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

Abstract

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 is elevated in dermal fibroblast cultures and muscle of patients with insulin resistance. We investigated the metabolic phenotype associated with impaired bone metabolism in mice lacking the NPP1 gene (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 sensitising bone-derived hormone osteocalcin but unchanged insulin signaling within osteoblasts. A fuller understanding of the pathways of NPP1 may inform the development of novel therapeutic strategies for treating insulin resistance.