1. Academic Validation
  2. Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis

Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis

  • Cell Metab. 2023 Jan 3;35(1):101-117.e11. doi: 10.1016/j.cmet.2022.11.012.
Zu-Guo Zheng 1 Yin-Yue Xu 2 Wen-Ping Liu 2 Yang Zhang 2 Chong Zhang 2 Han-Ling Liu 2 Xiao-Yu Zhang 2 Run-Zhou Liu 2 Yi-Ping Zhang 2 Meng-Ying Shi 2 Hua Yang 3 Ping Li 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected]
  • 2 State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
  • 3 State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected]
  • 4 State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected]
Abstract

sn-1,2-diacylglycerol (sn-1,2-DAG)-mediated activation of protein kinase Cε (PKCε) is a key pathway that is responsible for obesity-related lipid metabolism disorders, which induces hepatic Insulin resistance and type 2 diabetes. No small molecules have been previously reported to ameliorate these diseases through this pathway. Here, we screened and identified the phytochemical atractylenolide II (AT II) that reduces the hepatic sn-1,2-DAG levels, deactivates PKCε activity, and improves obesity-induced hyperlipidemia, hepatosteatosis, and Insulin resistance. Furthermore, using the ABPP strategy, the diacylglycerol kinase family member DGKQ was identified as a direct target of AT II. AT II may act on a novel drug-binding pocket in the CRD and PH domains of DGKQ to thereby allosterically regulate its kinase activity. Moreover, AT II also increases weight loss by activating DGKQ-AMPK-PGC1α-UCP-1 signaling in adipose tissue. These findings suggest that AT II is a promising lead compound to improve obesity-induced Insulin resistance.

Keywords

DGKQ; atractylenolide II; hepatosteatosis; insulin resistance; sn-1,2-DAG-PKCε signaling axis.

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