Carbamazepine Enhances Adipogenesis by Inhibiting Wnt/β-Catenin Expression

Cells - Tập 8 Số 11 - Trang 1460
Im .1,2, Hyung Min Kim1, Gia Cac Chau2, Sung Hee Um3,1,2
1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul 06351, Korea
2Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 16419, Korea
3Biomedical Institute Convergence at Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea

Tóm tắt

Carbamazepine is a drug that is widely used in the treatment of epilepsy and bipolar disorder. The prevalence of obesity in patients treated with carbamazepine has been frequently reported. However, whether carbamazepine affects adipogenesis, one of the critical steps in the development of obesity, remains unclear. Here, we show that carbamazepine increased the expression levels of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein β (C/EBPβ), and fatty acid synthase (FASN) in 3T3-L1 cells. Notably, carbamazepine inhibited the expression levels of β-catenin, a negative regulator of adipogenesis, leading to enhanced adipogenesis. Conversely, β-catenin overexpression abolished the effect of carbamazepine on adipogenic gene expression. However, depletion of β-catenin further enhanced PPARγ expression. In addition, carbamazepine reduced β-catenin expression by lowering the levels of phospho-low density lipoprotein receptor-related protein 6 (p-LRP6) and phospho-glycogen synthase kinase 3β (p-GSK3β) in Wnt/β-catenin signaling. Moreover, carbamazepine reduced Wnt mRNA expression and decreased the promoter activities of TCF, the target of β-catenin during adipogenesis. These results suggest that carbamazepine enhances adipogenesis by suppressing Wnt/β-catenin expression, indicating its potential effects on obesity-related metabolism.

Từ khóa


Tài liệu tham khảo

Goodwin, 2003, Evidence-based guidelines for treating bipolar disorder: Recommendations from the British Association for Psychopharmacology, J. Psychopharmacol., 17, 149, 10.1177/0269881103017002003

Brodie, 2017, Sodium Channel Blockers in the Treatment of Epilepsy, CNS Drugs, 31, 527, 10.1007/s40263-017-0441-0

Granger, 1995, Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin, Mol. Pharmacol., 47, 1189

Yoshida, 2007, Carbamazepine prevents breakdown of neurotransmitter release induced by hyperactivation of ryanodine receptor, Neuropharmacology, 52, 1538, 10.1016/j.neuropharm.2007.02.009

Garoufi, 2016, Weight gain in children on oxcarbazepine monotherapy, Epilepsy Res., 122, 110, 10.1016/j.eplepsyres.2016.03.004

Hogan, 2000, Total percentage body weight changes during add-on therapy with tiagabine, carbamazepine and phenytoin, Epilepsy Res., 41, 23, 10.1016/S0920-1211(00)00125-X

Hamed, 2009, States of serum leptin and insulin in children with epilepsy: Risk predictors of weight gain, Eur. J. Paediatr. Neurol., 13, 261, 10.1016/j.ejpn.2008.05.005

Bramswig, 2003, Lipoprotein(a) concentration increases during treatment with carbamazepine, Epilepsia, 44, 457, 10.1046/j.1528-1157.2003.44802.x

Mintzer, 2010, Metabolic consequences of antiepileptic drugs, Curr. Opin. Neurol., 23, 164, 10.1097/WCO.0b013e32833735e7

Luef, 2009, Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment, Epilepsy Res., 86, 42, 10.1016/j.eplepsyres.2009.04.004

Uludag, 2009, The effect of carbamazepine treatment on serum leptin levels, Epilepsy Res., 86, 48, 10.1016/j.eplepsyres.2009.04.005

Shattil, 1975, Platelet hypersensitivity induced by cholesterol incorporation, J. Clin. Investig., 55, 636, 10.1172/JCI107971

Mermelstein, 2007, Wnt/beta-catenin pathway activation and myogenic differentiation are induced by cholesterol depletion, Differ. Res. Biol. Divers., 75, 184

Cawthorn, 2012, Adipose tissue stem cells meet preadipocyte commitment: Going back to the future, J. Lipid Res., 53, 227, 10.1194/jlr.R021089

Rosen, 2014, What We Talk About When We Talk About Fat, Cell, 156, 20, 10.1016/j.cell.2013.12.012

Malik, 2013, Global obesity: Trends, risk factors and policy implications, Nat. Rev. Endocrinol., 9, 13, 10.1038/nrendo.2012.199

Isakson, 2009, Impaired preadipocyte differentiation in human abdominal obesity: Role of Wnt, tumor necrosis factor-alpha, and inflammation, Diabetes, 58, 1550, 10.2337/db08-1770

Madsen, 2005, Regulation of adipocyte differentiation and function by polyunsaturated fatty acids, Biochim. Biophys. Acta, 1740, 266, 10.1016/j.bbadis.2005.03.001

Rosen, 2000, Transcriptional regulation of adipogenesis, Genes Dev., 14, 1293, 10.1101/gad.14.11.1293

Ali, 2013, Adipocyte and adipogenesis, Eur. J. Cell Biol., 92, 229, 10.1016/j.ejcb.2013.06.001

