title: Hedgehog signaling in bone regulates whole-body energy metabolism through a bone-adipose endocrine relay mediated by PTHrP and adiponectin.
abstract: Bone plays a role in energy metabolism, but the interplay between bone and other organs in this process is not completely understood. Here, we show that upregulated Hh signaling in bones results in increased whole-body energy expenditure, white adipose tissue (WAT) browning, hypoglycemia and skeletal muscle atrophy. We found that Hh signaling induces PTHrP secretion from bones and causes WAT browning. Injection of PTHrP-neutralizing antibody attenuates WAT browning and improves the circulating blood glucose level while high-fat diet treatment only rescues hypoglycemia. Furthermore, bone-derived PTHrP stimulates adiponectin secretion in WAT and results in systemic increase of fatty acid oxidation and glucose uptake. Mechanistically, PTHrP activates both PKA/cAMP and Akt/Foxo pathways for Ucp1 expression in WAT. PTHrP couples adiponectin actions to activate the AMPK pathway in the skeletal muscles and liver, respectively, for fatty acid oxidation. Our findings establish a new bone-adipose hormonal relay that regulates whole-body energy metabolism.
authors.affiliation: Ministry of Education Key Laboratories for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Shatin, The Chinese University of Hong Kong, HKSAR, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Reproduction, Development and Endocrinology Thematic Research Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, HKSAR.
authors.forename: Qianni
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Imaging and Interventional Radiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, HKSAR.
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Reproduction, Development and Endocrinology Thematic Research Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, HKSAR.
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
authors.affiliation: Ministry of Education Key Laboratories for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Shatin, The Chinese University of Hong Kong, HKSAR, China.|Stem Cell and Regeneration Thematic Research Program, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, HKSAR.|School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China.
authors.forename: Kinglun Kingston
authors.initials: KK
authors.lastname: Mak
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001842:Bone and Bones / Q000378:metabolism*; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D044162:Parathyroid Hormone-Related Protein / Q000276:immunology / Q000378:metabolism*; D000072081:Patched-1 Receptor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D052242:Adiponectin; D057134:Antibodies, Neutralizing; D053823:Hedgehog Proteins; D007328:Insulin; D044162:Parathyroid Hormone-Related Protein; D000072081:Patched-1 Receptor; D015675:Osteocalcin