The Mechanism of Leptin on Inhibiting Fibrosis and Promoting Browning of White Fat by Reducing ITGA5 in Mice.

Yuexia Liu,Juntong Liang,Qiong Wu,Yongnian Liu,Yizhou Li,Chao Sun,Zhuwen Sun

doi:10.3390/ijms222212353

Abstract

Leptin is a small molecule protein secreted by adipocytes, which can promote white fat browning through activating the hypothalamic nervous system and inhibiting downstream signaling pathways. Moreover, white fat browning has been proven to alleviate fat tissue fibrosis. This study explores the mechanism of leptin in regulating adipose tissue fibrosis and white fat browning. After treating mice with leptin, we screened out the recombinant integrin alpha 5 (ITGA5) through proteomics sequencing, which may play a role in adipose tissue fibrosis. Through real-time quantitative PCR (qPCR), western blotting (WB), hematoxylin-eosin (HE) staining, Masson’s trichrome, immunofluorescence, immunohistochemistry, etc., the results showed that after leptin treated adipocytes, the expression of fibrosis-related genes and ITGA5 was significantly down-regulated in adipocytes. We constructed fibrosis model through transforming growth factor-β (TGF-β) and a high-fat diet (HFD), and treated with ITGA5 overexpression vector and interference fragments. The results indicated the expression of fibrosis-related genes were significantly down-regulated after interfering with ITGA5. After treating adipocytes with wortmannin, fibrosis-related gene expression was inhibited after overexpression of ITGA5. Moreover, after injecting mice with leptin, we also found that leptin significantly up-regulated the expression of adipose tissue browning-related genes. Overall, our research shows that leptin can inhibit the activation of phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) signaling pathway by reducing the expression of ITGA5, which could alleviate adipose tissue fibrosis, and further promote white fat browning. Our research provides a theoretical basis for further research on the effect of leptin in fibrosis-related adipose tissue metabolism.

Highlights

Adipose tissue has an important energy storage function in the body
Adipose tissue fibrosis is caused by obesity and other factors, which induce adipose tissue, to be in an environment of hypoxia and chronic inflammation for a long time, and eventually lead to the excessive deposition of extracellular matrix (ECM) in adipose tissue, resulting in adipose tissue metabolism disorder
In the process of adipose tissue fibrosis, adipose tissue ECM, HIF-1α, and inflammatory factors are in a state of continuous remodeling, leading to a significant increase in the expression of fibrosis-related genes such as COL1, COL3, COL6, and matrix metalloproteinase 9 (MMP9) in adipose tissue [31,32]

Summary

Introduction

Adipose tissue has an important energy storage function in the body. According to the source, shape, and function, adipocytes can be divided into three types: white adipocytes, brown adipocytes, and beige adipocytes [1]. Brown adipocytes mainly rely on the abundant uncoupling protein 1 (UCP1) in the mitochondria to leak the proton pump on the oxidative respiratory chain in the mitochondria, thereby converting energy into heat to deal with the body’s cold stimulation [3]. Beige adipocytes have multiple lipid droplets, and the content of mitochondria and UCP1 is higher than that of white adipocytes. This process is called white fat browning [3,4]. White fat browning is conducive to the consumption of excess lipids stored in white adipose tissue, reducing obesity, and improving adipocyte tissue inflammation [1,5]

Methods

Results

Conclusion