Adipocyte Glucocorticoid Receptor Inhibits Immune Regulatory Genes to Maintain Immune Cell Homeostasis in Adipose Tissue

Abstract

Glucocorticoids acting via the glucocorticoid receptors (GR) are key regulators of metabolism and the stress response. However, uncontrolled or excessive GR signaling adversely affects adipose tissue, including endocrine, immune, and metabolic functions. Inflammation of the adipose tissue promotes systemic metabolic dysfunction; however, the molecular mechanisms underlying the role of adipocyte GR in regulating genes associated with adipose tissue inflammation are poorly understood. We performed in vivo studies using adipocyte specific GR knockout mice (Adipo GRKO) in conjunction with in vitro studies to understand the contribution of adipocyte GR in regulating adipose tissue immune homeostasis. Our findings show that adipocyte specific GR signaling regulates adipokines at both mRNA and plasma levels, and immune regulatory (Coch, Pdcd1, Cemip, and Cxcr2) mRNA gene expression, which affects myeloid immune cell presence in white adipose tissue. We found that in adipocytes, GR directly influences Cxcr2. This chemokine receptor promotes immune cell migration, indirectly affecting Pdcd1 and Cemip gene expression in non-adipocyte or stromal cells. Our findings suggest that GR adipocyte signaling suppresses inflammatory signals, maintaining immune homeostasis. We also found that GR signaling in adipose tissue in response to stress is sexually dimorphic. Understanding the molecular relationship between GR signaling and adipose tissue inflammation could help develop potential targets to improve local and systemic inflammation, insulin sensitivity, and metabolic health.

Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction

“…While GR has previously been shown to mediate stress erythropoiesis ( 41 ), we hypothesize that the lack of changes in circulating red blood cells in BMAd-Nr3c1 -/- mice is because this process mostly occurs in the spleen ( 76 ). In WAT, adipocyte GR suppresses the immune system, maintaining immune homeostasis ( 77 , 78 ). While circulating white blood cells were decreased during the day in BMAd-Nr3c1 -/- mice, we did not observe differences in the abundance of bone marrow progenitor cell populations in the tibiae of BMAd-Nr3c1 -/- mice.…”

Comparative Evaluation of Adipolin Expression in Gingival Crevicular Fluid and Serum of Healthy Subjects and Periodontitis Patients with and without Type 2 Diabetes Mellitus

“…Adipolin (FAM132A/CTRP12/Clq/TNF-related protein gene) is a novel adipokine that is influenced by a decrease in Kruppel-like factor-15 (KLF-15) and in T2DM patients, insulin resistance disrupts the insulin-adipolin homeostatic response, which could lead to lower adipolin levels [18,19]. Predominantly macrophages and almost all major types of immune cells are involved in the linkage of endocrine function of adipose tissue in systemic metabolic regulation [20].…”