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NPY signalling in early osteoblasts controls glucose homeostasis.

Lee NJ, Nguyen AD, Enriquez RF, Luzuriaga J, Bensellam M, Laybutt R, Baldock PA, Herzog H - Mol Metab (2015)

Bottom Line: Y1f3.6Cre mice not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis; significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance.Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway.Importantly, osteocalcin a secreted osteoblastic factor previously identified as a modulator of insulin secretion was not altered in the Y1f3.6Cre model.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.

ABSTRACT

Objective: The skeleton has recently emerged as an additional player in the control of whole-body glucose metabolism; however, the mechanism behind this is not clear.

Methods: Here we employ mice lacking neuropeptide Y, Y1 receptors solely in cells of the early osteoblastic lineage (Y1f3.6Cre), to examine the role of osteoblastic Y1 signalling in glycaemic control.

Results: Y1f3.6Cre mice not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis; significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance. The reduced glucose tolerance and elevated bone mass was corrected in Y1f3.6Cre mice by bone marrow transplant from wildtype animals, reinforcing the osteoblastic nature of this pathway. Importantly, when fed a high fat diet, Y1f3.6Cre mice, while equally gaining body weight and fat mass compared to controls, showed significantly improved glucose and insulin tolerance. Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway. Importantly, osteocalcin a secreted osteoblastic factor previously identified as a modulator of insulin secretion was not altered in the Y1f3.6Cre model.

Conclusion: This study identifies the existence of other osteoblast-derived regulators of pancreas function and insulin secretion and illustrates a mechanism by which NPY signalling in bone tissue is capable of regulating pancreatic function and glucose homeostasis.

No MeSH data available.


Related in: MedlinePlus

Reinstating early osteoblastic Y1 receptor signalling normalises glucose tolerance and bone mass. Y1F3.6Cre mice which had osteoblastic Y1 receptors reinstated by reconstitution with wildtype bone marrow following lethal irradiation (Y1F3.6Cre + WT) had similar glucose levels throughout an insulin tolerance test (A) to wildtype mice lethally irradiated and reconstituted with wildtype bone marrow (Y1F3.6WT + WT). The 2 groups also displayed similar glucose tolerance with no difference in serum glucose levels (B), glucose area under the curve (C), serum insulin levels (D), or insulin area under the curve (E) during a glucose tolerance test or basal circulating glucose (F) or insulin (G) levels. They also displayed similar femoral trabecular bone volume (H) and trabecular number (I) whilst Y1F3.6Cre + WT mice had a significant reduction in trabecular thickness compared to controls (J) as determined by microCT analysis. A representative picture of a femur with reinstated osteoblastic Y1 receptors is shown in (K). Data are means ± SEM of 7–9 mice per group. ** = p < 0.01 versus control or as indicated.
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fig5: Reinstating early osteoblastic Y1 receptor signalling normalises glucose tolerance and bone mass. Y1F3.6Cre mice which had osteoblastic Y1 receptors reinstated by reconstitution with wildtype bone marrow following lethal irradiation (Y1F3.6Cre + WT) had similar glucose levels throughout an insulin tolerance test (A) to wildtype mice lethally irradiated and reconstituted with wildtype bone marrow (Y1F3.6WT + WT). The 2 groups also displayed similar glucose tolerance with no difference in serum glucose levels (B), glucose area under the curve (C), serum insulin levels (D), or insulin area under the curve (E) during a glucose tolerance test or basal circulating glucose (F) or insulin (G) levels. They also displayed similar femoral trabecular bone volume (H) and trabecular number (I) whilst Y1F3.6Cre + WT mice had a significant reduction in trabecular thickness compared to controls (J) as determined by microCT analysis. A representative picture of a femur with reinstated osteoblastic Y1 receptors is shown in (K). Data are means ± SEM of 7–9 mice per group. ** = p < 0.01 versus control or as indicated.

