Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation.

Abstract

Angptl7 is a secreted and circulating cytokine that belongs to Angiopoietin-like family. The current knowledge about the function of Angptl7 is still limited, and its biological role is only marginally known, such as in the promotion of angiogenesis and inflammation. Here, we demonstrated that Angptl7 promotes insulin resistance and type 2 diabetes mellitus (T2DM). We found that the circulating Angptl7 levels in T2DM patient and mouse models were significantly elevated. Artificial overexpression of Angptl7 in hepatic cells inhibited glucose uptake and impaired insulin signaling pathway. Furthermore, in vivo overexpression of Angptl7 in experimental healthy mice also caused insulin resistance-like characteristics. Mechanistic studies revealed that Angptl7 can upregulate SOCS3 expression, leading to the IRS1 degradation in proteasome. Furthermore, over-expressed Angptl7 inhibited the phosphorylation of Akt and promoted the phosphorylation of ERK1/2, which was known to be associated with insulin resistance. Taken together, our study provided strong evidence that Angptl7 promotes insulin resistance and T2DM by multiple mechanisms, which made Angptl7 a new potential therapeutic target for treatment of insulin resistance and T2DM.

• Authors: Tong Xu, Lilei Xu, Panpan Meng, Xuqian Ma, Xiaoqing Yang, Yaru Zhou, Mingqian Feng
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 10 Pg. 13548-13560 (Oct 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32786125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• ANGPTL7 protein, human
• ANGPTL7 protein, mouse
• Angiopoietin-Like Protein 7
• Angiopoietin-like Proteins
• IRS1 protein, human
• Insulin
• Insulin Receptor Substrate Proteins
• SOCS3 protein, human
• Suppressor of Cytokine Signaling 3 Protein

Topics

• Aged
• Angiopoietin-Like Protein 7
• Angiopoietin-like Proteins (blood, physiology)
• Animals
• Case-Control Studies
• Cohort Studies
• Diabetes Mellitus, Type 2 (metabolism)
• Female
• Hep G2 Cells
• Hepatocytes (metabolism, pathology)
• Humans
• Insulin (metabolism)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Suppressor of Cytokine Signaling 3 Protein (metabolism)