Abstract
Background:
Chronic inflammation in adipose tissue together with obesity induces insulin resistance. Inhibitors of chronic inflammation in adipose tissue can be a potent candidate for the treatment of diabetes; however, only a few compounds have been discovered so far. The objective of this study was to find a novel inhibitor that can suppress the inflammatory response in adipose tissue and to elucidate the intracellular signaling mechanisms of the compound.
Methods:
To find the active compounds, we established an assay system to evaluate the inhibition of induced MCP-1 production in adipocyte/macrophage coculture in a plant extract library. The active compound was isolated by performing high-performance liquid chromatography (HPLC) and was determined as 4β-hydroxywithanolide E (4βHWE) by nuclear magnetic resonance (NMR) and mass spectroscopy (MS) spectral analyses. The effect of 4βHWE on inflammation in adipose tissue was assessed with adipocyte culture and db/db mice.
Results:
During the screening process, Physalis pruinosa calyx extract was found to inhibit production of MCP-1 in coculture strongly. 4βHWE belongs to the withanolide family of compounds, and it has the strongest MCP-1 production inhibitory effect and lowest toxicity than any other withanolides in coculture. Its anti-inflammatory effect was partially dependent on the attenuation of NF-κB signaling in adipocyte. Moreover, in vivo experiments showed that the oral administration of 4βHWE to db/db mice resulted in the inhibition of macrophage invasion and cytokine expression in adipose tissue after 2 weeks of treatment; improved the plasma adiponectin, non-esterified fatty acids and MCP-1 concentrations; and increased glucose tolerance after 3 to 4 weeks of treatment.
Conclusions:
These results suggest that 4βHWE has anti-inflammatory effect via inhibition of NF-κB activation in adipocyte. Moreover, the attenuation of inflammation in adipocyte has an effect on the inhibition of macrophage accumulation in obese adipose tissue. Consequently, 4βHWE improves impaired glucose tolerance. Thus, 4βHWE is a useful natural anti-inflammatory compound to attenuate progression of diabetes and obesity.
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Acknowledgements
We thank Hiroaki Kisaka and Ryuji Sugiyama for supplying the plant extract library and the Physalis calyx from Kamikoani, Shin Harumatsu for providing technical assistance and Reika Nakagawa for the screening and identification of active fractions with the coculture assay. We also thank Naoko Akimoto for her assistance with 4βHWE purification.
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T Takimoto, Y Kanbayashi, T Toyoda, Y Adachi, C Furuta, K Suzuki, T Miwa and M Bannai are employees of Ajinomoto.
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Takimoto, T., Kanbayashi, Y., Toyoda, T. et al. 4β-Hydroxywithanolide E isolated from Physalis pruinosa calyx decreases inflammatory responses by inhibiting the NF-κB signaling in diabetic mouse adipose tissue. Int J Obes 38, 1432–1439 (2014). https://doi.org/10.1038/ijo.2014.33
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DOI: https://doi.org/10.1038/ijo.2014.33
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