0.03) 1 week after FAL compared to controls (R/L foot ratio 0.24±0.01; p<0.001). Collateral-dependent perfusion measured under conditions of maximal vasodilatation 1 week after FAL using fluorescent microspheres was impaired in apoE-/- on WTD compared to WT mice (R/L leg ratio in WT 78±13 vs. apoE-/- 56±6; p<0.001) and was normalized by aleglitazar treatment. Neoangiogenesis was measured in-vivo by subcutaneously implanting discs covered with cell-impermeable filters. The vascularized area of the discs was quantified after 14 days by perfusion of the animals with space-filling fluorescent microspheres. Aleglitazar increased neoangiogenesis in WT mice by 178±18% compared to vehicle (p<0.05). Endothelium-dependent relaxation of aortic rings was impaired in apoE-/- mice on WTD for 6 weeks (relaxation to 52±5% of max. contraction) compared to WT animals (relaxation to 18±5% of max. contraction) (p<0.001). Aleglitazar treatment improved endothelial function (relaxation to 39±5% of max. contraction; p<0.05). In parallel, number and function of EPC were improved in mice. Studies in human EPC showed that 1) aleglitazar’s effects were mediated by both PPAR-α and -γ signalling and Akt and 2) migration and colony forming units were up-regulated by aleglitazar in cultivated EPC from CAD patients. Conclusion: The study provides evidence for beneficial effects of the dual PPAR-α/γ agonist aleglitazar on vascular function in addition to or mediated by its metabolic actions.

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