Heat shock protein 60 (HSP60) modulates adiponectin signaling by stabilizing adiponectin receptor

Deling Zhang,Zhongyuan Wen,Yuyang Zheng,Junfeng Li,Yemin Zhang,Yalin Fu,Jie Wu,Mingke Ma,Hua Liu,Changhua Wang

doi:10.1186/s12964-020-00546-5

Abstract

Adiponectin, an adipokine produced and secreted by adipocytes, is involved in regulating the development and progression of insulin resistance, diabetes, and diabetic complications. Heat shock protein 60 (HSP60) is a molecular chaperone, most commonly presenting in mitochondria and participating in the maintenance of protein homeostasis. Accumulating studies have demonstrated that the elevated circulating HSP60 and the decreased intracellular HSP60 are closely associated with diabetic complications such as diabetic cardiomyopathy. However, the underlying mechanism remains poorly understood. In the present study, we reported that HSP60 interacted directly with adiponectin receptors. Its abundance was positively associated with adiponectin action. Furthermore, HSP60 depletion markedly mitigated the protective impacts of adiponectin on high glucose-induced oxidative stress and cell apoptosis in rat cardiac H9c2 cells. In addition, HSP60 knockdown significantly enhanced proteasome activity leading to the degradation of adiponectin receptor 1. Taken together, we showed for the first time that HSP60 interacted with adiponectin receptors and mediated adiponectin signaling through stabilizing adiponectin receptor. This in vitro study also provides an alternative explanation for mechanism by which adiponectin exerts its action.B94avigycLYsoGgop984zWVideo abstract

Highlights

Adiponectin is the most abundant adipokine produced and secreted by adipocytes
Heat shock protein 60 (HSP60) associated with adiponectin receptors Adiponectin receptors, Adiponectin receptor 1 (AdipoR1) and AdipoR2, are important members in a new family of cell surface receptor, called Progestin and AdipoQ Receptor (PAQR) family [31]
We found that phosphorylation of AMPK and p38 MAPK in response to adiponectin stimulation were greatly suppressed in HSP60-KD H9c2 cells (Fig. 2a and b) and HepIR cells (Fig. 2c and d) but obviously enhanced in HSP60-OE H9c2 cells (Additional file 1: Figure S1a and S1b) and HepIR cells (Additional file 1: Figure S1c and S1d), respectively

Summary

Introduction

Adiponectin is the most abundant adipokine produced and secreted by adipocytes. Through binding with its specific receptors adiponectin receptor 1 (AdipoR1) and AdipoR2, adiponectin initiates intracellular signaling pathways and exerts promising effects in the prevention or treatment of diabetes and metabolic syndrome, cardiovascular diseases, cancers, central nervous system disorders and so on [1,2,3,4]. Zhang et al Cell Communication and Signaling (2020) 18:60 to the cytosol and cell membrane, and secrete into blood to form serum (or circulating) HSP60 [9]. The ability of HSP60 in response to different stress greatly dependents on its localization [10]. HSP60 expression and secretion can be promoted in viable cells such as cardiomyocytes, adipocytes, astrocytes, and peripheral blood mononuclear cells, in response to proinflammatory cytokines as diverse as IL-1β and TNF-α [11,12,13,14]. Serum HSP60 has been recognized as a potent inductor of proinflammatory mediators in various cells indulging innate immune cells, skeletal muscle, cardiomyocytes, and adipocytes [11, 15,16,17]. The high levels of serum HSP60 have been found in the individuals with adjuvant arthritis and atherosclerosis [18, 19]

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