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GGCX and VKORC1 inhibit osteocalcin endocrine functions.

Ferron M, Lacombe J, Germain A, Oury F, Karsenty G - J. Cell Biol. (2015)

Bottom Line: Before being secreted by osteoblasts in the bone extracellular matrix, OCN is γ-carboxylated by the γ-carboxylase (GGCX) on three glutamic acid residues, a cellular process requiring reduction of vitamin K (VK) by a second enzyme, a reductase called VKORC1.We further show that VKORC1 is required for OCN γ-carboxylation in osteoblasts, whereas its paralogue, VKORC1L1, is dispensable for this function and cannot compensate for the absence of VKORC1 in osteoblasts.This study genetically and biochemically delineates the functions of the enzymes required for OCN modification and demonstrates that it is the uncarboxylated form of OCN that acts as a hormone.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada mathieu.ferron@ircm.qc.ca gk2172@columbia.edu.

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Improved glucose tolerance, insulin sensitivity, and energy expenditure in Ggcxfl/fl;Col1a1-Cre mice. (A) GTTs in Ggcxfl/fl (n = 11) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3-mo-old male mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (B) ITTs in Ggcxfl/fl (n = 16) and Ggcxfl/fl;Col1a1-Cre (n = 11) 2–3-mo-old male mice. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (C) Body weight (left) and epididymal fat pad weight normalized to body weight (right) in Ggcxfl/fl (n = 10) and Ggcxfl/fl;Col1a1-Cre (n = 10) 5-mo-old male mice. (D) Metabolic rates and heat production (energy expenditure) in Ggcxfl/fl (n = 9) and Ggcxfl/fl;Col1a1-Cre (n = 8) 3-mo-old male mice during the dark 12-h phases. (E) GTTs in Ggcxfl/fl (n = 13) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3 mo-old female mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (F) ITTs in Ggcxfl/fl (n = 12) and Ggcxfl/fl;Col1a1-Cre (n = 8) 2–3-mo-old female mice. Mice were fasted for 4 h and injected i.p. with 0.3 U/kg insulin. Results are given as means ± SEM. *, P < 0.05; **, P < 0.01.
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fig2: Improved glucose tolerance, insulin sensitivity, and energy expenditure in Ggcxfl/fl;Col1a1-Cre mice. (A) GTTs in Ggcxfl/fl (n = 11) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3-mo-old male mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (B) ITTs in Ggcxfl/fl (n = 16) and Ggcxfl/fl;Col1a1-Cre (n = 11) 2–3-mo-old male mice. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (C) Body weight (left) and epididymal fat pad weight normalized to body weight (right) in Ggcxfl/fl (n = 10) and Ggcxfl/fl;Col1a1-Cre (n = 10) 5-mo-old male mice. (D) Metabolic rates and heat production (energy expenditure) in Ggcxfl/fl (n = 9) and Ggcxfl/fl;Col1a1-Cre (n = 8) 3-mo-old male mice during the dark 12-h phases. (E) GTTs in Ggcxfl/fl (n = 13) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3 mo-old female mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (F) ITTs in Ggcxfl/fl (n = 12) and Ggcxfl/fl;Col1a1-Cre (n = 8) 2–3-mo-old female mice. Mice were fasted for 4 h and injected i.p. with 0.3 U/kg insulin. Results are given as means ± SEM. *, P < 0.05; **, P < 0.01.

Mentions: As a way to characterize the impact of reducing GGCX activity in osteoblasts on the endocrine functions of OCN, we tested, in adult Ggcxfl/fl;Col1a1-Cre and control mice fed an ND, an array of physiological functions known to be regulated by OCN (Lee et al., 2007; Ferron et al., 2008, 2010a; Fulzele et al., 2010). Intraperitoneal glucose tolerance tests (GTTs) revealed that Ggcxfl/fl;Col1a1-Cre male mice handled a glucose load significantly better than control animals (Fig. 2 A). This was explained, at least in part, by an enhanced insulin sensitivity in Ggcxfl/fl;Col1a1-Cre mice as revealed by insulin tolerance tests (ITTs; Fig. 2 B). While performing these metabolic tests, we noticed that Ggcxfl/fl;Col1a1-Cre mice were consistently thinner than control age-matched Ggcxfl/fl littermates, and when Ggcxfl/fl;Col1a1-Cre mice were sacrificed at 4 mo of age, they had significantly reduced epididymal fat pad weight compared with control mice (Fig. 2 C), suggesting that the reduction in body weight was secondary to a decrease in the size of the fat depots in these mice. Because GLU-OCN injections or infusions can prevent fat accumulation by increasing whole body energy expenditure in mice (Ferron et al., 2008, 2012; Zhou et al., 2013), we also assessed energy expenditure of the Ggcxfl/fl;Col1a1-Cre mice through indirect calorimetry. Ggcxfl/fl;Col1a1-Cre mice had increased O2 consumption, CO2 production, and overall energy expenditure when compared with control littermates (Fig. 2 D).


GGCX and VKORC1 inhibit osteocalcin endocrine functions.

