PPARγ is a nuclear hormone receptor that functions as a master regulator of adipocyte differentiation and development. Full PPARγ agonists, such as the thiazolidinediones (TZDs), have been widely used to treat type 2 diabetes. However, they are characterized by undesirable side effects due to their strong agonist activities. Pseudoginsenoside F11 (p-F11) is an ocotillol-type ginsenoside isolated from Panax quinquefolium L. (American ginseng). In this study, we found that p-F11 activates PPARγ with modest adipogenic activity. In addition, p-F11 promotes adiponectin oligomerization and secretion in 3T3-L1 adipocytes. We also found that p-F11 inhibits obesity-linked phosphorylation of PPARγ at Ser-273 by Cdk5. Therefore, p-F11 is a novel partial PPARγ agonist, which might have the potential to be developed as a new PPARγ-targeted therapeutics for type 2 diabetes. 1. Introduction The nuclear hormone receptor PPARγ (peroxisome proliferator-activated receptor γ) is a ligand-activated transcription factor highly expressed in the adipose tissues [1]. By binding to PPARγ-responsive regulatory elements as heterodimers with retinoid X receptor (RXR), PPARγ regulates the expression of networks of genes involved in adipogenesis, lipid metabolism, inflammation, and maintenance of metabolic homeostasis [2]. PPARγ consists of an amino terminal activation domain (AF-1), a highly conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) containing a ligand-dependent transactivation domain (AF-2) [3]. Ligand binding promotes a conformational change which allows for differential recruitment of cofactors and subsequent modulation of PPARγ activity [4, 5]. PPARγ is the pharmacological target of the insulin-sensitizing thiazolidinediones (TZDs) that have been widely used in the treatment of type 2 diabetes. TZDs function as selective PPARγ ligands and induce transcription of PPARγ-targeted genes [6]. Derivatives of TZD, such as rosiglitazone (Avandia) and pioglitazone (Actos), are highly effective in treating type 2 diabetes and are well tolerated by the majority of patients [1]. However, they are associated with various undesirable side effects, including weight gain, fluid retention, edema, congestive heart failure, and bone fracture [7, 8]. Long-term use of TZDs may be associated with increased risk of bladder cancer [9]. These limitations have raised substantial concerns and significantly impaired their future in many countries [10]. Therefore, it is critical to develop TZD substitutes for improved therapies of type 2 diabetes. Studies in animal
References
[1]
M. Ahmadian, J. M. Suh, N. Hah, et al., “PPARγ signaling and metabolism: the good, the bad and the future,” Nature Medicine, vol. 19, no. 5, pp. 557–566, 2013.
[2]
M. Lehrke and M. A. Lazar, “The many faces of PPARgamma,” Cell, vol. 123, no. 6, pp. 993–999, 2005.
[3]
T. M. Willson, M. H. Lambert, and S. A. Kliewer, “Peroxisome proliferator-activated receptor and metabolic disease,” Annual Review of Biochemistry, vol. 70, pp. 341–367, 2001.
[4]
L. Nagy and J. Schwabe, “Mechanism of the nuclear receptor molecular switch,” Trends in Biochemical Sciences, vol. 29, no. 6, pp. 317–324, 2004.
[5]
C. K. Glass and M. G. Rosenfeld, “The coregulator exchange in transcriptional functions of nuclear receptors,” Genes & Development, vol. 14, no. 2, pp. 121–141, 2000.
[6]
J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR ),” The Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
[7]
R. A. Defronzo, “Banting Lecture. from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus,” Diabetes, vol. 58, no. 4, pp. 773–795, 2009.
[8]
B. L. Blazer-Yost, “PPARgamma agonists: blood pressure and edema,” PPAR Research, vol. 2010, Article ID 785369, 5 pages, 2010.
[9]
R. Mamtani, K. Haynes, W. B. Bilker, et al., “Association between longer therapy with thiazolidinediones and risk of bladder cancer: a cohort study,” Journal of the National Cancer Institute, vol. 104, no. 18, pp. 1411–1421, 2012.
[10]
D. Jones, “Potential remains for PPAR-targeted drugs,” Nature Reviews Drug Discovery, vol. 9, no. 9, pp. 668–669, 2010.
[11]
J. H. Choi, A. S. Banks, J. L. Estall et al., “Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR by Cdk5,” Nature, vol. 466, no. 7305, pp. 451–456, 2010.
