Targeting osteoblastic 11β-HSD1 to combat high fat diet-induced bone loss, glucose handing impairment and obesity

High-fat diet (HFD) not only causes obesity and glucose handling impairment, but also induces significant bone loss that increases the fracture risk in obese individuals, yet the underlying mechanism is still elusive. It was reported that mice with global knockout (KO) of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the key enzyme responsible for activating glucocorticoid (GC), were largely resistant to HFD-induced bone loss, glucose handling impairment and obesity. Intriguingly, a recent study demonstrated that disrupting skeletal GC signaling by genetically overexpressing 11β-HSD2, the enzyme responsible for inactivating GC, could prevent HFD-induced bone loss and glucose handling impairment in HFD-fed mice. These findings indicate the involvement of intraosseous GC signaling in HFD-induced bone loss, glucose handling impairment and obesity, wherein the role of osteoblastic 11β-HSD1 remains unexplored.

In our preliminary study on 60% HFD-fed C57B6/L mice, we observed the notable bone loss that developed after 12 weeks of HFD induction. Interestingly, the mRNA expressions of 11βHSD1 and glucocorticoid-induced leucine zipper (Gilz, a GC target gene reflecting the activation of GC signaling) were markedly upregulated in bone, dominantly in osteoblasts, rather than other metabolic organs after 8 weeks of HFD induction. In a subsequent pilot study on the osteoblast-specific 11β-HSD1 KO mice (Hsd11b1ob-/- ) with small sample size, we were surprised to find that osteoblast-specific knockout of 11β-HSD1 mitigated body weight gain and prevented bone loss in HFD-fed Hsd11b1ob-/- mice. Excitingly, they showed less fat accumulation, improved glucose metabolism and enhanced glucose uptake into bone compared with the HFD-fed wildtype littermates. Mechanistically, we found that the aberrantly high 11βHSD1 triggered excessive GC signaling activation in osteoblast that restrained the glucose uptake capacity and osteogenic activity via repressing the early growth response protein-2 (Egr2)-promoted gene transcription. Thus, it suggests that the elevated 11β-HSD1 in osteoblast could directly contribute to the HFD-induced bone loss, glucose handing impairment and obesity. To determine whether osteoblastic 11β-HSD1 would be a therapeutic target for HFD-induced dysmetabolism, we developed an osteoblast-targeted 11β-HSD1 inhibitor ((DSS)6-inhibitor) for pharmacologically inhibiting osteoblastic 11β-HSD1 activity in vivo. Our pilot data implied that (DSS)6-inhibitor could exert potency on mitigating body weight gain and bone loss in HFD-fed C57B6/L mice. Taken all together, we hypothesize that targeting osteoblastic 11β-HSD1 could combat HFD-induced bone loss, glucose handing impairment and obesity.

We have the following three specific aims for testing the hypothesis:
Aim 1. To validate the effects of genetically disrupting osteoblastic 11β-HSD1 on bone loss, glucose handling impairment and obesity in 60% HFD-fed Hsd11b1ob-/- mice.
Aim 2. To compare the differences in GC signaling activation, glucose uptake and osteogenesis between primary osteoblasts derived from 60% HFD-fed Hsd11b1ob-/- mice and WT mice in vitro.
Aim 3. To evaluate the effects of pharmacologically inhibiting osteoblastic 11β-HSD1 activity on bone loss, glucose handling impairment and obesity in 60% HFD-fed mice treated with (DSS)6-inhibtor.

If our hypothesis could be supported, it will not only provide mechanistic insight into HFDinduced bone loss and dysmetabolism but also facilitate the development of novel therapeutic strategy for combating bone loss and glucose handling impairment in obese individuals.