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Exp Clin Endocrinol Diabetes 2015; 123(05): 308-316
DOI: 10.1055/s-0035-1548789
Article
© Georg Thieme Verlag KG Stuttgart · New York

Glucose- and Triglyceride-lowering Dietary Penta-O-galloyl-α-D-Glucose Reduces Expression of PPARγ and C/EBPα, Induces p21-Mediated G1 Phase Cell Cycle Arrest, and Inhibits Adipogenesis in 3T3-L1 Preadipocytes

X. Liu   *
1   Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
2   Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA
,
A. Malki   *
3   Department of Health Sciences, Biomedical Science Program, College of Art and Sciences, Qatar University, Doha, Qatar
4   Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
,
Y. Cao   *
1   Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
5   Department of Biological Sciences, Ohio University, Athens, Ohio, USA
6   Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA
,
Y. Li
1   Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
,
Y. Qian
1   Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
2   Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA
6   Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA
,
X. Wang
1   Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
5   Department of Biological Sciences, Ohio University, Athens, Ohio, USA
6   Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA
,
X. Chen
1   Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA
2   Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA
5   Department of Biological Sciences, Ohio University, Athens, Ohio, USA
6   Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA
7   Department of Biomedical Sciences of HCOM, Ohio University, Athens, Ohio, USA
› Author Affiliations
Further Information

Publication History

received 15 January 2015
first decision 03 March 2015

accepted 09 March 2015

Publication Date:
19 May 2015 (online)

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Abstract

Plant polyphenols, such as hydrolysable tannins, are present in the human diet and known to exhibit anti-diabetic and anti-obesity activity. We previously reported that the representative hydrolysable tannin compound α-penta-galloyl-glucose (α-PGG) is a small molecule insulin mimetic that, like insulin, binds to insulin receptor (IR) and activates the IR-Akt-GLUT4 signaling pathway to trigger glucose transport and reduce blood glucose levels in db/db and ob/ob diabetic mice. However, its effects on adipogenesis and lipid metabolism were not known. In this study, high fat diet (HFD)-induced diabetic and obese mice were treated with α-PGG to determine its effects on blood glucose and triglycerides. 3T3-L1 preadipocytes were used as a cell model for identifying the anti-adipogenic activity of α-PGG at molecular and cellular levels as a first step in elucidating the mechanism of action of the compound. In vivo, oral administration of α-PGG significantly reduced levels of blood glucose, triglyceride, and insulin in HFD-induced diabetic/obese mice (P<0.05). In vitro, α-PGG inhibited the differentiation of 3T3-L1 preadipocytes into mature adipocytes. α-PGG suppressed the expression of positive adipogenic factors PPARγ C/EBPα and mTOR and augmented the negative adipogenic factor Pref-1. Furthermore, α-PGG induced upregulation of p21 and G1 phase cell cycle arrest. In contrast, adipogenic signaling pathways mediated by insulin, the cAMP response element binding protein (CREB) and glucocorticoid receptor (GR), were not inhibited. RNAi knockdown of p21 led to a 4-fold increase in triglyceride level in 3T3-L1 preadipocytes treated with MDI and α-PGG compared to regular preadipocytes. These results indicate, for the first time, that α-PGG is blood triglyceride- and glucose-lowering in HFD-induced obese and diabetic mice. It selectively inhibited some but not all major adipogenic pathways as well as the mTOR-p21-mediated cell cycle regulatory pathway. It is very likely that these apparently diverse but coordinated activities together inhibited adipogenesis. These results expand our knowledge on how PGG works in adipocytes and further confirm that α-PGG functions as an orally-deliverable natural insulin mimetic with adipogenetic modulatory functions.

Key words

type 2 diabetes mellitus - obesity - insulin mimetic - hydrolyzable tannins - nutritional sciences

* X. Liu, A. Malki, and Y. Cao equally contributed to this study.


 

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