Postnatal loss of the insulin receptor in osteoprogenitor cells does not impart a metabolic phenotype

Abstract

The relationship between osteoblast-specific insulin signaling, osteocalcin activation and glucometabolic homeostasis has proven to be complex and potentially inconsistent across animal-model systems and in humans. Moreover, the impact of postnatally acquired, osteoblast-specific insulin deficiency on the pancreas-to-skeleton-to-pancreas circuit has not been studied. To explore this relationship, we created a model of postnatal elimination of insulin signaling in osteoprogenitors. Osteoprogenitor-selective ablation of the insulin receptor was induced after ~10 weeks of age in IR l°x/ lox /Osx-Cre +/− genotypic male and female mice (designated postnatal-OIRKO). At ~21 weeks of age, mice were then phenotypically and metabolically characterized. postnatal-oiRKo mice demonstrated a significant reduction in circulating concentrations of undercarboxylated osteocalcin (ucOC), in both males and females compared with control littermates. However, no differences were observed between postnatal-oiRKo and control mice in: body composition (lean or fat mass); fasting serum insulin; HbA1c; glucose dynamics during glucose tolerance testing; or in pancreatic islet area or islet morphology, demonstrating that while ucOC is impacted by insulin signaling in osteoprogenitors, there appears to be little to no relationship between osteocalcin, or its derivative (ucOC), and glucose homeostasis in this model.

Independent validation of experimental results requires timely and unrestricted access to animal models and reagents

“…We cannot comment on the protein's effect when given exogenously, since we did not inject osteocalcin into mice in our study. However, we [1], and others [5][6][7], found no evidence that supports an endogenous hormonal role for osteocalcin. Should Dr. Karsenty make available batches of his biologically-active osteocalcin without restriction, interested parties could avoid the potential confounder of reagent quality [8] and assess objectively whether osteocalcin has a hormonal role when administered exogenously.…”

Low Serum Osteocalcin Level as a Risk Factor for Metabolic Syndrome in Korean Men: A Retrospective Longitudinal Study

“…Furthermore, it was found that insulin signaling in murine osteoblasts enhanced the conversion of osteocalcin into the active, undercarboxylated form and regulated glucose homeostasis by signaling through GPRC6A in mice [34][35][36]. However, in another study, no signi cant changes were observed between mice with postnatal deletion of the insulin receptor in osteoprogenitor cells and control mice, although undercarboxylated osteocalcin levels were signi cantly decreased in the mutant mice [37]. Therefore, more studies are needed to clarify the molecular mechanism of action and functions of osteocalcin.…”

“…Considerable controversy has arisen over several ndings that mouse models may not satisfactorily represent the human osteocalcin physiology [38]. The reasons for the variable metabolic phenotypes in terms of glucose and energy metabolism in different mouse models remain unclear [37]. However, the involvement of serum osteocalcin in MetS has been largely studied through cross-sectional research in humans [10,11,24,25,[39][40][41], which showed that serum osteocalcin levels were negatively associated with MetS.…”