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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.

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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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Ggcxfl/fl;Col1a1-Cre mice are protected from diet-induced obesity and glucose intolerance. (A) Body weight curves. (B) Blood glucose levels after 16-h fasting. (C) GTTs. Mice were fasted for 16 h and injected i.p. with 1.3 g/kg glucose. (D) ITTs. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (B–D) Metabolic analyses were performed in mice fed an ND or HFD for 8 wk. Ggcxfl/fl ND (n = 14), Ggcxfl/fl;Col1a1-Cre ND (n = 14), Ggcxfl/fl HFD (n = 8), Ggcxfl/fl;Col1a1-Cre HFD (n = 11). Results are given as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 when comparing with Ggcxfl/fl ND group; #, P < 0.05; ##, P < 0.01; ###, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre ND group; &, P < 0.05; &&, P < 0.01; &&&, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre HFD group.
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fig3: Ggcxfl/fl;Col1a1-Cre mice are protected from diet-induced obesity and glucose intolerance. (A) Body weight curves. (B) Blood glucose levels after 16-h fasting. (C) GTTs. Mice were fasted for 16 h and injected i.p. with 1.3 g/kg glucose. (D) ITTs. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (B–D) Metabolic analyses were performed in mice fed an ND or HFD for 8 wk. Ggcxfl/fl ND (n = 14), Ggcxfl/fl;Col1a1-Cre ND (n = 14), Ggcxfl/fl HFD (n = 8), Ggcxfl/fl;Col1a1-Cre HFD (n = 11). Results are given as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 when comparing with Ggcxfl/fl ND group; #, P < 0.05; ##, P < 0.01; ###, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre ND group; &, P < 0.05; &&, P < 0.01; &&&, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre HFD group.

Mentions: In view of the results presented above, we next asked whether the chronic elevation of the circulating GLU-OCN levels in Ggcxfl/fl;Col1a1-Cre mice could weaken if not prevent the deleterious metabolic effects associated with consuming an HFD. To test this contention, 4-wk-old control and Ggcxfl/fl;Col1a1-Cre mice were fed an HFD for 14 wk, and body weight gain, glucose tolerance, and insulin sensitivity were then assessed at the end of this period. HFD-fed Ggcxfl/fl;Col1a1-Cre mice gained significantly less weight than age-matched control mice fed the same HFD, and this difference remained significant from 6 wk of HFD feeding onward (Fig. 3 A).


GGCX and VKORC1 inhibit osteocalcin endocrine functions.

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

Ggcxfl/fl;Col1a1-Cre mice are protected from diet-induced obesity and glucose intolerance. (A) Body weight curves. (B) Blood glucose levels after 16-h fasting. (C) GTTs. Mice were fasted for 16 h and injected i.p. with 1.3 g/kg glucose. (D) ITTs. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (B–D) Metabolic analyses were performed in mice fed an ND or HFD for 8 wk. Ggcxfl/fl ND (n = 14), Ggcxfl/fl;Col1a1-Cre ND (n = 14), Ggcxfl/fl HFD (n = 8), Ggcxfl/fl;Col1a1-Cre HFD (n = 11). Results are given as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 when comparing with Ggcxfl/fl ND group; #, P < 0.05; ##, P < 0.01; ###, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre ND group; &, P < 0.05; &&, P < 0.01; &&&, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre HFD group.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4362468&req=5

fig3: Ggcxfl/fl;Col1a1-Cre mice are protected from diet-induced obesity and glucose intolerance. (A) Body weight curves. (B) Blood glucose levels after 16-h fasting. (C) GTTs. Mice were fasted for 16 h and injected i.p. with 1.3 g/kg glucose. (D) ITTs. Mice were fasted for 4 h and injected i.p. with 0.7 U/kg insulin. (B–D) Metabolic analyses were performed in mice fed an ND or HFD for 8 wk. Ggcxfl/fl ND (n = 14), Ggcxfl/fl;Col1a1-Cre ND (n = 14), Ggcxfl/fl HFD (n = 8), Ggcxfl/fl;Col1a1-Cre HFD (n = 11). Results are given as means ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 when comparing with Ggcxfl/fl ND group; #, P < 0.05; ##, P < 0.01; ###, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre ND group; &, P < 0.05; &&, P < 0.01; &&&, P < 0.001 when comparing with Ggcxfl/fl;Col1a1-Cre HFD group.
Mentions: In view of the results presented above, we next asked whether the chronic elevation of the circulating GLU-OCN levels in Ggcxfl/fl;Col1a1-Cre mice could weaken if not prevent the deleterious metabolic effects associated with consuming an HFD. To test this contention, 4-wk-old control and Ggcxfl/fl;Col1a1-Cre mice were fed an HFD for 14 wk, and body weight gain, glucose tolerance, and insulin sensitivity were then assessed at the end of this period. HFD-fed Ggcxfl/fl;Col1a1-Cre mice gained significantly less weight than age-matched control mice fed the same HFD, and this difference remained significant from 6 wk of HFD feeding onward (Fig. 3 A).

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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