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Bile acid receptor agonist GW4064 regulates PPAR? coactivator-1? expression through estrogen receptor-related receptor ?.

ABSTRACT: Peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1? an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1? expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1? promoter reporter activity, mRNA, and protein expression. This induction in PGC-1? concomitantly enhances mitochondrial mass and expression of several PGC-1? target genes involved in mitochondrial function. Using FXR-rich or FXR-nonexpressing cell lines and tissues, we found that this effect of GW4064 is not mediated directly by FXR but occurs via activation of estrogen receptor-related receptor ? (ERR?). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1? mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1? expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differences revealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERR?-FXR-PGC-1? and small heterodimer partner offers new insights into the biological functions of ERR? and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.

SUBMITTER: Dwivedi SK

PROVIDER: S-EPMC5417256 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α.

Dwivedi Shailendra Kumar Dhar SK Singh Nidhi N Kumari Rashmi R Mishra Jay Sharan JS Tripathi Sarita S Banerjee Priyam P Shah Priyanka P Kukshal Vandana V Tyagi Abdul Malik AM Gaikwad Anil Nilkanth AN Chaturvedi Rajnish Kumar RK Mishra Durga Prasad DP Trivedi Arun Kumar AK Sanyal Somali S Chattopadhyay Naibedya N Ramachandran Ravishankar R Siddiqi Mohammad Imran MI Bandyopadhyay Arun A Arora Ashish A Lundåsen Thomas T Anakk Sayee Priyadarshini SP Moore David D DD Sanyal Sabyasachi S

Molecular endocrinology (Baltimore, Md.) 20110414 6

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expre ...[more]

PMID: 21493670

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Project description:Purpose: Mitochondrial dysfunction in adipose tissue has emerged as key to the development of obesity and diabetes. Salvianolic acid B (SalB) is a water-soluble ingredient derived from Salvia miltiorrhiza that has been shown to possess potential anti-obese and anti-diabetic activities. However, the cellular mechanism of SalB on mitochondrial function with respect to these metabolic disorders has not been elucidated. Therefore, we aim to investigate the effects of SalB on mitochondrial function in 3T3-L1 adipocytes and analyze the underlying molecular mechanism. Methods: The effects of SalB on adipocyte differentiation, glucose uptake, and glycerol release were evaluated in 3T3-L1 adipocytes. Differentiated adipocytes were treated with SalB (50 μM) with or without PPARγ antagonist (GW9662, 20 μM) for 48 h, and mitochondrial oxygen consumption rate (OCR) as well as extracellular acidification rate (ECAR) were assessed using an XF Extracellular Flux Analyzer. The mitochondrial distribution of adipocytes was assessed using Mito Tracker Green (MTG) and observed under a fluorescent microscope. In addition, the mRNA expression levels of peroxisome proliferators-activated receptor γ/α (PPARγ/α), CCAAT/enhancer binding proteinα (C/EBPα), Nuclear respiratory factor 1/2 (NRF1/2), Uncoupling protein 2 (UCP2), and phosphofructokinase 2/fructose-2, 6-bisphosphatase 2 (PFKFB2) were detected by RT-PCR. Finally, changes in the protein levels of peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α) were determined by western blotting and immunofluorescence analysis. Results: Treatment with SalB increased glucose uptake and mitochondrial respiration, reduced glycerol release and promoted adipocyte differentiation by increasing mRNA expression of adipogenic transcription factors including PPARγ, C/EBPα, and PPARα. Furthermore, SalB enhanced adipocytes mitochondrial content, mitochondrial respiration and glycolysis capacity, which had been attenuated by GW9662 treatment through the increased expression of PGC-1α. Conclusion: Our results provide novel insights into the role of PGC-1α and mitochondria as probable mediators of SalB activity in the regulation of adipocyte differentiation in 3T3-L1 adipocytes.

Dataset Information

Bile acid receptor agonist GW4064 regulates PPAR? coactivator-1? expression through estrogen receptor-related receptor ?.

Publications

Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α.

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