Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition

Abstract

Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from β-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice.

Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor

“…It is noteworthy that some of the actions of GCs may result from cross talk between tissues. For example, GCs promote lipid catabolism in adipose tissue, yet whether they drive lipolysis by directly or solely acting on adipocytes remains unclear [6–8]. It should also be mentioned that GCs exert rapid effects occurring in minutes that are insensitive to inhibitors of DNA transcription and protein synthesis [9].…”

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

“…In adipose tissue, GR is thought to mediate the lipolytic effects of GC treatment and has been found to be crucial for lipid mobilization in the postabsorptive state as well as in chronic GC exposure [4][5][6]. White adipose tissue (WAT) mainly acts as an energy storage organ, coping with excessive energy intake by storage in the form of triacylglycerol, and in turn liberating non-esterified fatty acids in periods of nutrient demand by other tissues or following lipolytic stimuli.…”

“…In adipose tissue, GR is thought to mediate the lipolytic effects of GC treatment and has been found to be crucial for lipid mobilization in the postabsorptive state as well as in chronic GC exposure [4][5][6]. Recent studies, however, have contested this notion: GR-deficient murine preadipocytes were shown to suffer only from a delay in triglyceride (TG) accumulation, and adiponectin-Cre-mediated deletion of GR led to no morphological difference in WAT depots [4,9]. GCs are contained in most in vitro adipogenic differentiation cocktails, and GR was found to bind cooperatively with CEBPB at transcriptional hotspots in early adipogenesis [8].…”

“…Moreover, GR had long been thought to play a major role in adipose tissue development and expansion via the process of adipocyte differentiation, thus contributing to adipocyte hyperplasia [7]. Thus, while GR seems to be crucial for lipid mobilization in the postabsorbtive state and in chronic GC exposure, adipose tissue expansion phenotypes have not been reported [4][5][6]. Recent studies, however, have contested this notion: GR-deficient murine preadipocytes were shown to suffer only from a delay in triglyceride (TG) accumulation, and adiponectin-Cre-mediated deletion of GR led to no morphological difference in WAT depots [4,9].…”

“…A vast number of studies in recent years have addressed the therapeutic potential of BAT in the treatment of obesity and insulin resistance. In another study, AdipoCre-driven constitutive knockdown of GR in all adipose tissues led to reduced BAT thermogenesis after a few hours of cold exposure, with a reduction in lipid droplets indicating that GR deficiency does not impair the lipolytic potential of BAT at 4°C [4]. Additionally, stimulation of the production and secretion of adipokines and lipokines has been exploited to target distant organs to increase, e.g., glucose uptake in skeletal muscle.…”