Endocrine Abstracts

Osteoporosis is a progressive disease characterized by excessive bone loss which is often accompanied by augments in marrow adiposity as a result of estrogen deficiency, metabolic abnormalities or medications. Nuclear receptor estrogen-related receptor alpha (ESRRA) has a demonstrated role in energy homeostasis and fat metabolism. To determine if ESRRA is a potential therapeutic target for regulating fat-bone balance, we generated an adipocyte-specific ESRRA knockout mice (ESRRAAKO) by using an Adiponectin recombinase which labels mature adipocytes within peripheral adipose depots and most bone marrow adipocytes (BMAds) derived from mesenchymal stem cells (BMSCs). We found that ESRRAAKO mice were protected from bone loss after ovariectomy or diet-induced obesity (DIO). Interestingly, marrow adipocytes were more resistant to estrogen deprivation and overfeeding than visceral white adipose tissue (WAT) in ESRRAAKO mice. Furthermore, CD31^hi Emcn^hi vessel (termed as type H vessels) formation was improved in ESRRAAKO mice following ovariectomy or DIO. By using microCT analysis, bone histology, immunofluorescence staining, calcein double labeling and ELISA assays, we demonstrated that loss of ESRRA in adipocytes alleviated fat-bone imbalance with reduction of marrow adipocytes expansion, stimulation of type H vessel formation and enhancement of trabecular bone formation. By using methods such as RNA-seq, Duo-luciferase reporter, chromatin immunoprecipitation assay, qRT-PCR and immunofluorescence staining of adipose sections, we revealed that ESRRA oppositely regulates transcriptional expression of Spp1 and Leptin within both WAT adipocytes and BMAds. SPP1 has been characterized as an negatively charged matrix glycoprotein preferring to anchor in bone environment. We performed transwell assay and matrigel tube formation assay of endothelial cells (ECs) cultured in conditioned medium from either gWAT or BMAds supplemented with anti-SPP1 neutralizing antibody or recombinant SPP1, and confirmed that increased secretion of SPP1 from ESRRAAKO mice enhancing the ability of ECs to migrate and form capillary-like network structures compared to control mice. On the other hand, LEPTIN is known to promote bone adipogenesis by LEPTIN/lepR signaling in BMSCs. In contrast, we further revealed that ESRRA ablation resulted in the suppression of LEPTIN secretion from adipocytes conferring osteogenic differentiation while constraining adipogenic differentiation of BMSCs. Finally, pharmacological treatment in DIO mice with an ESRRA specific inverse agonist compound 29 enhanced bone formation coupled with a reduction of MAT expansion. Collectively, our results proved that adipocyte ESRRA inhibition favored bone formation and may have important therapeutic implication in bone diseases associated with fat-bone imbalance.