[12]
A. A. Amato, S. Rajagopalan, J. Z. Lin, et al., “GQ-16, a novel peroxisome proliferator-activated receptor (PPAR ) ligand, promotes insulin sensitization without weight gain,” The Journal of Biological Chemistry, vol. 287, no. 33, pp. 28169–28179, 2012.
[13]
J. H. Choi, A. S. Banks, T. M. Kamenecka et al., “Antidiabetic actions of a non-agonist PPAR ligand blocking Cdk5-mediated phosphorylation,” Nature, vol. 477, no. 7365, pp. 477–481, 2011.
[14]
C. Weidner, J. C. de Groot, A. Prasad, et al., “Amorfrutins are potent antidiabetic dietary natural products,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 19, pp. 7257–7262, 2012.
[15]
D. H. Lee, H. Huang, K. Choi, C. Mantzoros, and Y.-B. Kim, “Selective PPAR modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice,” American Journal of Physiology—Endocrinology and Metabolism, vol. 302, no. 5, pp. E552–E560, 2012.
[16]
A. Chandalia, H. J. Clarke, L. E. Clemens et al., “MBX-102/JNJ39659100, a novel non-TZD selective partial PPAR- agonist lowers triglyceride independently of PPAR- activation,” PPAR Research, vol. 2009, Article ID 706852, 12 pages, 2009.
[17]
H. Waki, T. Yamauchi, J. Kamon et al., “Impaired multimerization of human adiponectin mutants associated with diabetes—molecular structure and multimer formation of adiponectin,” The Journal of Biological Chemistry, vol. 278, no. 41, pp. 40352–40363, 2003.
[18]
T.-S. Tsao, E. Tomas, H. E. Murrey et al., “Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity—different oligomers activate different signal transduction pathways,” The Journal of Biological Chemistry, vol. 278, no. 50, pp. 50810–50817, 2003.
[19]
U. B. Pajvani, M. Hawkins, T. P. Combs et al., “Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity,” The Journal of Biological Chemistry, vol. 279, no. 13, pp. 12152–12162, 2004.
[20]
Y. Wang, M.-H. Yau, A. M. Xu, and K. S. L. Lam, “Post-translational modifications of adiponectin: mechanisms and functional implications,” Biochemical Journal, vol. 409, no. 3, pp. 623–633, 2008.
[21]
T. Yamauchi and T. Kadowaki, “Adiponectin receptor as a key player in healthy longevity and obesity-related diseases,” Cell Metabolism, vol. 17, no. 2, pp. 185–196, 2013.
[22]
Y. Arita, S. Kihara, N. Ouchi et al., “Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity,” Biochemical and Biophysical Research Communications, vol. 257, no. 1, pp. 79–83, 1999.
[23]
K. Hotta, T. Funahashi, Y. Arita et al., “Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 6, pp. 1595–1599, 2000.
[24]
T. Bobbert, H. Rochlitz, U. Wegewitz et al., “Changes of adiponectin oligomer composition by moderate weight reduction,” Diabetes, vol. 54, no. 9, pp. 2712–2719, 2005.
[25]
T. P. Combs, A. H. Berg, M. W. Rajala et al., “Sexual differentiation, pregnancy, calorie restriction, and aging affect the adipocyte-specific secretory protein adiponectin,” Diabetes, vol. 52, no. 2, pp. 268–276, 2003.
[26]
N. Maeda, M. Takahashi, T. Funahashi et al., “PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein,” Diabetes, vol. 50, no. 9, pp. 2094–2099, 2001.
[27]
J. M. Tishinsky, D. J. Dyck, and L. E. Robinson, “Lifestyle factors increasing adiponectin synthesis and secretion,” Vitamins and Hormones, vol. 90, pp. 1–30, 2012.
[28]
M. Iwaki, M. Matsuda, N. Maeda et al., “Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors,” Diabetes, vol. 52, no. 7, pp. 1655–1663, 2003.
[29]
M. Liu, L. Zhou, A. Xu et al., “A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 47, pp. 18302–18307, 2008.
[30]
L. Qiang, H. Wang, and S. R. Farmer, “Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase ero1-1 alpha,” Molecular and Cellular Biology, vol. 27, no. 13, pp. 4698–4707, 2007.
