PHOSPHO1 is a skeletal regulator of insulin resistance and obesity

作者：Karla J. Suchacki, Nicholas M. Morton, Calvin Vary, Carmen Huesa, Manisha Yadav, Benjamin J. Thomas, Sophie Turban, L. Bünger, D. R. Ball, Martin E. Barrios‐Llerena, Anyonya R. Guntur, Zohreh Khavandgar, William P. Cawthorn, Mathieu Ferron, Gérard Karsenty, Monzur Murshed, Clifford J. Rosen, Vicky E. MacRae, José Luís Millán, Colin Farquharson · 发表于：BMC Biology · 年份：2020 · DOI：10.1186/s12915-020-00880-7 · 被引用次数：27 · 研究领域：Alkaline Phosphatase Research Studies、Bone Metabolism and Diseases、Bone health and osteoporosis research

Abstract Background The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear. Here, we probe the mechanism underlying metabolic regulation by analysing Phospho1 mutant mice. Results Phospho1 −/− mice exhibited improved basal glucose homeostasis and resisted high-fat-diet-induced weight gain and diabetes. The metabolic protection in Phospho1 −/− mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1 −/− mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1 −/− mice. However, the decreased serum choline levels in Phospho1 −/− mice were normalised by feeding a 2% choline rich diet resulting in a normalisation in insulin sensitivity and fat mass. Conclusion We show that mice lacking the bone mineralisation enzyme PHOSPHO1 exhibit improved bas...