PHOSPHO1 is a skeletal regulator of insulin resistance and obesity

Karla Suchacki, Nicholas M Morton, Calvin Vary , Carmen Huesa, Manisha Yadav, Benjamin Thomas, Sophie Turban, Lutz Bungar , Derek Ball, Martin Barrios-Llerena, Anyonya Guntur, Zohreh Khavandgar, William P Cawthorn, Mathieu Ferron, Gerard Karsenty, Monzur Murshed, Clifford J. Rosen, Vicky MacRae, Jose-Luis Millan, Colin Farquharson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 mineralization, 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 analyzing 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 normalized by feeding a 2% choline rich diet resulting in a normalization in insulin sensitivity and fat mass.

Conclusion: We show that mice lacking the bone mineralization enzyme PHOSPHO1 exhibit improved basal glucose homeostasis and resist high-fat-diet induced weight gain and diabetes. This study identifies PHOSPHO1 as a potential bone-derived therapeutic target for the treatment of obesity and diabetes.
Original languageEnglish
Article number149 (2020)
Number of pages20
JournalBMC Biology
Issue number149
Publication statusPublished - 22 Oct 2020

Keywords / Materials (for Non-textual outputs)

  • Osteocalcin
  • Choline
  • Bone
  • Energy Metabolism
  • Insulin
  • Endocrine Organ
  • Skeleton
  • Obesity


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