title: Intermittent injections of osteocalcin reverse autophagic dysfunction and endoplasmic reticulum stress resulting from diet-induced obesity in the vascular tissue via the NFκB-p65-dependent mechanism.
abstract: The osteoblast-specific secreted molecule osteocalcin behaves as a hormone-regulating glucose and lipid metabolism, but the role of osteocalcin in cardiovascular disease (CVD) is not fully understood. In the present study, we investigated the effect of osteocalcin on autophagy and endoplasmic reticulum (ER) stress secondary to diet-induced obesity in the vascular tissue of mice and in vascular cell models and clarified the intracellular events responsible for osteocalcin-mediated effects. The evidences showed that intermittent injections of osteocalcin in mice fed the high-fat diet were associated with a reduced body weight gain, decreased blood glucose and improved insulin sensitivity compared with mice fed the high-fat diet receiving vehicle. Simultaneously, the administration of osteocalcin not only attenuated autophagy and ER stress but also rescued impaired insulin signaling in vascular tissues of mice fed a high-fat diet. Consistent with these results in vivo, the addition of osteocalcin reversed autophagy and ER stress and restored defective insulin sensitivity in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) in the presence of tunicamycin or in knockout XBP-1 (a transcription factor which mediates ER stress response) cells or in Atg7(-/-) cells. The protective effects of osteocalcin were nullified by suppression of Akt, mammalian target of rapamycin (mTOR) or nuclear factor kappa B (NFκB), suggesting that osteocalcin inhibits autophagy, ER stress and improves insulin signaling in the vascular tissue and cells under insulin resistance in a NFκB-dependent manner, which may be a promising therapeutic strategies of cardiovascular dysfunction secondary to obesity.
authors.affiliation: Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.forename: Huixia
authors.initials: H
authors.lastname: Li
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Weijin
authors.initials: W
authors.lastname: Zang
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Sun
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D020868:Gene Silencing; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015675:Osteocalcin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D015675:Osteocalcin; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; ER stress; NFκB; autophagy; mTOR; obesity; osteocalcin