Glucocorticoids (GC) negatively affect brown adipose tissue function, which may contribute to GC-induced metabolic dysfunction. We have recently demonstrated that some of the adverse metabolic outcomes of GCs are mediated via the osteoblast (JCI 20121). The present study aimed to evaluate the contribution of osteoblastic GC-signaling in GC-induced brown adipose tissue dysfunction.
We used a transgenic (tg) mouse model in which GC-signaling had been selectively disrupted in osteoblasts and osteocytes via targeted overexpression of the GC-inactivating enzyme, 11ß-HSD2. Eight-week-old tg mice and their wild-type (wt) littermates were subcutaneously implanted with pellets containing either 1.5mg corticosterone or placebo for 4 weeks. At endpoint, white intra-abdominal fat pads and the inter-scapular brown fat pad were assessed.
Compared to respective placebo-treated controls (wt+plc/tg+plc), treatment of wt mice with corticosterone (wt+GC) resulted in a substantial increase in both white and brown adipose tissue mass, while in treated tg mice (tg+GC) only marginal changes in fat pad mass were observed (White fat: wt+GC:+0.9g vs. tg+GC:+0.4g, p<0.001; Brown fat: wt+GC:+0.31g vs. tg+GC:+0.18g, p<0.001). Histology revealed that treatment of wt mice with corticosterone increased lipid deposits in the brown fat, giving it the appearance of white adipose with large, lipid filled adipocytes rather than the small and dense multilocular adipocytes typical of brown fat. This effect was markedly attenuated in GC-treated tg mice, which displayed significantly lower fat accumulation and smaller lipid droplets than their wt counterparts (lipid area: wt+GC:51% vs. tg+GC:36%, p=0.005; lipid droplet size: wt+GC:1160μm2 vs. tg+GC:574μm2, p=0.006). Moreover, upon immunohistochemical assessment no UCP1 positive cells were apparent in wt+GC brown fat, whereas tg+GC mice displayed abundant positive staining, evidence for the protection of thermogenic potential in tg+GC mice.
Our findings demonstrate that the actions of high-dose GCs on the osteoblast play a hitherto unknown role in the adverse effects of GC treatment on brown adipose tissue in mice.