Ferron M, Lacombe J, Germain A, Oury F, Karsenty G - J. Cell Biol. (2015)

Improved glucose tolerance, insulin sensitivity, and energy expenditure in Ggcxfl/fl;Col1a1-Cre mice. (A) GTTs in Ggcxfl/fl (n = 11) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3-mo-old male mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (B) ITTs in Ggcxfl/fl (n = 16) and Ggcxfl/fl;Col1a1-Cre (n = 11) 2–3-mo-old male mice. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (C) Body weight (left) and epididymal fat pad weight normalized to body weight (right) in Ggcxfl/fl (n = 10) and Ggcxfl/fl;Col1a1-Cre (n = 10) 5-mo-old male mice. (D) Metabolic rates and heat production (energy expenditure) in Ggcxfl/fl (n = 9) and Ggcxfl/fl;Col1a1-Cre (n = 8) 3-mo-old male mice during the dark 12-h phases. (E) GTTs in Ggcxfl/fl (n = 13) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3 mo-old female mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (F) ITTs in Ggcxfl/fl (n = 12) and Ggcxfl/fl;Col1a1-Cre (n = 8) 2–3-mo-old female mice. Mice were fasted for 4 h and injected i.p. with 0.3 U/kg insulin. Results are given as means ± SEM. *, P < 0.05; **, P < 0.01.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig2: Improved glucose tolerance, insulin sensitivity, and energy expenditure in Ggcxfl/fl;Col1a1-Cre mice. (A) GTTs in Ggcxfl/fl (n = 11) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3-mo-old male mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (B) ITTs in Ggcxfl/fl (n = 16) and Ggcxfl/fl;Col1a1-Cre (n = 11) 2–3-mo-old male mice. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (C) Body weight (left) and epididymal fat pad weight normalized to body weight (right) in Ggcxfl/fl (n = 10) and Ggcxfl/fl;Col1a1-Cre (n = 10) 5-mo-old male mice. (D) Metabolic rates and heat production (energy expenditure) in Ggcxfl/fl (n = 9) and Ggcxfl/fl;Col1a1-Cre (n = 8) 3-mo-old male mice during the dark 12-h phases. (E) GTTs in Ggcxfl/fl (n = 13) and Ggcxfl/fl;Col1a1-Cre (n = 9) 2–3 mo-old female mice. Mice were fasted for 16 h and injected i.p. with 2 g/kg glucose. (F) ITTs in Ggcxfl/fl (n = 12) and Ggcxfl/fl;Col1a1-Cre (n = 8) 2–3-mo-old female mice. Mice were fasted for 4 h and injected i.p. with 0.3 U/kg insulin. Results are given as means ± SEM. *, P < 0.05; **, P < 0.01.
Mentions: As a way to characterize the impact of reducing GGCX activity in osteoblasts on the endocrine functions of OCN, we tested, in adult Ggcxfl/fl;Col1a1-Cre and control mice fed an ND, an array of physiological functions known to be regulated by OCN (Lee et al., 2007; Ferron et al., 2008, 2010a; Fulzele et al., 2010). Intraperitoneal glucose tolerance tests (GTTs) revealed that Ggcxfl/fl;Col1a1-Cre male mice handled a glucose load significantly better than control animals (Fig. 2 A). This was explained, at least in part, by an enhanced insulin sensitivity in Ggcxfl/fl;Col1a1-Cre mice as revealed by insulin tolerance tests (ITTs; Fig. 2 B). While performing these metabolic tests, we noticed that Ggcxfl/fl;Col1a1-Cre mice were consistently thinner than control age-matched Ggcxfl/fl littermates, and when Ggcxfl/fl;Col1a1-Cre mice were sacrificed at 4 mo of age, they had significantly reduced epididymal fat pad weight compared with control mice (Fig. 2 C), suggesting that the reduction in body weight was secondary to a decrease in the size of the fat depots in these mice. Because GLU-OCN injections or infusions can prevent fat accumulation by increasing whole body energy expenditure in mice (Ferron et al., 2008, 2012; Zhou et al., 2013), we also assessed energy expenditure of the Ggcxfl/fl;Col1a1-Cre mice through indirect calorimetry. Ggcxfl/fl;Col1a1-Cre mice had increased O2 consumption, CO2 production, and overall energy expenditure when compared with control littermates (Fig. 2 D).

Bottom Line: Before being secreted by osteoblasts in the bone extracellular matrix, OCN is γ-carboxylated by the γ-carboxylase (GGCX) on three glutamic acid residues, a cellular process requiring reduction of vitamin K (VK) by a second enzyme, a reductase called VKORC1.We further show that VKORC1 is required for OCN γ-carboxylation in osteoblasts, whereas its paralogue, VKORC1L1, is dispensable for this function and cannot compensate for the absence of VKORC1 in osteoblasts.This study genetically and biochemically delineates the functions of the enzymes required for OCN modification and demonstrates that it is the uncarboxylated form of OCN that acts as a hormone.

View Article: PubMed Central - HTML - PubMed

Affiliation: Unité de recherche en physiologie intégrative et moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Québec H2W 1R7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Département de médecine, Département de biochimie et médecine moléculaire, and Programmes de biologie moléculaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada mathieu.ferron@ircm.qc.ca gk2172@columbia.edu.

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Related in: MedlinePlus