Glucocorticoids Suppress the Browning of Adipose Tissue via miR-19b in Male Mice

Abstract

Physiological levels of glucocorticoids (GCs) are required for proper metabolic control, and excessive GC action has been linked to a variety of pandemic metabolic diseases. MicroRNA (miRNA)-19b plays a critical role in the pathogenesis of GC-induced metabolic diseases. This study explored the potential of miRNA-based therapeutics targeting adipose tissue. Our results showed that overexpressed miR-19b in stromal vascular fraction (SVF) cells derived from subcutaneous adipose tissue had the same effects as dexamethasone (DEX) treatment on the inhibition of adipose browning and oxygen consumption rate. The inhibition of miR-19b blocked DEX-mediated suppression of the expression of browning marker genes as well as the oxygen consumption rate in differentiated SVF cells derived from subcutaneous and brown adipose tissue. Overexpressed miR-19b in SVF cells derived from brown adipose tissue had the same effects as DEX treatment on the inhibition of brown adipose differentiation and energy expenditure. Glucocorticoids transcriptionally regulate the expression of miR-19b via a GC receptor-mediated direct DNA binding mechanism. This study confirmed that miR-19b is an essential target for GC-mediated control of adipose tissue browning. It is hoped that the plasticity of the adipose organ can be exploited in the next generation of therapeutic strategies to combat the increasing incidence of metabolic diseases, including obesity and diabetes.

Glucocorticoid-Induced Obesity Develops Independently of UCP1

“…Earlier studies have indicated that glucocorticoid-induced obesity is secondary to a repressed expression of the brown fat-specific protein UCP1 and an ensuing decrease in thermogenesis (van den Beukel et al, 2015;Lv et al, 2018;Strack et al, 1995;Viengchareun et al, 2001). In the present investigation, we have examined the significance of UCP1 for the development of glucocorticoid-induced obesity.…”

“…The exact mechanisms behind the development of obesity and obesity-related diseases in response to high levels of glucocorticoids are not known. However, an involvement of brown adipose tissue (BAT), the main site for non-shivering thermogenesis in most mammals, has been discussed (van den Beukel et al, 2015;Liu et al, 2013;Lv et al, 2018;Strack et al, 1995;Viengchareun et al, 2001). Normally, upon activation by the sympathetic nervous system in response to cold exposure or certain diets, BAT produces heat through the tissue-specific mitochondrial uncoupling protein 1 (UCP1) that uncouples substrate oxidation from ATP production and dissipates the proton gradient across the inner mitochondrial membrane as heat (Cannon and Nedergaard, 2004).…”

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

“…Despite a number of in vitro studies suggesting an important role of the GR in both white and brown adipose tissue differentiation and cell function [11,23,[30][31][32], more recent studies have revealed that the absence of the GR in WAT is dispensable for WAT differentiation and function in vivo [4,9,33]. In this respect, our genetic loss-of-function study now addresses a key question in the field of BAT research and GR-dependent endocrine control of metabolism by demonstrating that in contrast to previous assumptions, the GR in BAT is largely dispensable for systemic energy homeostasis during both short and long-term metabolic adaptations.…”

Glucocorticoid Receptor and Adipocyte Biology

“…Notably, certain studies find that glucocorticoids enhance, rather than suppress, insulin actions in human primary adipocytes [ 26 , 27 ]. Finally, glucocorticoids have been shown to repress the thermogenic activity of brown and beige adipocytes in rodents [ 28 – 31 ]. However, recent studies show that acute glucocorticoid exposure enhances the thermogenic activity of human brown adipose tissue [ 32 ].…”