Autophagic dysfunction is improved by intermittent administration of osteocalcin in obese mice

Osteoblast-specific secreted osteocalcin has been considered as an important regulator of energy and glucose metabolism, however, the causative role and clinical potential of osteocalcin implicated in insulin resistance remains not fully understood.

Osteocalcin was administered intermittently in vivo and in vitro, and metabolic parameters, autophagy and insulin signaling were assessed.

The intermittent injections of osteocalcin in mice fed high-fat diet resulted in decreased body weight gain, fat-pad weight gain, serum triglycerides, serum-free fatty acid, blood glucose, insulin level and partial normalization of glucose tolerance relative to the mice fed high-fat diet and received vehicle injections. Meanwhile, the intermittent administration of osteocalcin not only led to the alleviation of autophagic dysfunction and endoplasmic reticulum (ER) stress, but also contributed to the restoration of the impaired insulin signaling in adipose tissue and skeleton muscle of mice consumed the high-fat diet. In accordance with these findings in vivo, osteocalcin treatment also displayed a protective impact on adipocytes and myocytes against tunicamycin- or palmitate-induced ER stress and autophagy dysfunction in an XBP-1-independent manner, with these effects of osteocalcin being reversed by inhibition of mammalian target of rapamycin (mTOR) or nuclear factor-κB (NF-κB).

Intermittent administration of osteocalcin efficiently reversed the attenuated autophagy and ER stress, and restored the impaired insulin sensitivity in cellular and mice models of insulin resistance. Our findings provide new insights into the clinical potential of osteocalcin in metabolic homeostasis, and suggest an innovative strategy for the treatment against diabetes, obesity and metabolic syndrome.