Flattened circadian glucocorticoid oscillations cause obesity due to increased lipid turnover and lipid uptake

Chronic stressors flatten circadian glucocorticoid (GC) oscillations, which has been correlated with negative health outcomes including obesity. How such flattened circadian GC oscillations affect metabolism and fat storage remains unknown. Here we investigated the consequences in mice and found that flattening of GC oscillations results not only in body weight gain, mainly due to increases in white fat depot mass, but also leads to hyperinsulinemia and fat accumulation in brown adipose tissue. Global analysis of the transcriptome of WAT and BAT revealed alterations in gene expression dependent on flattened GC oscillations and point to increased lipid turnover and lipid uptake in both fat depots. To elucidate how gene expression is globally affected by flattening of glucocorticoid oscillations as a potential cause for the expansion of fat depots, we performed RNAseq analysis of vWAT and BAT. Mice were subcutaneously implanted with corticosterone pellets to flatten their corticosterone oscillations and compared to mice inplanted with a placebo pellet. The fat depots (vWAT and BAT) were harvested 0, 3, 7, and 14 days after pellet implantation. To control that observed changes in gene expression are due to flattening of diurnal corticosterone oscillations and not caused by the amount of corticosterone released by the corticosterone pellet, a similar RNAseq analysis was performed, in which mice were injected with the same amount of corticosterone released by the corticosterone pellet per day in one single injection, thereby increasing the peak amplitude of corticosterone in the evening phase. Also these fat depots (vWAT and BAT) were harvested 0, 3, 7, and 14 days after start of injection.