PAR2 Deficiency Induces Mitochondrial ROS Generation and Dysfunctions, Leading to the Inhibition of Adipocyte Differentiation.

Yeo Jin Park,Min-Kyeong Lee,Bonggi Lee,Younghoon Go,Dae Hyun Kim,Sugyeong Ha,Hae Young Chung,Eun-Bin Kwon,Hak Sun Yu,Pasquale Pagliaro

doi:10.1155/2021/6683033

Abstract

Protease-activated receptor 2 (PAR2) is a member of G-protein-coupled receptors and affects ligand-modulated calcium signaling. Although PAR2 signaling promotes obesity and adipose tissue inflammation in high fat- (HF-) fed conditions, its role in adipocyte differentiation under nonobesogenic conditions needs to be elucidated. Here, we used several tissues and primary-cultured adipocytes of mice lacking PAR2 to study its role in the development of adipose tissues. C57BL/6J mice with PAR2 deficiency exhibited a mild lipodystrophy-like phenotype in a chow diet-fed condition. When adipocyte differentiation was examined using primary-cultured preadipocytes, PAR2 deficiency led to a notable decrease in adipocyte differentiation and related protein expression, and PAR2 agonist treatment elevated adipocyte differentiation. Regarding the mechanism, PAR2-deficient preadipocytes exhibited impaired mitochondrial energy consumption. Further studies indicated that calcium-related signaling pathways for mitochondrial biogenesis are disrupted in the adipose tissues of PAR2-deficient mice and PAR2-deficient preadipocytes. Also, a PAR2 antagonist elevated mitochondrial reactive oxygen species and reduced the MitoTracker fluorescent signal in preadipocytes. Our studies revealed that PAR2 is important for the development of adipose tissue under basal conditions through the regulation of mitochondrial biogenesis and adipocyte differentiation.

Highlights

Adipocytes store excess energy as triglycerides (TGs) and act as a dynamic autocrine, paracrine, and endocrine organ that releases hormonal factors
Protease-activated receptor 2 (PAR2) signaling is involved in obesity and metabolic syndrome under a high fat- (HF-)fed condition, PAR2 signaling is important for cell differentiation and tissue regeneration [17, 18] and for preventing apoptosis [17, 19]
Because it is unclear whether PAR2 signaling affects adipose tissue development under nonobesogenic conditions, we investigated the effects of PAR2 deficiency on energy balance and adipose tissue development under a chow diet-fed condition

Summary

Introduction

Adipocytes store excess energy as triglycerides (TGs) and act as a dynamic autocrine, paracrine, and endocrine organ that releases hormonal factors. Excessive growth of white adipose tissue [1] by hyperplasia and hypertrophy can lead to obesity, disruption of adipocyte differentiation results in metabolic syndrome via ectopic lipid accumulation and lipotoxicity. Various animal studies showed that healthy fat accumulation elevated body weight but greatly improved metabolic syndrome. While overexpressing adiponectin, exhibited increased expression levels of peroxisome proliferator-activated receptor γ (PPARγ), a master transcription factor of adipogenesis, leading to the expansion of adipose tissue; these mice showed an improvement in the metabolic syndrome [4]. PPARγ agonists improve insulin resistance and dyslipidemia, despite the increase in fat mass. A supply of fresh adipocytes is essential to maintain energy homeostasis

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Conclusion