Abstract
The emergence of bone as an endocrine regulator has prompted a re-evaluation of the role of bone mineralization factors in the development of metabolic disease. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) controls bone mineralization through the generation of pyrophosphate, and levels of NPP1 are elevated both in dermal fibroblast cultures and muscle of individuals with insulin resistance. We investigated the metabolic phenotype associated with impaired bone metabolism in mice lacking the gene that encodes NPP1 (Enpp1−/− mice). Enpp1−/− mice exhibited mildly improved glucose homeostasis on a normal diet but showed a pronounced resistance to obesity and insulin resistance in response to chronic high-fat feeding. Enpp1−/− mice had increased levels of the insulin-sensitizing bone-derived hormone osteocalcin but unchanged insulin signalling within osteoblasts. A fuller understanding of the pathways of NPP1 could inform the development of novel therapeutic strategies for treating insulin resistance.
Highlights
Bone remodelling is a highly conserved and regulated process that controls bone homeostasis and maintains skeletal structural integrity
Enpp1-/- mice show unaltered fat mass on control diet There was no significant difference in body weight gain from 4 weeks of age between WT and Enpp1-/- mice (Fig. 1A), yet a significant reduction in quadratus femoris muscle mass was observed from 4 weeks of age in Enpp1-/- mice (12%; P
Do osteoblasts regulate insulin sensitivity in the Enpp1-/- mice? Given that NPP1 is a negative regulator of insulin signaling, we investigated whether osteoblast insulin signaling might link NPP1 deficiency and improved whole glucose homeostasis
Summary
Bone remodelling is a highly conserved and regulated process that controls bone homeostasis and maintains skeletal structural integrity. This vital function is characterized by alternating phases of bone resorption by osteoclasts and bone formation by osteoblasts, and has a high energetic cost (Ducy et al, 2000). Active osteocalcin (in an under- or un-carboxylated form) acts to increase β-cell proliferation, insulin secretion, peripheral insulin sensitivity and energy expenditure (Ferron et al, 2008; Fulzele et al, 2010) This raises the possibility that other factors controlling bone remodelling impact upon metabolic homeostasis
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