The role of beige adipocytes in anabolic bone remodeling

• Applicant: Dr. Mascha Koenen
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496561564

Thermogenic adipose tissue has been recognized for its beneficial impact on whole body metabolism. In contrast to white adipocytes that store excess energy as triglycerides, thermogenic adipocytes can dissipate heat through uncoupled respiration. In addition, thermogenic adipocytes are dynamic secretory cells that contribute to whole body physiology through local and endocrine mechanisms. Small clinical studies in women and children suggest a beneficial role for thermogenic adipose tissue on bone quality; however, the specific effects of thermogenic adipocytes on bone remodeling are not well understood. Defective bone remodeling, the process balancing new bone formation by osteoblasts and removal of brittle bone by osteoclasts, results in reduced bone quality. Pathological bone loss seen in osteoporotic patients affects more than 75 million people in the western world, causing over 8.9 million annual fractures worldwide, and anabolic treatment strategies are limited. In preliminary experiments, I showed that genetic ablation of thermogenic adipocytes in mice results in loss of bone volume and quality, while activation by cold exposure improves these parameters. Serum analysis of bone remodeling markers suggests that these effects are a result of reduced osteoblast activity rather than increased resorption. Flow cytometry analysis of progenitor cells did not reveal any changes in abundance in the bone marrow or differentiation capacity in vitro. These preliminary data suggest that beige adipocytes may regulate bone remodeling via yet to be described secreted mediators. In support of this model, RNA sequencing of adipose tissue from mice lacking thermogenic adipocytes demonstrated significant induction of mRNA encoding the sulfhydryl oxidase Qsox1. Qsox1 is the only known secreted enzyme to generate extracellular de novo disulfide bonds and was recently associated with specific bone traits in humans. In this proposal, I will test the novel hypothesis that thermogenic adipocytes regulate bone metabolism via a secreted mediator through the following aims: (1) determine the impact of loss and gain of thermogenic adipocyte activity on bone, (2) determine the spatial distribution of thermogenic adipocytes in bone marrow in relation to osteoblast and osteoclasts and (3) investigate the impact of adipocyte derived Qsox1 on bone remodeling. These studies will provide an entirely new understanding of the local association and systemic impact of thermogenic adipocytes on bone cells and have the potential to identify novel therapeutic targets for anabolic bone remodeling.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Paul Cohen, Ph.D.