Journal
SCIENTIFIC REPORTS
Volume 10, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-020-68113-z
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Funding
- NIH [R01 DK120567, R01 AR37308]
- ADA [1-13-BS-149-BR]
- NIH National Cancer Institute [P30CA13148]
- NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30AR048311]
- NIH NIDDK [P30 DK074038, P30 DK05336, P60 DK079626]
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GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targeted genomic humanization of mice by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) system to replace the RKLP sequence in the ICL3 of the GPRC6A mouse gene with the uniquely human KGKY sequence to create Gprc6a-(KGKY-knockin) mice. Knock-in of a human KGKY sequence resulted in a reduction in basal blood glucose levels and increased circulating serum insulin and FGF-21 concentrations. Gprc6a-(KGKY-knockin) mice demonstrated improved glucose tolerance, despite impaired insulin sensitivity and enhanced pyruvate-mediated gluconeogenesis. Liver transcriptome analysis of Gprc6a-(KGKY-knockin) mice identified alterations in glucose, glycogen and fat metabolism pathways. Thus, the uniquely human GPRC6A-(KGKY) variant appears to be a gain-of-function polymorphism that positively regulates energy metabolism in mice.
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