Liver-specific deletion of Ppp2cα enhances glucose metabolism and insulin sensitivity.

Li Xian,Siyuan Hou,Zhaoyu Lin,An Tang,Shujun Jiang,Zan Huang,Anying Song,Qinghua Wang,Shiying Guo,Peiliang Shi,Xiang Gao

doi:10.18632/aging.100725

Abstract

Protein phosphatase 2A (PP2A) is a key negative regulator of phosphatidylinositol 3-kinase/Akt pathway. Previous study showed that, in the liver, the catalytic subunit of PP2A (PP2Ac) is closely associated with insulin resistance syndrome, which is characterized by glucose intolerance and dyslipidemia. Here we studied the role of liver PP2Ac in glucose metabolism and evaluated whether PP2Ac is a suitable therapeutic target for treating insulin resistance syndrome. Liver-specific Ppp2cα knockout mice (Ppp2cα(loxp/loxp): Alb) exhibited improved glucose homeostasis compared with littermate controls in both normal and high-fat diet conditions, despite no significant changes in body weight and liver weight under chow diet. Ppp2cα(loxp/loxp): Alb mice showed enhanced glycogen deposition, serum triglyceride, cholesterol, low density lipoprotein and high density lipoprotein, activated insulin signaling, decreased expressions of gluconeogenic genes G6P and PEPCK, and lower liver triglyceride. Liver-specific Ppp2cα knockout mice showed enhanced glucose homeostasis and increased insulin sensitivity by activation of insulin signaling through Akt. These findings suggest that inhibition of hepatic Ppp2cα may be a useful strategy for the treatment of insulin resistance syndrome.

Highlights

Low insulin sensitivity is referred to as insulin resistance, in which insulin fails to efficiently modulate glucose uptake, production, and storage in insulinsensitive tissues [1, 2]
To investigate more details about the association between Ppp2cα and insulin resistance in the liver, we first examined the expression of Ppp2cα in the livers of two mice models of obesity and type 2 diabetes, leptin-deficient ob/ob and high-fat diet (HFD) mice
Insulin resistance in the liver has been viewed as a central feature of the pathophysiology of metabolic disorders, including glucose intolerance, dyslipidemia, and insulin action

Summary

Introduction

Low insulin sensitivity is referred to as insulin resistance, in which insulin fails to efficiently modulate glucose uptake, production, and storage in insulinsensitive tissues [1, 2]. Hepatic insulin resistance is a key factor in the pathogenesis of insulin resistance syndrome, which is characterized by obesity, type 2 diabetes, coronary artery disease, and so on [3]. Researchers have got a clear picture of insulin-signaling network based on various considerable data, beginning with the binding of insulin-receptor tyrosine kinase and phosphorylation of the insulinreceptor substrates (IRS1 and IRS2). The activated receptor initiates a linear signaling cascade by phosphorylation of downstream target proteins [4,5,6,7,8]. Among the several components of the insulin-signaling network, phosphorylation of phosphatidylinositol 3-. Kinase (PI3K)/Akt is a critical node that regulates most actions of insulin [9,10,11]. Impairment of insulin signaling can lead to insulin resistance syndrome [12, 13]

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Conclusion