Endocrine Abstracts

Insulin resistance and obesity are a global health problem and directly linked to macrophage-driven inflammation of the adipose tissue. Glucocorticoid therapy, used to treat inflammatory conditions, increases adiposity and insulin resistance. It is unknown however, whether anti-inflammatory actions of glucocorticoids at physiological levels can have beneficial effects on adipose tissue inflammation, potentially limiting insulin resistance. Using a macrophage specific deletion of the glucocorticoid receptor (GR), we show that the glucocorticoid signalling in macrophages protects against obesity related insulin resistance. We found that obese mice lacking the glucocorticoid receptor in macrophages have increased adipose tissue inflammation along with a diminished anti-inflammatory polarisation of adipose tissue macrophages. Macrophages deficient for GR show diminished IL-4 signalling which consequently leads to diminished maintenance of body temperature during cold exposure, linking glucocorticoid action in macrophages to homeothermy. Unexpectedly, this was only attributed to limited browning in subcutaneous but not brown adipose tissue. Similarly, loss of macrophage GR reduced inflammation regulated adipose tissue browning, which increases the drop in body temperature during endotoxin shock. Our results demonstrate that glucocorticoids play an important homeostatic role in macrophages during obesity to limit adipose tissue inflammation and promote insulin sensitivity. We also identify a cooperation of glucocorticoid signalling and IL-4 signalling in macrophages to promote alternative activation, in turn assisting in homeothermy.