PHOSPHO1, a novel skeletal regulator of insulin resistance and obesity

Abstract

AbstractThe skeleton is recognised as a key endocrine regulator of metabolism. Here we show that mice lacking the bone mineralization enzyme PHOSPHO1 (Phospho1-/-) exhibited improved basal glucose homeostasis and resisted high-fat-diet induced weight gain and diabetes. The metabolic protection inPhospho1-/-mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated fromPhospho1-/-mice were enriched for genes associated with energy metabolism and diabetes;Phospho1both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adultPhospho1-/-mice. However, the decreased serum choline levels inPhospho1-/-mice were normalized by feeding a 2% choline rich diet resulting in a normalization in insulin sensitivity and fat mass. This study identifies PHOSPHO1 as a potential therapeutic target for the treatment of obesity and diabetes.