Lefterova, 2009, New developments in adipogenesis, Trends Endocrinol. Metab., 20, 107, 10.1016/j.tem.2008.11.005

Phelps, 2005, Oxcarbazepine: A brief review, J. Pediatr. Pharmacol. Ther. Jppt Off. J. Ppag, 10, 248

Vallee, 2018, Opposite Interplay Between the Canonical WNT/beta-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas, Neurosci. Bull., 34, 573, 10.1007/s12264-018-0219-5

Ross, 2000, Inhibition of adipogenesis by Wnt signaling, Science, 289, 950, 10.1126/science.289.5481.950

Moldes, 2003, Peroxisome-proliferator-activated receptor gamma suppresses Wnt/beta-catenin signalling during adipogenesis, Biochem. J., 376, 607, 10.1042/bj20030426

Longo, 2004, Wnt10b inhibits development of white and brown adipose tissues, J. Biol. Chem., 279, 35503, 10.1074/jbc.M402937200

MacDonald, 2009, Wnt/beta-catenin signaling: Components, mechanisms, and diseases, Dev. Cell, 17, 9, 10.1016/j.devcel.2009.06.016

Clevers, 2012, Wnt/beta-catenin signaling and disease, Cell, 149, 1192, 10.1016/j.cell.2012.05.012

Acebron, 2016, beta-Catenin-Independent Roles of Wnt/LRP6 Signaling, Trends Cell Biol., 26, 956, 10.1016/j.tcb.2016.07.009

Niehrs, 2010, Wnt signaling: Multivesicular bodies hold GSK3 captive, Cell, 143, 1044, 10.1016/j.cell.2010.12.003

Chung, 2012, Regulation of Wnt/beta-catenin signaling by CCAAT/enhancer binding protein beta during adipogenesis, Obesity, 20, 482, 10.1038/oby.2011.212

Nusse, 2017, Wnt/beta-Catenin Signaling, Disease, and Emerging Therapeutic Modalities, Cell, 169, 985, 10.1016/j.cell.2017.05.016

Li, 2012, Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex, Cell, 149, 1245, 10.1016/j.cell.2012.05.002

Kennell, 2005, Wnt signaling inhibits adipogenesis through beta-catenin-dependent and -independent mechanisms, J. Biol. Chem., 280, 24004, 10.1074/jbc.M501080200

Cawthorn, 2012, Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a beta-catenin-dependent mechanism, Bone, 50, 477, 10.1016/j.bone.2011.08.010

Grunze, 2010, Anticonvulsants in bipolar disorder, J. Ment. Health, 19, 127, 10.3109/09638230903469186

Fagiolini, 2003, Obesity as a correlate of outcome in patients with bipolar I disorder, Am. J. Psychiatry, 160, 112, 10.1176/appi.ajp.160.1.112

Grootens, 2018, Weight changes associated with antiepileptic mood stabilizers in the treatment of bipolar disorder, Eur. J. Clin. Pharmacol., 74, 1485, 10.1007/s00228-018-2517-2

Yamamoto, 2016, Influence of antiepileptic drugs on serum lipid levels in adult epilepsy patients, Epilepsy Res., 127, 101, 10.1016/j.eplepsyres.2016.08.027

Talley, 2008, Bipolar disorder and weight gain: A multifactorial assessment, J. Am. Psychiatr. Nurses Assoc., 13, 345, 10.1177/10783903080130060401

Foufelle, 1996, Regulation of lipogenic enzyme expression by glucose in liver and adipose tissue: A review of the potential cellular and molecular mechanisms, Adv. Enzym. Regul., 36, 199, 10.1016/0065-2571(95)00010-0

Turpin, 2013, Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway, Br. J. Pharmacol., 168, 139, 10.1111/j.1476-5381.2012.02140.x

Zhang, H.H., Huang, J., Duvel, K., Boback, B., Wu, S., Squillace, R.M., Wu, C.L., and Manning, B.D. (2009). Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS ONE, 4.

Zeve, 2012, Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake, Cell Metab., 15, 492, 10.1016/j.cmet.2012.03.010

Behari, 2014, beta-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice, Am. J. Pathol., 184, 3284, 10.1016/j.ajpath.2014.08.022

Prestwich, 2007, Wnt/beta-catenin signaling in adipogenesis and metabolism, Curr. Opin. Cell Biol., 19, 612, 10.1016/j.ceb.2007.09.014

Mao, 2001, Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway, Mol. Cell, 7, 801, 10.1016/S1097-2765(01)00224-6

MacDonald, B.T., and He, X. (2012). Frizzled and LRP5/6 receptors for Wnt/beta-catenin signaling. Cold Spring Harb. Perspect. Biol., 4.

Christodoulides, 2009, Adipogenesis and WNT signalling, Trends Endocrinol. Metab., 20, 16, 10.1016/j.tem.2008.09.002

Liu, 2004, Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes, J. Biol. Chem., 279, 45020, 10.1074/jbc.M407050200

Thông tin
Thông tin xuất bản

Cells

Tập 8 Số 11

1460

Thông tin tác giả