Adiponectin Regulates Bone Mass via Opposite Central and Peripheral Mechanisms through FoxO1

• Published in: Cell metabolism Vol. 17; no. 6; pp. 901 - 915
• Main Authors: Kajimura, Daisuke, Lee, Ha Won, Riley, Kyle J., Arteaga-Solis, Emilio, Ferron, Mathieu, Zhou, Bin, Clarke, Christopher J., Hannun, Yusuf A., DePinho, Ronald A., Guo, X. Edward, Mann, J. John, Karsenty, Gerard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-06-2013
• Subjects: Adiponectin - genetics; Adiponectin - metabolism; Animals; Apoptosis; Bone and Bones - metabolism; Bone Density - physiology; Cell Proliferation; Energy Metabolism; Female; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Leptin - metabolism; Locus Coeruleus - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts - metabolism; Osteocalcin - blood; Osteocalcin - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Signal Transduction; Sympathetic Nervous System - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2013.04.009

The synthesis of adiponectin, an adipokine with ill-defined functions in animals fed a normal diet, is enhanced by the osteoblast-derived hormone osteocalcin. Here we show that adiponectin signals back in osteoblasts to hamper their proliferation and favor their apoptosis, altogether decreasing bone mass and circulating osteocalcin levels. Adiponectin fulfills these functions, independently of its known receptors and signaling pathways, by decreasing FoxO1 activity in a PI3-kinase-dependent manner. Over time, however, these local effects are masked because adiponectin signals in neurons of the locus coeruleus, also through FoxO1, to decrease the sympathetic tone, thereby increasing bone mass and decreasing energy expenditure. This study reveals that adiponectin has the unusual ability to regulate the same function in two opposite manners depending on where it acts and that it opposes, partially, leptin’s influence on the sympathetic nervous system. It also proposes that adiponectin regulation of bone mass occurs through a PI3-kinase-FoxO1 pathway.
•Adiponectin regulates bone mass through two mechanisms that oppose each other•By acting centrally, adiponectin opposes several functions of leptin•The adipocyte synthesizes two hormones with opposite functions•Adiponectin signals by decreasing FoxO1 activity in osteoblasts and neurons