Mentions: To further confirm that the alterations in insulin production and glucose tolerance seen in Y1f3.6Cre mice are a direct result of the lack of Y1 signalling in osteoblasts, we reinstated osteoblastic Y1 receptors in Y1f3.6Cre mice by generating bone marrow chimeric mice. Y1f3.6Cre mice were lethally irradiated and then reconstituted with bone marrow taken from wildtype donors. As a control, wildtype littermates were also irradiated and reconstituted with wildtype bone marrow. Mice were left to recover for 7 weeks and were then tested for insulin and glucose tolerance. Osteoblastic Y1 receptor deletion had no effect on the response to insulin tolerance tests under chow conditions (Figure 2J) and as expected, reinstating osteoblastic Y1 receptor signalling also had no effect on insulin action (Figure 5A). Importantly however, reconstituting Y1f3.6Cre mice with wildtype bone marrow normalised their glucose and insulin levels throughout the glucose tolerance test (Figure 5B,D) and also when expressed as area under the curve (Figure 5C,E). Mice were culled 3 months following reconstitution to enable sufficient time to observe changes in bone mass. At this time, levels of circulating glucose and insulin were also measured and revealed that reinstating osteoblastic Y1 receptor signalling normalised glucose and insulin levels (Figure 5F,G). Moreover the previously observed difference in pancreas weight and islet size was no longer obvious (data not shown) further confirming that Y1 signalling in osteoblasts critically influences these parameters. Furthermore, the high bone mass phenotype of normal Y1f3.6Cre mice was no longer evident and in fact micro-CT revealed that wildtype-reconstituted Y1f3.6Cre mice had similar trabecular bone mass (Figure 5H) and trabecular number (Figure 5I) with a significant reduction in trabecular thickness (Figure 5J) compared to control mice. A representative image of the effect of reconstituting Y1f3.6Cre mice with wildtype bone marrow is shown in Figure 5K.


NPY signalling in early osteoblasts controls glucose homeostasis.

Lee NJ, Nguyen AD, Enriquez RF, Luzuriaga J, Bensellam M, Laybutt R, Baldock PA, Herzog H - Mol Metab (2015)

