Department of Metabolism and Nutrition, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, 930-0194, Japan; First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, 930-0194, Japan.
First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, 930-0194, Japan; Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi, 321-0293, Japan.
Biochem Biophys Res Commun. 2018 Sep 26;504(1):309-314. doi: 10.1016/j.bbrc.2018.08.180. Epub 2018 Sep 1.
Serine is a nonessential amino acid and plays an important role in cellular metabolism. In mammalian serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH) is considered a rate-limiting enzyme and is required for normal development. Although the biological functions of PHGHD in the nervous system have been intensively studied, its function in adipose tissue is unknown. In this study, we found that PHGDH is abundantly expressed in mature adipocytes of white adipose tissue. We generated an adipocyte-specific PHGDH knockout mouse (PHGDH FKO) and used it to investigate the role of serine biosynthesis in adipose tissues. Although PHGDH FKO mice had no apparent defects in adipose tissue development, these mice ameliorated glucose intolerance upon diet-induced obesity. Additionally, we found that the serine levels increase drastically in the adipose tissues of obese wild type mice, whereas no significant rise was observed in PHGDH FKO mice. Furthermore, wild type mice fed a serine-deficient diet also exhibited better glucose tolerance. These results suggest that PHGDH-mediated serine biosynthesis has important roles in adipose tissue glucose metabolism and could be a therapeutic target for diabetes in humans.
丝氨酸是一种非必需氨基酸，在细胞代谢中发挥重要作用。在哺乳动物丝氨酸生物合成中，3-磷酸甘油酸脱氢酶（PHGDH）被认为是限速酶，是正常发育所必需的。尽管 PHGHD 在神经系统中的生物学功能已被深入研究，但它在脂肪组织中的功能尚不清楚。在这项研究中，我们发现 PHGDH 在白色脂肪组织的成熟脂肪细胞中大量表达。我们生成了脂肪细胞特异性 PHGDH 敲除小鼠（PHGDH FKO），并利用它来研究丝氨酸生物合成在脂肪组织中的作用。尽管 PHGDH FKO 小鼠在脂肪组织发育方面没有明显缺陷，但这些小鼠在饮食诱导肥胖时改善了葡萄糖不耐受。此外，我们发现肥胖野生型小鼠的脂肪组织中丝氨酸水平急剧升高，而 PHGDH FKO 小鼠则没有明显升高。此外，给予丝氨酸缺乏饮食的野生型小鼠也表现出更好的葡萄糖耐量。这些结果表明，PHGDH 介导的丝氨酸生物合成在脂肪组织葡萄糖代谢中具有重要作用，可能成为人类糖尿病的治疗靶点。
