Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation
<span style="font-variant: small-caps;">l</span>-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (<i>Phgdh</i>). A previous study reported that feeding a protein-free diet increas...
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MDPI AG
2021-09-01
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| Online Access: | https://www.mdpi.com/2072-6643/13/10/3468 |
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| author | Momoko Hamano Kayoko Esaki Kazuki Moriyasu Tokio Yasuda Sinya Mohri Kosuke Tashiro Yoshio Hirabayashi Shigeki Furuya |
| author_facet | Momoko Hamano Kayoko Esaki Kazuki Moriyasu Tokio Yasuda Sinya Mohri Kosuke Tashiro Yoshio Hirabayashi Shigeki Furuya |
| author_sort | Momoko Hamano |
| collection | DOAJ |
| description | <span style="font-variant: small-caps;">l</span>-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (<i>Phgdh</i>). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific <i>Phgdh</i> KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that <i>Phgdh</i>-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation. |
| first_indexed | 2024-03-10T06:18:30Z |
| format | Article |
| id | doaj.art-bbcd7ae7556241d194bc9af141de3d12 |
| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-10T06:18:30Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
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| series | Nutrients |
| spelling | doaj.art-bbcd7ae7556241d194bc9af141de3d122023-11-22T19:29:02ZengMDPI AGNutrients2072-66432021-09-011310346810.3390/nu13103468Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein StarvationMomoko Hamano0Kayoko Esaki1Kazuki Moriyasu2Tokio Yasuda3Sinya Mohri4Kosuke Tashiro5Yoshio Hirabayashi6Shigeki Furuya7Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 820-8502, JapanLaboratory for Neural Cell Dynamics, RIKEN Center for Brain Science, Wako 351-0198, JapanDepartment of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, JapanDepartment of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, JapanDepartment of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, JapanDepartment of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, JapanCellular Informatics Laboratory, RIKEN, Wako 351-0198, JapanLaboratory of Functional Genomics and Metabolism, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan<span style="font-variant: small-caps;">l</span>-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (<i>Phgdh</i>). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific <i>Phgdh</i> KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insulin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that <i>Phgdh</i>-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starvation.https://www.mdpi.com/2072-6643/13/10/3468<i>Phgdh</i>liver<span style="font-variant: small-caps">l</span>-serine deficiencyinsulin signalingglucose tolerance |
| spellingShingle | Momoko Hamano Kayoko Esaki Kazuki Moriyasu Tokio Yasuda Sinya Mohri Kosuke Tashiro Yoshio Hirabayashi Shigeki Furuya Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation Nutrients <i>Phgdh</i> liver <span style="font-variant: small-caps">l</span>-serine deficiency insulin signaling glucose tolerance |
| title | Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation |
| title_full | Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation |
| title_fullStr | Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation |
| title_full_unstemmed | Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation |
| title_short | Hepatocyte-Specific <i>Phgdh</i>-Deficient Mice Culminate in Mild Obesity, Insulin Resistance, and Enhanced Vulnerability to Protein Starvation |
| title_sort | hepatocyte specific i phgdh i deficient mice culminate in mild obesity insulin resistance and enhanced vulnerability to protein starvation |
| topic | <i>Phgdh</i> liver <span style="font-variant: small-caps">l</span>-serine deficiency insulin signaling glucose tolerance |
| url | https://www.mdpi.com/2072-6643/13/10/3468 |
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