title: Metformin enhances the anti-adipogenic effects of atorvastatin via modulation of STAT3 and TGF-β/Smad3 signaling.
abstract: Adipocyte accumulation is associated with the development of obesity and obesity-related diseases. Interactions of master transcription factors and signaling cascades are required for adipogenesis. Regulation of excessive adipogenic processes may be an attractive therapeutic for treatment of obesity and obesity-related diseases. In this study, we found that atorvastatin exerts an anti-adipogenic activity in 3T3-L1 pre-adipocytes, and that this activity is elevated in combination with metformin. Expression of the adipogenic master regulators PPARγ and C/EBPα, and their target gene aP2, was suppressed by atorvastatin. Furthermore, atorvastatin treatment resulted in increased activation of the key master regulator of cellular energy homeostasis, AMPK. These biological activities of atorvastatin were elevated in combination with metformin. These anti-adipogenic activities were associated with regulation of the STAT3 and TGF-β signaling cascades, resulting in the regulation of the expression of STAT3 target genes, such as KLF5, p53, and cyclin D1, and TGF-β signaling inhibitory genes, such as SMAD7. Our results suggest that combination therapy with atorvastatin and metformin may have therapeutic potential for the treatment of obesity and obesity-related diseases caused by excessive adipogenesis.
authors.affiliation: Department of Pharmacology & Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Biomedical Science Project (BK21[PLUS]), Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology & Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Songhee
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pharmacology & Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Haeri
authors.initials: H
authors.lastname: Lee
authors.affiliation: R&D Center, CJ HealthCare Corp., Gyeonggi-do 467-812, Republic of Korea.
authors.forename: Chi Hye
authors.initials: CH
authors.lastname: Park
authors.affiliation: R&D Center, CJ HealthCare Corp., Gyeonggi-do 467-812, Republic of Korea.
authors.forename: Young Mee
authors.initials: YM
authors.lastname: Chung
authors.affiliation: R&D Center, CJ HealthCare Corp., Gyeonggi-do 467-812, Republic of Korea.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Shin
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Pharmacology & Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea. Electronic address: sangkyu@snu.ac.kr.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis; D000818:Animals; D000069059:Atorvastatin; D002454:Cell Differentiation; D002470:Cell Survival; D019938:Cyclin D1 / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D011758:Pyrroles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; D006538:Heptanoic Acids; D007004:Hypoglycemic Agents; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D008687:Metformin; D000069059:Atorvastatin
keywords: Adipogenesis; Atorvastatin; Metformin; STAT3; TGF-β