Abstract
Proper timely management of various external and internal stresses is critical for metabolic and redox homeostasis in mammals. In particular, dysregulation of mechanistic target of rapamycin complex (mTORC) triggered from metabolic stress and accumulation of reactive oxygen species (ROS) generated from environmental and genotoxic stress are well-known culprits leading to chronic metabolic disease conditions in humans. Sestrins are one of the metabolic and environmental stress-responsive groups of proteins, which solely have the ability to regulate both mTORC activity and ROS levels in cells, tissues and organs. While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. In this review, we discuss recent studies that investigated and manipulated Sestrins-mediated stress signaling pathways in metabolic and environmental health. Sestrins as an emerging dynamic group of stress-sensor proteins are drawing a spotlight as a preventive or therapeutic mechanism in both metabolic stress-associated pathologies and aging processes at the same time.
Highlights
OF SESTRINsSESTRINs (Sestrin1, 2, and 3, gene name: Sesn) are a classical family of stress-inducible proteins that regulate metabolism through sensing nutrient level and redox status in cells, tissues and organs
While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging
The study using adiposespecific Sestrin2 overexpressing mice (PG-Sesn2) suggests that Sestrin2 interferes with brown adipose tissue (BAT)-specific expression of uncoupling protein 1 (UCP1) through suppression of reactive oxygen species (ROS)-mediated p38 MAPK activation, and resulted in the undesirable accumulation of lipids in BAT (Ro et al, 2014a). These results indicate that maintaining the physiological level and activity of Sestrins in each tissues are critical for metabolic homeostasis and may provide a new therapeutic approach for the prevention of obesity, insulin resistance and diabetes
Summary
While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. SESTRINs (Sestrin1, 2, and 3, gene name: Sesn) are a classical family of stress-inducible proteins that regulate metabolism through sensing nutrient level and redox status in cells, tissues and organs.
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