Reinstating early osteoblastic Y1 receptor signalling normalises glucose tolerance and bone mass. Y1F3.6Cre mice which had osteoblastic Y1 receptors reinstated by reconstitution with wildtype bone marrow following lethal irradiation (Y1F3.6Cre + WT) had similar glucose levels throughout an insulin tolerance test (A) to wildtype mice lethally irradiated and reconstituted with wildtype bone marrow (Y1F3.6WT + WT). The 2 groups also displayed similar glucose tolerance with no difference in serum glucose levels (B), glucose area under the curve (C), serum insulin levels (D), or insulin area under the curve (E) during a glucose tolerance test or basal circulating glucose (F) or insulin (G) levels. They also displayed similar femoral trabecular bone volume (H) and trabecular number (I) whilst Y1F3.6Cre + WT mice had a significant reduction in trabecular thickness compared to controls (J) as determined by microCT analysis. A representative picture of a femur with reinstated osteoblastic Y1 receptors is shown in (K). Data are means ± SEM of 7–9 mice per group. ** = p < 0.01 versus control or as indicated.
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fig5: Reinstating early osteoblastic Y1 receptor signalling normalises glucose tolerance and bone mass. Y1F3.6Cre mice which had osteoblastic Y1 receptors reinstated by reconstitution with wildtype bone marrow following lethal irradiation (Y1F3.6Cre + WT) had similar glucose levels throughout an insulin tolerance test (A) to wildtype mice lethally irradiated and reconstituted with wildtype bone marrow (Y1F3.6WT + WT). The 2 groups also displayed similar glucose tolerance with no difference in serum glucose levels (B), glucose area under the curve (C), serum insulin levels (D), or insulin area under the curve (E) during a glucose tolerance test or basal circulating glucose (F) or insulin (G) levels. They also displayed similar femoral trabecular bone volume (H) and trabecular number (I) whilst Y1F3.6Cre + WT mice had a significant reduction in trabecular thickness compared to controls (J) as determined by microCT analysis. A representative picture of a femur with reinstated osteoblastic Y1 receptors is shown in (K). Data are means ± SEM of 7–9 mice per group. ** = p < 0.01 versus control or as indicated.
Mentions: To further confirm that the alterations in insulin production and glucose tolerance seen in Y1f3.6Cre mice are a direct result of the lack of Y1 signalling in osteoblasts, we reinstated osteoblastic Y1 receptors in Y1f3.6Cre mice by generating bone marrow chimeric mice. Y1f3.6Cre mice were lethally irradiated and then reconstituted with bone marrow taken from wildtype donors. As a control, wildtype littermates were also irradiated and reconstituted with wildtype bone marrow. Mice were left to recover for 7 weeks and were then tested for insulin and glucose tolerance. Osteoblastic Y1 receptor deletion had no effect on the response to insulin tolerance tests under chow conditions (Figure 2J) and as expected, reinstating osteoblastic Y1 receptor signalling also had no effect on insulin action (Figure 5A). Importantly however, reconstituting Y1f3.6Cre mice with wildtype bone marrow normalised their glucose and insulin levels throughout the glucose tolerance test (Figure 5B,D) and also when expressed as area under the curve (Figure 5C,E). Mice were culled 3 months following reconstitution to enable sufficient time to observe changes in bone mass. At this time, levels of circulating glucose and insulin were also measured and revealed that reinstating osteoblastic Y1 receptor signalling normalised glucose and insulin levels (Figure 5F,G). Moreover the previously observed difference in pancreas weight and islet size was no longer obvious (data not shown) further confirming that Y1 signalling in osteoblasts critically influences these parameters. Furthermore, the high bone mass phenotype of normal Y1f3.6Cre mice was no longer evident and in fact micro-CT revealed that wildtype-reconstituted Y1f3.6Cre mice had similar trabecular bone mass (Figure 5H) and trabecular number (Figure 5I) with a significant reduction in trabecular thickness (Figure 5J) compared to control mice. A representative image of the effect of reconstituting Y1f3.6Cre mice with wildtype bone marrow is shown in Figure 5K.

Bottom Line: Y1f3.6Cre mice not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis; significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance.Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway.Importantly, osteocalcin a secreted osteoblastic factor previously identified as a modulator of insulin secretion was not altered in the Y1f3.6Cre model.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.

ABSTRACT

Objective: The skeleton has recently emerged as an additional player in the control of whole-body glucose metabolism; however, the mechanism behind this is not clear.

Methods: Here we employ mice lacking neuropeptide Y, Y1 receptors solely in cells of the early osteoblastic lineage (Y1f3.6Cre), to examine the role of osteoblastic Y1 signalling in glycaemic control.

Results: Y1f3.6Cre mice not only have a high bone mass phenotype, but importantly also display altered glucose homeostasis; significantly decreased pancreas weight, islet number and pancreatic insulin content leading to elevated glucose levels and reduced glucose tolerance, but with no effect on insulin induced glucose clearance. The reduced glucose tolerance and elevated bone mass was corrected in Y1f3.6Cre mice by bone marrow transplant from wildtype animals, reinforcing the osteoblastic nature of this pathway. Importantly, when fed a high fat diet, Y1f3.6Cre mice, while equally gaining body weight and fat mass compared to controls, showed significantly improved glucose and insulin tolerance. Conditioned media from Y1f3.6Cre osteoblastic cultures was unable to stimulate insulin expression in MIN6 cells compared to conditioned media from wildtype osteoblast, indicating a direct signalling pathway. Importantly, osteocalcin a secreted osteoblastic factor previously identified as a modulator of insulin secretion was not altered in the Y1f3.6Cre model.

Conclusion: This study identifies the existence of other osteoblast-derived regulators of pancreas function and insulin secretion and illustrates a mechanism by which NPY signalling in bone tissue is capable of regulating pancreatic function and glucose homeostasis.

No MeSH data available.


Related in: MedlinePlus