Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK

Ruoxuan Bao,Cheng Zhang,Zengxia Li,Changsheng Zhang,Yongjun Dang,Yongmei Meng,Wei Jiang,Chensong Zhang,Wei Li,Haibo Zhang,Renqiang Sun,Jinye Zhang,Chen Yang,Hai-Xin Yuan

doi:10.1038/s41419-021-04264-9

Abstract

Obesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer-cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly, instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high-fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.

Highlights

An alarming increase in obesity has been observed worldwide, bringing about huge economic and social burdens [1,2,3]
These results demonstrate that AMPK phosphorylation by liverkinase B1 (LKB1) is essential for Ela-induced AMPK activation, but LKB1 is not a direct target of Ela
To further investigate whether Ela promotes glucose consumption, we investigated the effects of Ela on metabolite changes of the tricarboxylic acid (TCA) cycle and amino acid metabolism in primary hepatocytes

Summary

INTRODUCTION

An alarming increase in obesity has been observed worldwide, bringing about huge economic and social burdens [1,2,3]. Ela did not promote the activity of LKB1 toward AMPK–Thr172 as revealed by in vitro kinase assays (Fig. 5f) These results demonstrate that AMPK phosphorylation by LKB1 is essential for Ela-induced AMPK activation, but LKB1 is not a direct target of Ela. Ela induces energy stress by rapidly increasing AMP/ATP and ADP/ATP ratios To further explore how Ela activates AMPK, we performed an Ela time-course experiment. In addition to being phosphorylated by upstream kinases, cellular energy stress reflected by changes in the adenine-nucleotide level is essential for AMPK activation [29] For this reason, we measured AMP, ADP, and ATP levels in MEF, primary hepatocytes, and differentiated primary adipocytes. These results demonstrate that Ela promotes glucose consumption and fatty acid oxidation

DISCUSSION

Findings

MATERIALS AND METHODS