Vitamin B12–dependent taurine synthesis regulates growth and bone mass
Pablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, Vijay K. Yadav
Pablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, Vijay K. Yadav
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Research Article Bone biology

Vitamin B12–dependent taurine synthesis regulates growth and bone mass

Abstract

Both maternal and offspring-derived factors contribute to lifelong growth and bone mass accrual, although the specific role of maternal deficiencies in the growth and bone mass of offspring is poorly understood. In the present study, we have shown that vitamin B12 (B12) deficiency in a murine genetic model results in severe postweaning growth retardation and osteoporosis, and the severity and time of onset of this phenotype in the offspring depends on the maternal genotype. Using integrated physiological and metabolomic analysis, we determined that B12 deficiency in the offspring decreases liver taurine production and associates with abrogation of a growth hormone/insulin-like growth factor 1 (GH/IGF1) axis. Taurine increased GH-dependent IGF1 synthesis in the liver, which subsequently enhanced osteoblast function, and in B12-deficient offspring, oral administration of taurine rescued their growth retardation and osteoporosis phenotypes. These results identify B12 as an essential vitamin that positively regulates postweaning growth and bone formation through taurine synthesis and suggests potential therapies to increase bone mass.

Authors

Pablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, Vijay K. Yadav

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Figure 5

GH regulates taurine synthesis in a STAT5- and B12-dependent manner.

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GH regulates taurine synthesis in a STAT5- and B12-dependent manner. (A)...
(A) Relationship among taurine, STAT5, and B12 in the liver. (B) Experimental regimen used to test B12 involvement in GH regulation of taurine synthesis. Also shown is RT-PCR analysis to detect Oleosin transcript in the cells after transfection with empty vector or TCOL construct. (C) STAT5 phosphorylation upon GH treatment in empty vector– or TCOL-transfected HepG2 cells. Blots were run noncontiguously. (D) Taurine levels upon GH treatment in empty vector– or TCOL-transfected HepG2 cells. (E) PLSDA-VIP scores plot of metabolomics data from hepatocytes after empty or TCOL transfection. (F) Experimental regimen used to test STAT5 involvement in GH regulation of taurine production. Photomicrographs show immunohistochemistry of STAT5 in HepG2 cells transfected with nontargeting (empty) or STAT5 (shSTAT5) shRNA. (G) Relative expression of IGF1 upon GH treatment in empty or STAT5 shRNA–transfected HepG2 cells. (H) Taurine levels upon GH treatment in empty or STAT5 shRNA–transfected HepG2 cells. (I) Real-time PCR analysis of enzymes in the taurine synthesis pathway in empty, TCOL, or STAT5 shRNA–transfected cells treated with vehicle or GH. (J) GH regulation of the taurine synthesis pathway. Red metabolites and genes, upregulated (only those upregulated by GH and that do not respond to GH upon STAT5 shRNA or TCOL transfection); green metabolites and genes, downregulated; black metabolites and genes, not altered; gray metabolites and genes, not measured. *P < 0.05; #P < 0.01. Values are mean ± SEM. Scale bars: 20 μm (F). See also Supplemental Figure 5.