Membrane Protein Amuc_1100 Derived from Akkermansia muciniphila Facilitates Lipolysis and Browning via Activating the AC3/PKA/HSL Pathway

Xifen Zheng; Wenting Huang; Qianbei Li; Yun Chen; Linyan Wu; Yifan Dong; Xinyue Huang; Xiaojing He; Zihao Ou; Yongzheng Peng

doi:10.1128/spectrum.04323-22

Membrane Protein Amuc_1100 Derived from Akkermansia muciniphila Facilitates Lipolysis and Browning via Activating the AC3/PKA/HSL Pathway

Microbiol Spectr. 2023 Feb 27;11(2):e0432322. doi: 10.1128/spectrum.04323-22. Online ahead of print.

Authors

Xifen Zheng^#¹, Wenting Huang^#¹, Qianbei Li^#², Yun Chen³, Linyan Wu¹, Yifan Dong¹, Xinyue Huang², Xiaojing He², Zihao Ou², Yongzheng Peng^{1

4}

Affiliations

¹ Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
² Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Department of Gynaecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁴ Department of Transfusion Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

^# Contributed equally.

Abstract

Obesity, defined as a disorder of lipid metabolism caused by white fat accumulation, is closely related to the gut microbiota. Akkermansia muciniphila (Akk), one of the most common gut commensals, can reduce fat storage and promote the browning of white adipocytes, alleviating disorders of lipid metabolism. However, which components of Akk produce the effect remain unclear, limiting the application of Akk in the treatment of obesity. Here, we found that the membrane protein Amuc_1100 of Akk decreased formation of lipid droplets and fat accumulation during the differentiation process and stimulated browning in vivo and in vitro. Transcriptomics revealed that Amuc_1100 accelerated lipolysis through upregulation of the AC3/PKA/HSL pathway in 3T3-L1 preadipocytes. Quantitative PCR (qPCR) and Western blotting showed that Amuc_1100 intervention promotes steatolysis and browning of preadipocytes by increasing lipolysis-related genes (AC3/PKA/HSL) and brown adipocyte marker genes (PPARγ, UCP1, and PGC1α) at both the mRNA and protein levels. These findings introduce new insight into the effects of beneficial bacteria and provide new avenues for the treatment of obesity. IMPORTANCE An important intestinal bacterial strain Akkermansia muciniphila contributes to improving carbohydrate and lipid metabolism, thus alleviating obesity symptoms. Here, we find that the Akk membrane protein Amuc_1100 regulates lipid metabolism in 3T3-L1 preadipocytes. Amuc_1100 inhibits lipid adipogenesis and accumulation during the differentiation process of preadipocytes, upregulates the browning-related genes of preadipocytes, and promotes thermogenesis through activation of uncoupling protein-1 (UCP-1), including Acox1 involved in lipid oxidation. Amuc_1100 accelerates lipolysis via the AC3/PKA/HSL pathway, phosphorylating HSL at Ser 660. The experiments illustrated here identify the specific molecules and functional mechanisms of Akk. Therapeutic approaches with Amuc_1100 derived from Akk may help alleviate obesity and metabolic disorders.

Keywords: AC3/PKA/HSL pathway; Amuc_1100; browning; lipolysis; preadipocytes.