Targeting Bone Marrow Lipid Metabolism with Adiponectin Receptor Agonist for Diabetic and Postmenopausal Osteoporosis

Abstract Osteoporosis is a malady of multiple cell types associated with the bone marrow (BM) fat accumulation. This study focused on understanding the role of adiponectin in osteoblast and osteoclast lipid metabolism in diabetic and ovariectomized mice with osteoporosis and exploring the effects of the adiponectin receptor (AdipoR) agonist, AdipoRon. AdopoRon prevented systemic bone resorption and oxidative stress, and excessive lipid accumulation in BM. AdipoRon activated AMPK and PPARɑ through AdipoR1 and AdipoR2, leading to a reduction in lipotoxicity-induced osteocyte apoptosis, oxidative stress, and inflammation with M1 polarization. All these changes increased osteogenic RUNX2/OPG/FOXO1 expression, decreased osteolytic RANKL/PPARγ expression, and preserved bony phenotypes and growth plate thicknesses in the lumbar vertebrae and femur. AdipoR1/R2 knockout in pre-osteoblasts and osteoclasts in high-glucose and palmitate media confirmed the positive action of AdipoRon on bone formation, which was achieved by activating AMPK and PPARɑ to the same degree through both AdipoR1 and AdipoR2. These activations were closely associated with the amelioration of osteocyte apoptosis, oxidative stress, inflammation, and autophagy induced by high-glucose and palmitate, which were controlled by regulating lipid metabolism. We revealed that AdipoRon may safeguard lipotoxicity in BM in diabetic and ovariectomized osteoporosis by modulating lipid metabolism in osteoclasts and osteoblasts.