[31]
R.-M. Yu, Q.-X. Jin, H. Sun, W.-C. Ye, and Y. Zhao, “The growth characteristics and ginsenosides isolation of suspension-cultured crown gall of Panax quinquefolium,” Chinese Journal of Biotechnology, vol. 21, no. 5, pp. 754–758, 2005.
[32]
T. W. Chan, P. P. But, S. W. Cheng, I. M. Y. Kwok, F. W. Lau, and H. X. Xu, “Differentiation and authentication of Panax ginseng, Panax quinquefolius, and ginseng products by using HPLC/MS,” Analytical Chemistry, vol. 72, no. 6, pp. 1281–1287, 2000.
[33]
W. Li, C. Gu, H. Zhang et al., “Use of high-performance liquid chromatography-tandem mass spectrometry to distinguish Panax ginseng C. A. Meyer (Asian ginseng) and Panax quinquefolius L. (North American ginseng),” Analytical Chemistry, vol. 72, no. 21, pp. 5417–5422, 2000.
[34]
Z. Li, C. F. Wu, G. Pei, Y. Y. Guo, and X. Li, “Antagonistic effect of pseudoginsenoside-F11 on the behavioral actions of morphine in mice,” Pharmacology Biochemistry and Behavior, vol. 66, no. 3, pp. 595–601, 2000.
[35]
Y. Hao, J. Y. Yang, C. F. Wu, and M. F. Wu, “Pseudoginsenoside-F11 decreases morphine-induced behavioral sensitization and extracellular glutamate levels in the medial prefrontal cortex in mice,” Pharmacology Biochemistry and Behavior, vol. 86, no. 4, pp. 660–666, 2007.
[36]
Z. Li, Y. Y. Guo, C. F. Wu, X. Li, and J. H. Wang, “Protective effects of pseudoginsenoside-F11 on scopolamine-induced memory impairment in mice and rats,” Journal of Pharmacy and Pharmacology, vol. 51, no. 4, pp. 435–440, 1999.
[37]
C. F. Wu, Y. L. Liu, M. Song et al., “Protective effects of pseudoginsenoside-F11 on methamphetamine-induced neurotoxicity in mice,” Pharmacology Biochemistry and Behavior, vol. 76, no. 1, pp. 103–109, 2003.
[38]
C. M. Wang, M. Y. Liu, F. Wang, et al., “Anti-amnesic effect of pseudoginsenoside-F11 in two mouse models of Alzheimer's disease,” Pharmacology Biochemistry and Behavior, vol. 106, pp. 57–67, 2013.
[39]
Y. Li, P. C. Wang, Y. Zhuang et al., “Activation of AMPK by berberine promotes adiponectin multimerization in 3T3-L1 adipocytes,” FEBS Letters, vol. 585, no. 12, pp. 1735–1740, 2011.
[40]
Z. F. Chen, L. Zhang, J. Y. Yi, et al., “Promotion of adiponectin multimerization by emodin: a novel AMPK activator with PPAR -agonist activity,” Journal of Cellular Biochemistry, vol. 113, no. 11, pp. 3547–3558, 2012.
[41]
P. Tontonoz, E. D. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPAR 2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994.
[42]
R. T. Gampe Jr., V. G. Montana, M. H. Lambert et al., “Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors,” Molecular Cell, vol. 5, no. 3, pp. 545–555, 2000.
[43]
A. Motani, Z. Wang, J. Weiszmann et al., “INT131: a selective modulator of PPAR gamma,” Journal of Molecular Biology, vol. 386, no. 5, pp. 1301–1311, 2009.
[44]
Z. E. Floyd and J. M. Stephens, “Controlling a master switch of adipocyte development and insulin sensitivity: covalent modifications of PPAR ,” Biochimica et Biophysica Acta, vol. 1822, no. 7, pp. 1090–1095, 2012.
[45]
J. P. Whitehead, “Diabetes: new conductors for the peroxisome proliferator-activated receptor (PPAR ) orchestra,” The International Journal of Biochemistry & Cell Biology, vol. 43, no. 8, pp. 1071–1074, 2011.
[46]
I. Mucalo, D. Rahelic, E. Jovanovski, et al., “Effect of American ginseng (Panax quinquefolius L.) on glycemic control in type 2 diabetes,” Collegium Antropologicum, vol. 36, no. 4, pp. 1435–1440, 2012.
