Regulation of Insulin Sensitivity by Osteoblasts

• Applicant: Julia Luther, Ph.D.
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465465934

Recent evidence has supported the concept that the skeleton is an endocrine organ and that osteoblasts are not only required for bone formation, but also for regulating energy metabolism. This concept is mostly based on several findings in mouse models, where undercarboxylated osteocalcin was proposed to represent a bone-derived hormone that promotes insulin secretion and sensitivity in non-skeletal tissues. It is however important to state that the clinical relevance of these findings is still debated and that two novel publications on osteocalcin-deficient mice without metabolic phenotype raised concerns about the endocrine functions of osteocalcin, even in mice. Since osteocalcin is not the only candidate for an osteoblast-derived molecule with endocrine actions and since additional mechanisms of an interaction between bone and energy metabolism have been suggested, it is now important to use alternative approaches in order to study the impact of activated bone formation on glucose homeostasis and insulin sensitivity.The present application is based on our characterization of a transgenic mouse model (Fra1Tg) with high bone mass due to increased osteoblastogenesis that additionally displays improved insulin sensitivity. These mice display normal blood glucose levels despite high adipose tissue mass, when combined with a diabetic background (Lepob/ob). Importantly however, since the Fra1Tg mice display an intrinsic defect of adipogenesis, we now plan to use other mouse models to address the question, if increased bone formation increases insulin sensitivity and if osteoanabolic treatment could be beneficial to counteract insulin-resistance in type II diabetes mellitus (T2DM).More specifically, we will take advantage of a mouse model (Wnt1Tg) allowing osteoblast-specific induction of Wnt1, which causes a rapid, strong and reversible activation of bone formation. Here we will embark on a full metabolic phenotyping, including glucose and insulin tolerance assays and a screening for affected circulating molecules by candidate and unbiased approaches (WP1). We will also perform these experiments in combination with a high-fat diet to challenge these mice by inducing adiposity and T2DM (WP2). Finally, we will utilize other models (mice carrying activating mutations of Lrp5 or wildtype mice receiving daily injection of PTH), which receive or mimic the influence of existing osteoanabolic treatment options, in order to study the influence of osteoblast activation on glucose homeostasis and insulin sensitivity (WP3).The expected results could not only improve the understanding of the interactions between bone and energy metabolism, but also provide a proof-of-principal for the potential clinical translation of our observations to improve of T2DM-associated metabolic complications.

• DFG Programme: Research Grants