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.
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Abbreviations
- PTHrP:
-
parathyroid hormone-related protein
- Hh:
-
hedgehog
- eWAT:
-
epididymal white adipose tissue
- iWAT:
-
inguinal white adipose tissues
- HFD:
-
high-fat diet
- ACC:
-
acetyl-coA carboxylase
- Ucp1:
-
uncoupling protein-1
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Acknowledgements
We thank members of the Mak lab for stimulating discussions. We thank Drs Yu Huang, School of Biomedical Sciences, The Chinese University of Hong Kong for sharing of reagents, Aimin Xu, Department of Pharmacology & Pharmacy, The University of Hong Kong for sharing the CLAM system. This work is supported by the Seed Fund of the School of Biomedical Sciences, The Chinese University of Hong Kong (4620504), SBS group research grant, The Chinese University of Hong Kong (BL12986), Direct grant for research from Research Grant Council, Hong Kong (BL12615), Guangdong Science and Technology Bureau International Science and Technology Collaboration Program (20130501c).
Author contributions
XZ designed and performed most of the experiments; QC and PL designed and performed experiments related to glucose homeostasis; YW performed NMR analysis; KKM analyzed, interpreted data and supervised the project; and XZ and KKM wrote the manuscript.
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Zhang, X., Cheng, Q., Wang, Y. et al. Hedgehog signaling in bone regulates whole-body energy metabolism through a bone–adipose endocrine relay mediated by PTHrP and adiponectin. Cell Death Differ 24, 225–237 (2017). https://doi.org/10.1038/cdd.2016.113
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DOI: https://doi.org/10.1038/cdd.2016.113
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