Bone Abstracts (2013) 1 OC6.2 | DOI: 10.1530/boneabs.01.OC6.2

Deficiency of the bone mineralisation inhibitor NPP1 protects against obesity and diabetes

Carmen Huesa1, Nicholas M Morton1, Mathieu Ferron4, Gerard Karsenty4, Jose Luis Millan2, Faisal Ahmed3, Colin Farquharson1 & Vicky E MacRae1

1University of Edinburgh, Edinburgh, UK; 2Sandford Burnham Medical Research institute, La Jolla, California, USA; 3University of Glasgow, Glasgow, UK; 4Columbia University Medical Centre, New York City, NY, USA.

Bone has recently emerged as a novel endocrine organ regulating glucose metabolism. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) controls bone mineralisation by generating the mineralisation inhibitor pyrophosphate. In clinical studies increased activity of NPP1 has been found in patients with insulin resistance, and it has been shown to directly inhibit the insulin receptor. We hypothesised that mice lacking NPP1 (Enpp1−/−) would exhibit improved insulin signalling and glucose metabolism.

Enpp1−/− mice had reduced body mass compared to wild-type (WT) controls at 16 weeks (13%; P<0.05) that was likely accounted for by lower muscle mass (Quadratus femoris reduced by 12%; in Enpp1−/− mice; P<0.01). The loss of muscle mass is a likely consequence of the arthritis these mice exhibit.

Under normal dietary conditions Enpp1−/− mice exhibited normal glucose homeostasis with a reduced peak endogenous insulin response, indicating insulin sensitisation. There was no difference in insulin receptor number, distribution or insulin-stimulated Akt, Erk1/2 or GSK3β phosphorylation between Enpp1−/− and WT osteoblasts, indicating metabolic effects are independent of bone insulin signalling. The undercarboxylated form of osteocalcin acts as a hormone improving energy expenditure, insulin secretion and insulin sensitivity. Interestingly, Enpp1−/− mice exhibited increased levels of under-carboxylated (119%, P<0.05) and un-carboxylated (156%, P<0.05) serum osteocalcin compared to WT. Further studies are required to establish the mechanisms through which NPP1 regulates osteocalcin carboxylation status in bone.

Enpp1−/− mice showed a pronounced obesity-resistance in response to a chronic high fat diet challenge (reduced gonadal, subcutaneous and mesenteric fat mass; P<0.001) but increased brown fat pad mass (P<0.05). Consistent with reduced adiposity, Enpp1−/− mice showed a trend for improved glucose tolerance (n=7) and significantly improved insulin tolerance (P<0.05) compared to WT.

Enpp1−/− mice are protected from obesity and insulin resistant diabetes. The use of tissue specific inhibition of NPP1 activity may represent a novel therapeutic strategy for treating insulin resistance.

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