Journal
INTERNATIONAL JOURNAL OF OBESITY
Volume 37, Issue 4, Pages 584-592Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ijo.2012.85
Keywords
cocoa polyphenols; adipogenesis; mitotic clonal expansion; insulin receptor
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Funding
- World Class University Program [R31-2008-00-10056-0]
- National Leap Research Program through the National Research Foundation of Korea [2010-0029233]
- Ministry of Education, Science and Technology, Republic of Korea
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OBJECTIVE: To investigate the inhibitory effect of cocoa polyphenol extract (CPE) on adipogenesis and obesity along with its mechanism of action. METHODS AND RESULTS: 3T3-L1 preadipocytes were cultured with isobutylmethylxanthine, dexamethasone and insulin (MDI), and male C57BL/6N mice (N = 44) were fed a high-fat diet (HFD) for 5 weeks with or without CPE. CPE at 100 or 200 mu g ml(-1) inhibited MDI-induced lipid accumulation without diminishing cell viability. In particular, CPE reduced the protein expression levels of PPAR gamma and CEBP alpha, and blocked mitotic clonal expansion (MCE) of preadipocytes by reducing proliferating signaling pathways. This in turn attenuates lipid accumulation during the differentiation of 3T3-L1 preadipocytes. CPE effectively suppressed MDI-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and their downstream signals. We then examined whether CPE regulates insulin receptor (IR), a common upstream regulator of ERK and Akt. We found that although CPE does not affect the protein expression level of IR, it significantly inhibits the activity of IR kinase via direct binding. Collectively, the results suggested that CPE, a direct inhibitor of IR kinase activity, inhibits cellular differentiation and lipid accumulation in 3T3-L1 preadipocytes. Consistently, CPE attenuated HFD-induced body weight gain and fat accumulation in obese mice fed with a HFD. We also found that HFD-induced increased fasting glucose levels remained unaffected by CPE. CONCLUSION: This study demonstrates that CPE inhibits IR kinase activity and its proliferative downstream signaling markers, such as ERK and Akt, in 3T3-L1 preadipocytes, and also prevents the development of obesity in mice fed with a HFD. International Journal of Obesity (2013) 37, 584-592; doi:10.1038/ijo.2012.85; published online 29 May 2012
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