ECTS2013 Oral Communications Mineralisation and energy metabolism (6 abstracts)
An emerging role of phospho1 in the regulation of energy metabolism
Karla Oldknow 1 , Nik Morton’s Morton 3 , Manisha Yadav 5 , Sophie Rajoanah 3 , Carmen Huesa 1 , Lutz Bunger 2 , Mathieu Ferron 4 , Gerard Karsenty 4 , Vicky MacRae 1 , Jose Luis Milan 5 & Colin Farquharson 1
1The Roslin Institute, Edinburgh, UK; 2SRUC, Edinburgh, UK; 3Queen’s Medical Research Institute, Edinburgh, UK; 4Columbia University, New York, New York, USA; 5Sanford Children’s Health Research Center, San Diego, California, USA.
Genetic approaches to bone physiology utilising judicious gain and loss of function models have identified bone as an endocrine organ, being involved in the regulation of energy metabolism and reproduction. Recent advances expand our understanding and identify a new and unconventional role of bone beyond its classical functions. PHOSPHO1 is a bone specific phosphatase with a recognised role in bone mineralisation, but our present studies have now identified a novel role for PHOSPHO1 in energy homeostasis.
An initial microarray screen identified Esp, encoding the phosphatase OST-PTP, to be highly expressed by Phospho1−/− osteoblasts. This was confirmed by RT-qPCR (20-fold increase; P<0.05) whereas Esp expression was significantly decreased in PHOSPHO1 overexpressing osteoblasts (P<0.001). Unexpectedly, no change was noted in serum levels of uncarboxylated (Glu) and undercarboxylated (Glu13) osteocalcin. Nevertheless, 120 day-old Phospho1−/− mice were hypoglycaemic (P<0.05) and showed significantly improved glucose (P<0.05) and insulin tolerance (P<0.05) compared to wild-type mice. These observations were consistent with smaller subcutaneous, mesenteric and epididymal fat deposits noted in Phospho1−/− mice (P<0.001), confirmed by MRI analysis which showed substantial differences in body composition. Metabolic and phenotypic changes were conserved following a chronic 12 weeks high-fat diet challenge, suggesting Phospho1−/− mice are protected from obesity. Ambulatory activity was unchanged in the Phospho1−/− mice and not the cause of increased energy requirements.
Histological analysis of target tissues of Phospho1−/− mice revealed; smaller epididymal adipocytes, decreased fat content and increased mitochondria number in brown fat and decreased islet number in the pancreas (P<0.05). MRI indicated a fatty liver in Phospho1−/− mice. Significantly, PHOSPHO1 expression (mRNA and protein) was specific to bone with negligible levels recorded in liver, pancreas, muscle and fat, suggestive of a bone driven phenotype.
Our findings indicate a novel role of PHOSPHO1 in the regulation of energy status in an osteocalcin independent manner with yet unidentified mechanisms.
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Bone Abstracts
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