title: Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-κB signaling pathway.
abstract: Osteocalcin, a synthetic osteoblast-specific protein, has recently emerged as an important regulator of energy metabolism, but the underlying mechanisms are not fully understood. In the present study, mice fed a high-fat diet and receiving osteocalcin showed reduced body weight gain, less fat pad gain, and improved insulin sensitivity as well as increased energy expenditure compared with mice fed a high-fat diet and receiving vehicle. Meanwhile, increased endoplasmic reticulum (ER) stress, defective insulin signaling, and mitochondrial dysfunction induced by obesity were also effectively alleviated by treatment with osteocalcin. Consistent with these findings, the addition of osteocalcin to the culture medium of 3T3-L1 adipocytes, Fao liver cells, and L6 muscle cells markedly reduced ER stress and restored insulin sensitivity. These effects were nullified by blockade of nuclear factor-κB (NF-κB) or phosphatidylinositol 3-kinase but not by U0126, a mitogen-activated protein kinase inhibitor, indicating the causative role of phosphatidylinositol 3-kinase/NF-κB in action of osteocalcin. In addition, the reversal effects of osteocalcin in cells deficient in X-box-binding protein-1, a transcription factor that modulates ER stress response, further confirmed its protective role against ER stress and insulin resistance. Our findings suggest that osteocalcin attenuates ER stress and rescues impaired insulin sensitivity in insulin resistance via the NF-κB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.
authors: Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
authors: Bo
authors: B
authors: Zhou
authors: Huixia
authors: H
authors: Li
authors: Lin
authors: L
authors: Xu
authors: Weijin
authors: W
authors: Zang
authors: Shufang
authors: S
authors: Wu
authors: Hongzhi
authors: H
authors: Sun
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D015675:Osteocalcin; D014415:Tunicamycin; D011972:Receptor, Insulin; D005947:Glucose