Sestrin2 Regulates Beneficial β3-Adrenergic Receptor-Mediated Effects Observed in Inguinal White Adipose Tissue and Soleus Muscle

Abstract

Sestrin2, a well-known adenosine monophosphate-activated protein kinase (AMPK) regulator, plays a protective role against metabolic stress. The β3-adrenergic receptor (β3AR) induces fat browning and inhibits muscle atrophy in an AMPK-dependent manner. However, no prior research has examined the relationship of sestrin2 with β3AR in body composition changes. In this study, CL 316,243 (CL), a β3AR agonist, was administered to wild-type and sestrin2-knockout (KO) mice for 2 weeks, and fat and muscle tissues were harvested. CL induced AMPK phosphorylation, expression of brown-fat markers, and mitochondrial biogenesis, which resulted in the reduction of lipid droplet size in inguinal white adipose tissue (iWAT). These effects were not observed in sestrin2-KO mice. In CL-treated soleus muscle, sestrin2-KO was related to decreased myogenic gene expression and increased levels of muscle atrophy-related molecules. Our results suggest that sestrin2 is associated with beneficial β3AR-mediated changes in body composition, especially in iWAT and in the soleus.

Sestrin2 in diabetes and diabetic complications

“…Sestrin2 overexpression suppresses oxidative stress and cell apoptosis by activating Nrf2-ARE signaling ( 54 , 55 ). Also, Sestrin2/Nrf2 signaling may be important for the mediation of ER stress as a downstream regulator of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway ( 56 ), which is illustrated below.…”

“…Recent finding suggested Sestrin2 as a regulator of motohormesis in brown adipose tissue ( 135 ). Also, Sestrin2 was found to be related to beneficial body composition changes, including the decrease of lipid droplet size in inguinal white adipose tissue and the increase of soleus muscle mass ( 56 ). Monocytes and macrophages are critically involved in atherosclerosis and participate in the atherosclerotic lesion progression associated with diabetes ( 136 ).…”