PHOSPHO1 is a skeletal regulator of insulin resistance and obesity

BMC Biology

Anyonya R. Guntur¹  Calvin Vary¹  Clifford J. Rosen¹  Sophie Turban²  William P. Cawthorn²  Benjamin J. Thomas²  Nicholas M. Morton²  Gérard Karsenty³  Zohreh Khavandgar⁴  Monzur Murshed⁴  Martin E. Barrios-Llerena⁵  Derek Ball⁶  Mathieu Ferron⁷  Colin Farquharson⁸  Vicky E. MacRae⁸  Karla J. Suchacki⁹  Carmen Huesa^1,10  Jose Luis Millán^1,11  Manisha C. Yadav^1,11  Lutz Bunger^1,12 

[1] Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA;Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, Scotland, UK;Department of Genetics and Development, Columbia University Medical Center, New York, USA;Department of Medicine and Faculty of Dentistry, McGill University, Montreal, Canada;International Clinical Research Center, Brno, Czech Republic;Medical Sciences and Nutrition, School of Medicine, University of Aberdeen, Aberdeen, Scotland, UK;Molecular Physiology Research Unit, Institut de recherches cliniques de Montréal, Montreal, Canada;Roslin Institute, R(D)SVS, University of Edinburgh, Edinburgh, Scotland, UK;Roslin Institute, R(D)SVS, University of Edinburgh, Edinburgh, Scotland, UK;Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, Scotland, UK;Roslin Institute, R(D)SVS, University of Edinburgh, Edinburgh, Scotland, UK;MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, Scotland, UK;Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA;Scottish Rural College, Edinburgh, Scotland, UK;

关键词: PHOSPHO1;    Osteocalcin;    Choline;    Bone;    Energy metabolism;    Insulin;    Endocrine organ;    Skeleton;    Obesity;   

DOI  :  10.1186/s12915-020-00880-7

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsPhospho1−/− 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.ConclusionWe show that mice lacking the bone mineralisation 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.

【 授权许可】

CC BY