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Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway

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Abstract

Insulin resistance in skeletal muscle is a key feature in the pathogenesis of type 2 diabetes (T2D) that often manifests early in its development. Pharmaceutical and dietary strategies have targeted insulin resistance to control T2D, and many natural products with excellent pharmacological properties are good candidates for the control or prevention of T2D. Dihydromyricetin (DHM) is a natural flavonol which provides a wide range of health benefits including anti-inflammatory and anti-tumor effects. However, little information is available regarding the effects of DHM on skeletal muscle insulin sensitivity as well as the underlying mechanisms. In the present study, we found that DHM activated insulin signaling and increased glucose uptake in skeletal muscle in vitro and in vivo. The expression of light chain 3, the degradation of sequestosome 1, and the formation of autophagosomes were also upregulated by DHM. DHM-induced insulin sensitivity improvement was significantly abolished in the presence of 3-methyladenine, bafilomycin A1, or Atg5 siRNA in C2C12 myotubes. Furthermore, DHM increased the levels of phosphorylated AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), and Sirt3 in skeletal muscle in vitro and in vivo. Autophagy was inhibited in the presence of Sirt3 siRNA in C2C12 myotubes and in skeletal muscles from Sirt3−/− mice. Additionally, PGC-1α or AMPK siRNA transfection attenuated DHM-induced Sirt3 expression, thereby abrogating DHM-induced autophagy in C2C12 myotubes. In conclusion, DHM improved skeletal muscle insulin sensitivity by partially inducing autophagy via activation of the AMPK-PGC-1α-Sirt3 signaling pathway.

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Abbreviations

3-MA:

3-Methyladenine

Akt:

Protein kinase B

AMPK:

AMP-activated protein kinase

Atg:

Autophagy-related gene

BafA1:

Bafilomycin A1

DHM:

Dihydromyricetin

IRS-1:

Insulin receptor substrate-1

LC3:

Light chain 3

PGC-1α:

Peroxisome proliferator-activated receptor coactivator-1α

siRNA:

Small interfering RNA

T2D:

Type 2 diabetes

Sirt3:

Silent mating-type information regulation 2 homolog 3

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Acknowledgments

This work was supported by the research Grant from National Natural Science Foundation of China (81372975) and the special fund of Chongqing key laboratory (CSTC) for Nutrition and Food Safety.

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Research Center for Nutrition and Food safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People’s Republic of China

    Linying Shi, Ting Zhang, Yong Zhou, Xianglong Zeng, Li Ran, Qianyong Zhang, Jundong Zhu & Mantian Mi

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  1. Linying Shi
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  2. Ting Zhang
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  3. Yong Zhou
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Correspondence to Jundong Zhu or Mantian Mi.

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Shi, L., Zhang, T., Zhou, Y. et al. Dihydromyricetin improves skeletal muscle insulin sensitivity by inducing autophagy via the AMPK-PGC-1α-Sirt3 signaling pathway. Endocrine 50, 378–389 (2015). https://doi.org/10.1007/s12020-015-0599-5

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  • DOI: https://doi.org/10.1007/s12020-015-0599-5

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