Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis

Aung Than,Peng Chen,Melvinkhee-Shing Leow,Ru Li,Lei Sun,Shaohai Xu

doi:10.1038/sigtrans.2017.22

Abstract

Brown adipose tissue dissipates energy in the form of heat. Recent studies have shown that adult humans possess both classical brown and beige adipocytes (brown-like adipocytes in white adipose tissue, WAT), and stimulating brown and beige adipocyte formation can be a new avenue to treat obesity. Angiotensin II (AngII) is a peptide hormone that plays important roles in energy metabolism via its angiotensin type 1 or type 2 receptors (AT1R and AT2R). Adipose tissue is a major source of AngII and expresses both types of its receptors, implying the autocrine and paracrine role of AngII in regulating adipose functions and self-remodeling. Here, based on the in vitro studies on primary cultures of mouse white adipocytes, we report that, AT2R activation, either by AngII or AT2R agonist (C21), induces white adipocyte browning, by increasing PPARγ expression, at least in part, via ERK1/2, PI3kinase/Akt and AMPK signaling pathways. It is also found that AngII–AT2R enhances brown adipogenesis. In the in vivo studies on mice, administration of AT1R antagonist (ZD7155) or AT2R agonist (C21) leads to the increase of WAT browning, body temperature and serum adiponectin, as well as the decrease of WAT mass and the serum levels of TNFα, triglycerides and free fatty acids. In addition, AT2R-induced browning effect is also observed in human white adipocytes, as evidenced by the increased UCP1 expression and oxygen consumption. Finally, we provide evidence that AT2R plays important roles in hormone T3-induced white adipose browning. This study, for the first time, reveals the browning and brown adipogenic effects of AT2R and suggests a potential therapeutic target to combat obesity and related metabolic disorders.

Highlights

The excess white adipose tissue (WAT) that characterizes obesity is a major risk factor for the development of many diseases, such as diabetes, coronary heart disease, hypertension, stoke and some types of cancers.[1,2] In contrast to the notorious WAT that stores energy as lipids, brown adipose tissue (BAT) dissipates energy directly as heat by uncoupling oxidative phosphorylation from adenosine triphosphate (ATP) production through the action of brown adipocyte-specific uncoupling protein 1 (UCP1).[3]
And c, mouse white adipocytes have AT2R browning pathway. This is consistent with a recent study negligible amount of uncoupling protein 1 (UCP1, brown adipocyte-specific protein and thermogenic marker), which is consistent with our previous finding and other studies.[13,30] showing the upregulation of thermogenic gene expression in WAT of AT1R knockout mice.[34]
We observed that M024/C21,35–37 but not UCP1 level was significantly increased in Angiotensin II (AngII)- CGP42112, stimulated the expressions of

Summary

Introduction

The excess white adipose tissue (WAT) that characterizes obesity is a major risk factor for the development of many diseases, such as diabetes, coronary heart disease, hypertension, stoke and some types of cancers (for example, colorectal cancer).[1,2] In contrast to the notorious WAT that stores energy as lipids, brown adipose tissue (BAT) dissipates energy directly as heat by uncoupling oxidative phosphorylation from adenosine triphosphate (ATP) production through the action of brown adipocyte-specific uncoupling protein 1 (UCP1).[3] BAT improves insulin sensitivity and regulates glucose homeostasis.[4] Recent studies have shown that metabolically active BAT, which was thought to disappear after infancy, is present in adult humans.[5] BAT is rare (present as small clusters in supraclavicular and paraspinal regions) in adult humans and even less in obese people, brownlike adipose cells (called beige cells) have been identified in certain WAT depots (for example, subcutaneous WAT).[6,7] Emerging evidence suggests that beige adipocytes in WAT promote body energy consumption, and confer beneficial effects on obesity and insulin resistance.[6,8] The development of beige cells in WAT (a process known as WAT browning) occurs in response to prolonged cold exposure (or β-adrenergic stimulation), and some hormones (for example, thyroid hormone T3, fibroblast growth factor 21).[8] the recent discovery of inducible beige cells in WAT have inspired the possibility to treat obesity and related metabolic disorders through stimulating ameliorative selfremodeling of WAT

Methods

Results

Conclusion