Carboxylated and Uncarboxylated Forms of Osteocalcin Directly Modulate the Glucose Transport System and Inflammation in Adipocytes

Abstract

Osteocalcin is secreted by osteoblasts and improves insulin sensitivity in vivo, although mechanisms remain unclear. We tested the hypothesis that osteocalcin directly modulates cell biology in insulin-targeted peripheral tissues. In L-6 myocytes, osteocalcin stimulated glucose transport both in the absence (basal) and presence of insulin. Similarly, in primary cultured adipocytes, both carboxylated and uncarboxylated osteocalcin increased basal and insulin-stimulated glucose transport as well as insulin sensitivity. Osteocalcin also increased basal and insulin-stimulated glucose oxidation, though there was no effect on fatty acid synthesis or lipolysis. In primary-cultured adipocytes, both forms of osteocalcin suppressed secretion of tumor necrosis factor alpha into the media; however, only carboxylated osteocalcin suppressed interleukin 6 release, and neither form of osteocalcin modulated monocyte chemoattractant protein-1 secretion. Both carboxylated and uncarboxylated osteocalcin increased secretion of adiponectin and the anti-inflammatory cytokine interleukin 10. In conclusion, both carboxylated and uncarboxylated osteocalcin directly increase glucose transport in adipocytes and muscle cells, while suppressing proinflammatory cytokine secretion and stimulating interleukin 10 and adiponectin release. Thus, these results provide a mechanism for the insulin-sensitizing effects of osteocalcin and help elucidate the role that bone plays in regulating systemic metabolism.

Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet

“…Moreover, daily intraperitoneal injection of GluOC for 14 wk in mice resulted not only in a substantial improvement in glucose tolerance and insulin sensitivity but also in full recovery from hepatic steatosis induced by a high-fat diet (13). Although many studies indicate that GluOC is the only form of osteocalcin that exerts favorable effects on metabolism, both GluOC and carboxylated osteocalcin (GlaOC) were found to modulate adipocyte and myoblast function in one study (19). However, the increased GluOC and reduced GlaOC levels in serum of mice with osteoblast-specific inactivation of the genes for ␥-carboxylase or vitamin K epoxide reductase were associated with improved endocrine function (12).…”

Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model

“…Moreover, blood glucose homeostasis could be regulated by other different signaling. Several studies show that blood glucose could be modulated by intestine G6PC activity [44], glucose transportation [43] and glucose uptake [45], resulting in irrelevance between plasma glucose level and hepatic G6Pase activity. In XLH mouse model, decreased renal glucose reabsorption activity is also considered contributory to the decreased blood glucose [22].…”

“…In XLH mouse model, decreased renal glucose reabsorption activity is also considered contributory to the decreased blood glucose [22]. Otherwise the reduced blood glucose of PUG mice resulted from abnormal glucose transport and oxidation stimulated by OCN [45].…”

“…Correlations between circulating OCN levels and β-cell functions or glucose metabolism were observed in obese adults and type II diabetes patients [65,66], suggesting secretion role of skeleton in regulating lipid anabolism and catabolism. Adiponectin secretion was accelerated by OCN [45] while serum OCN level was positively correlated with adiponectin receptor 1 (AdipoR1) expression [67], developing a feedback loop between osseous tissue and energy metabolism [68,69]. Therefore, OCN elevation in XLH disease is probable to exhibit damaged lipid metabolism.…”

Análise do potencial osteogênico e adipogênico de células-tronco mesenquimais derivadas de medula óssea e de tecido adiposo

“…Entre os fatores derivados de adipócitos, os estrógenos e adipocinas têm efeitos sobre a diferenciação osteoblástica, tendo sido demonstrado que o estradiol induz a diferenciação osteogênica e adipogênica de pré-osteoblastos enquanto a adiponectina inibe a diferenciação osteoblástica (OKAZAKI et al, 2002;SHINODA et al, 2006). Em relação aos fatores secretados por osteoblastos, foi observado que a osteocalcina favorece o transporte de glicose e a liberação de adiponectina em culturas adipocíticas (HILL et al, 2014).…”