Glucocorticoid Receptor ß as an inducer of obesity-associated cardiovascular disease
Genesee Martinez1, Zackary A. Kipp1, David E. Stec2, and Terry D. Hinds, Jr.1,3,4
1Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY
2 Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS
3Markey Cancer Center, University of Kentucky, Lexington, KY
4Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY
The leading cause of death globally is cardiovascular disease, which might be worsened with the increasing rates of obesity. Nuclear receptors play an important role in the regulation of many bodily systems, including the immune system, respiratory system, endocrine system, and cardiovascular system. However, long-term glucocorticoid therapy causes weight gain and adiposity that can lead to type II diabetes, and cardiovascular disease (CVD). Thus, the glucocorticoid receptor (GR) is noteworthy when addressing CVD and may serve as a potential target for therapeutics. The GR has two isoforms, alpha and beta, through which physiological processes like metabolism, cardiovascular function, immune function, reproduction, and development are regulated. It is largely thought that GRb inhibits GRa and that this interaction is the cause of glucocorticoid-related disease states, especially in glucocorticoid-resistant diseases. We have shown that GRb suppresses the activity of the fat-burning nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa). However, we hypothesize that GRb has a positive relationship with PPARg to induce adiposity. We found in our GRb knockout (KO) mice that were fed a high-fat diet that they had significantly less fat pad sizes, and PPARg expression in white adipose tissue (WAT) was significantly lower. During obesity, WAT can secrete inflammatory cytokines that can be damaging to the cardiovascular system and lead to obesity-induced CVD. We have shown that increasing GRb activates NFkB and cytokine production causing a shift in the macrophage population from anti-inflammatory M2 to pro-inflammatory M1. In our future work, we will determine whether the GRb-PPARg axis in WAT is a factor that contributes to CVD associated with obesity. Our work may reveal an important axis that leads to cardiovascular events.