Mechanisms underlying enhanced bone marrow adipogenesis in diabetes
Abstract
Morbidity and mortality associated with diabetes are due to secondary vascular complications that include both micro- and macro-vascular organ dysfunctions. Our recent studies show that vascular dysfunction and inadequate vessel repair in diabetes may potentially be due to impaired vasculogenesis (de novo vessel formation). Specifically, we have shown that diabetes enhances adipogenesis in the bone marrow and reduces the number of marrow-resident vascular regenerative stem cells. In this study, I have determined the mechanisms of deleterious bone marrow adipogenesis, which may alter the cellular composition of the marrow and lead to the depletion of vascular regenerative stem cells.
My initial work focused on understanding the early changes induced by diabetes in the bone marrow. To identify these changes, I induced diabetes in mice using streptozotocin. Even as early as 1 month after disease onset, changes—both structural and molecular—were evident in the bone marrow of diabetic mice. Importantly, I showed that short-term diabetes enhances adipogenesis in tibiae of mice. This enhanced adipogenesis was found to be associated with suppressed transforming growth factor beta (TGFB) signalling pathway.
Using bone marrow-derived mesenchymal progenitor cells (bm-MPCs), I then investigated the functional significance of TGFB signalling suppression. My studies showed that exposure of bm-MPCs to high levels of glucose suppresses the TGFB pathway, similar to the observations in diabetic mice. Supplementation of TGFB prevented adipogenic differentiation of bm-MPCs. Dissection of the intracellular signalling pathways revealed that TGFB1 utilizes the non-canonical TGFB-activated kinase 1 (TAK1)-mediated mechanism to inhibit adipogenesis. Transcriptome-wide gene expression profiling revealed a potential involvement of the Wnt pathway, confirming previous studies in our laboratory.
Finally, I tested the effect of a known inhibitor of adipogenesis that blocks peroxisome proliferator-activated receptor gamma (PPARG) in diabetic mice. My results showed that adipogenesis inhibition prevents lipid accumulation in the liver of diabetic mice but does not affect the enhanced adipogenesis in the bone marrow.
Taken together, my studies identified enhanced bone marrow adipogenesis in diabetic mice before other known diabetic complications become evident. I further identified suppressed TGFB signalling pathway as a mechanism that potentially leads to deleterious adipogenesis in bones. This suggests that restoration of TGFB signalling in the marrow may offer therapeutic benefit to patients with diabetes and help preserve vascular regenerative stem cells to endogenously repair the damaged vasculature.