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Int J Mol Sci. 2018 Mar 23;19(4). pii: E968. doi: 10.3390/ijms19040968.

Protective Effects of Gomisin N against Hepatic Cannabinoid Type 1 Receptor-Induced Insulin Resistance and Gluconeogenesis.

Author information

1
Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. arulbiotechtnau@gmail.com.
2
Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. arulbiotechtnau@gmail.com.
3
Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. dyjung999@naver.com.
4
Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. dyjung999@naver.com.
5
Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. kimji77@pusan.ac.kr.
6
Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. kimji77@pusan.ac.kr.
7
Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. jung0603@pusan.ac.kr.
8
Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan 50612, Korea. jung0603@pusan.ac.kr.

Abstract

Activation of the hepatic cannabinoid type 1 receptor (CB1R) induces insulin resistance and gluconeogenesis via endoplasmic reticulum (ER) stress, thereby contributing to hyperglycemia. Gomisin N (GN) is a phytochemical derived from Schisandra chinensis. In the current study, we investigated the inhibitory effects of GN on hepatic CB1R-mediated insulin resistance and gluconeogenesis in 2-arachidonoylglycerol (AG; an agonist of CB1R)-treated HepG2 cells and in high-fat diet (HFD)-induced obese mice. Treatment with 2-AG induced the expression of ER stress markers, serine/threonine phosphatase PHLPP1, Lipin1, and ceramide synthesis genes, but reduced the expression of ceramide degradation genes in HepG2 cells. However, GN reversed 2-AG-mediated effects and improved the 2-AG-mediated impairment of insulin signaling. Furthermore, GN inhibited 2-AG-induced intracellular triglyceride accumulation and glucose production in HepG2 cells by downregulation of lipogenesis and gluconeogenesis genes, respectively. In vivo, GN administration to HFD obese mice reduced the HFD-induced increase in fasting blood glucose and insulin levels, which was accompanied with downregulation of HFD-induced expression of CB1R, ER stress markers, ceramide synthesis gene, and gluconeogenesis genes in the livers of HFD obese mice. These findings demonstrate that GN protects against hepatic CB1-mediated impairment of insulin signaling and gluconeogenesis, thereby contributing to the amelioration of hyperglycemia.

KEYWORDS:

cannabinoid type 1 receptor; endoplasmic reticulum stress; gluconeogenesis; gomisin N; insulin resistance; lipogenesis

PMID:
29570673
PMCID:
PMC5979504
DOI:
10.3390/ijms19040968
[Indexed for MEDLINE]
Free PMC Article

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