Glucocorticoids are widely prescribed anti-inflammatory drugs, and key physiological mediators of stress.While these steroids are well known to cause insulin resistance, less is known about how glucocorticoids function differently in lean and obese individuals.


Diet-induced mice, as well as serum and adipose tissue biopsies from lean and obese humans were used to evaluate insulin sensitivity, muscle strength, lipolysis and markers thereof.Tissue-specific inducible knockout of the glucocorticoid receptor in adipose tissue was used to delineate the roles of adipose vs systemic GR signaling.


Using data from humans and mice, we show that obesity enhances glucocorticoid-dependent processes including insulin resistance, NAFLD and muscle atrophy.Using an adipose-specific knockout model we show that adipocyte glucocorticoid action is critical for the obesity-stimulated glucocorticoid-dependent insulin resistance and NAFLD, but is dispensable for elevated muscle atrophy.In terms of an underlying mechanism, our data suggests that obesity modifies the chromatin landscape around select loci enabling more efficient glucocorticoid-dependent transactivation of target genes.


Our data supports the hypothesis that obesity may promote responses to elevated glucocorticoids, and that adipocytes are critical for this phenotype. These data support the hypothesis that there are considerable risks associated with raised glucocorticoid levels in people with obesity.