Fellowship for Genesee Martinez: The Glucocorticoid Receptor-b (GRb) as a Mediator of Adiposity and Cardiovascular Disease

Title: The Glucocorticoid Receptor-β (GRβ) as a mediator of adiposity and cardiovascular disease Summary: The increasing rates of obesity have led to a higher prevalence of its associated comorbidities, which include insulin-resistant type II diabetes and cardiovascular disease (CVD). Short-term exposure to glucocorticoids reduces body weight, and long-term exposure typically increases it. We hypothesize that the switch from reducing to increasing body weight is due to the protein receptor for glucocorticoids, the glucocorticoid receptor (GR), which has two major isoforms, GRα and GRβ. The GR isoforms are formed from the alternative splicing of exon 9 of the GR gene (NR3C1). The mechanistic actions of GRβ has been shown to inhibit the GRα isoform. We hypothesize that increasing levels of GRβ may lead to adiposity that cause deleterious cardiovascular outcomes that are associated with long-term glucocorticoid therapy. To test our hypothesis, we established the first GRβ knockout (KO) mice via a specialized CRISPR technology approach that knocks out GRβ without affecting the GRα protein levels in mice. We did not obtain any live GRβ homozygous KO (GRβ-/-) mice, which could indicate that they are embryonically lethal. However, the heterozygous (GRβ+/-) mice are viable and have no observable differences in metabolic phenotypes on a standard chow diet. Therefore, in our preliminary studies, we used GRβ+/- and GRβ+/+ mice to determine the effects of the loss of GRβ on adiposity. We placed the GRβ+/- and GRβ+/+ mice on a high-fat diet (HFD) for 8 weeks and measured body composition, weights, adiposity, and signaling mechanisms. The GRβ+/- on a HFD had significantly reduced body weights, fat pads (iWAT and eWAT), and heart weights, compared to littermate controls. We also found significantly reduced PPARγ levels in iWAT of the GRβ+/- mice. Rosiglitazone, a potent agonist of PPARγ, has been used to treat type II diabetes but was shown to induce CVD in some patient populations. However, the cause is unknown. The goal of this proposal is to determine if the loss of GRβ protects from weight gain and adiposity-induced CVD. For Aim 1, we will characterize the function of GRβ in the fat pads and how they signal to the cardiovascular system. In Aim 2, we will assess how the loss of GRβ relates to heart failure and cardiac steatosis by treating the GRβ+/- and GRβ+/+ mice with rosiglitazone while fed a HFD. Our studies will be the first to dissect the functions of the GRβ isoform as it relates to adiposity and CVD, and if it is associated with rosiglitazone-induced CVD.