SFEBES2014 Oral Communications Thyroid and bone (6 abstracts)
PHOSPHO1: roles beyond skeletal mineralisation
Karla Oldknow 1 , Nik Morton 2 , Manisha Yadav 3 , Sophie Rajoanah 2 , Carmen Huesa 1 , Lutz Bunger 5 , Derek Ball 4 , Mathieu Ferron 6 , Gerard Karsenty 7 , Vicky MacRae 1 , Jose Luis Millan 3 & Colin Farquharson 1
1The Roslin Institute, Edinburgh, UK; 2The University of Edinburgh, Edinburgh, UK; 3Sanford Children’s Health Research Center, La Jolla, California, USA; 4Heriot-Watt University, Edinburgh, UK; 5SRUC, Edinburgh, UK; 6Institut de Recherches Cliniques de Montréal Montréal, Québec, Canada; 7Columbia University, New York, New York, USA.
Advances in genetic approaches to bone physiology have expanded our understanding of the mechanisms by which bone and energy homeostasis interact. PHOSPHO1, a bone specific phosphatase is essential for the initiation of bone mineralisation. Here we now show that Phospho1 ablation confers a remarkable protection against obesity and diabetes in mice. To understand the mechanism whereby Phospho1 impacts metabolism, microarray analysis of osteoblasts, the primary site of Phospho1 expression was performed. Esp (encoding the phosphatase OST-PTP) which controls hormonally active osteocalcin secretion, was 20-fold more highly expressed in Phospho1−/− osteoblasts (P<0.05). Conversely, Esp mRNA was decreased in Phospho1 overexpressing osteoblasts (P<0.001). Unexpectedly, serum levels of uncarboxylated and undercarboxylated osteocalcin were normal suggesting an osteocalcin-independent mechanism of PHOSPHO1 regulated energy metabolism. 120 day-old Phospho1−/− mice were hypoglycaemic (WT 9.48±0.31 mmol/l, Phospho1−/− 8.30±0.26 mmol/l; P<0.01) and showed improved glucose and insulin tolerance compared to WT mice (P<0.05). These observations were consistent with the finding of smaller (mg/g BW) subcutaneous (WT 4.51±0.37, Phospho1−/− 2.79±0.42; P<0.01) and mesenteric (WT 13.2±1.34, Phospho1−/− 5.56±1.61; P<0.01) fat deposits noted in Phospho1−/− mice at necropsy and confirmed by MRI. Remarkably, Phospho1−/− mice resisted the pronounced weight gain (WT 38.0±1.54 g, Phospho1−/− 32.4±1.26 g; P<0.05) and diabetes (WT 10.3±0.53 mmol/l, Phospho1−/− 9.27±0.77 mmol/l; P<0.05) exhibited by WT mice when fed a chronic high fat diet (HFD; 14 weeks, 58% kcal as fat) and this was not explained by altered activity. Histology revealed smaller epididymal adipocytes, decreased fat content, decreased pancreatic islet number and increased mitochondria number in brown fat (P<0.05). However, no differences were observed in brown fat specific genes including Ucp1 suggesting canonical thermogenesis does not underlie metabolic protection. Our findings indicate Phospho1 deficiency improves the metabolic profile of mice in vivo and confers resistance to obesity and diabetes most likely through a primary effect on bone metabolism/turnover.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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