Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
EBioMedicine. 2017 Apr;18:118-127. doi: 10.1016/j.ebiom.2017.03.011. Epub 2017 Mar 8.
The with-no-lysine kinase (WNK) 4 gene is a causative gene in pseudohypoaldosteronism type II. Although WNKs are widely expressed in the body, neither their metabolic functions nor their extrarenal role is clear. In this study, we found that WNK4 was expressed in mouse adipose tissue and 3T3-L1 adipocytes. In mouse primary preadipocytes and in 3T3-L1 adipocytes, WNK4 was markedly induced in the early phase of adipocyte differentiation. WNK4 expression preceded the expression of key transcriptional factors PPARγ and C/EBPα. WNK4-siRNA-transfected 3T3-L1 cells and human mesenchymal stem cells showed reduced expression of PPARγ and C/EBPα and lipid accumulation. WNK4 protein affected the DNA-binding ability of C/EBPβ and thereby reduced PPARγ expression. In the WNK4 mice, PPARγ and C/EBPα expression were decreased in adipose tissues, and the mice exhibited partial resistance to high-fat diet-induced adiposity. These data suggest that WNK4 may be a proadipogenic factor, and offer insights into the relationship between WNKs and energy metabolism.
无赖氨酸激酶（WNK）4 基因是假性醛固酮增多症 II 型的致病基因。尽管 WNK 广泛表达于全身，但它们的代谢功能及其在肾脏外的作用尚不清楚。在本研究中，我们发现 WNK4 在小鼠脂肪组织和 3T3-L1 脂肪细胞中表达。在小鼠原代前体脂肪细胞和 3T3-L1 脂肪细胞中，WNK4 在脂肪细胞分化的早期阶段被明显诱导。WNK4 的表达先于关键转录因子 PPARγ 和 C/EBPα 的表达。用 WNK4-siRNA 转染的 3T3-L1 细胞和人骨髓间充质干细胞显示出 PPARγ 和 C/EBPα 的表达减少和脂质堆积。WNK4 蛋白影响 C/EBPβ 的 DNA 结合能力，从而降低 PPARγ 的表达。在 WNK4 小鼠中，脂肪组织中 PPARγ 和 C/EBPα 的表达减少，且这些小鼠对高脂肪饮食诱导的肥胖具有部分抗性。这些数据表明 WNK4 可能是一种促脂肪生成因子，并为 WNK 与能量代谢之间的关系提供了新的见解。
