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Cocoa polyphenols suppress adipogenesis in vitro and obesity in vivo by targeting insulin receptor

Abstract

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 μg ml−1 inhibited MDI-induced lipid accumulation without diminishing cell viability. In particular, CPE reduced the protein expression levels of PPARγ and CEBPα, 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.

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Acknowledgements

This work was supported by grants from the World Class University Program (R31-2008-00-10056-0) and the National Leap Research Program (No. 2010-0029233) through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology, Republic of Korea.

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Correspondence to H J Lee or K W Lee.

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Min, S., Yang, H., Seo, S. et al. Cocoa polyphenols suppress adipogenesis in vitro and obesity in vivo by targeting insulin receptor. Int J Obes 37, 584–592 (2013). https://doi.org/10.1038/ijo.2012.85

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  • DOI: https://doi.org/10.1038/ijo.2012.85

Keywords

  • cocoa polyphenols
  • adipogenesis
  • mitotic clonal expansion
  • insulin receptor

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