WNK4 is an Adipogenic Factor and Its Deletion Reduces Diet-Induced Obesity in Mice.
WNK4 is an Adipogenic Factor and Its Deletion Reduces Diet-Induced Obesity in Mice.
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DOI：
10.1016/j.ebiom.2017.03.011
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发表时间：
2017-04
期刊：
影响因子：
11.1
通讯作者：
Uchida S
中科院分区：
文献类型：
--
作者：
Takahashi D;Mori T;Sohara E;Tanaka M;Chiga M;Inoue Y;Nomura N;Zeniya M;Ochi H;Takeda S;Suganami T;Rai T;Uchida S
无赖氨酸激酶（WNK）4基因是II型假性醛固酮减少症的致病基因。虽然WNK在体内广泛表达，但其代谢功能和肾外作用均不清楚。在本研究中，我们发现WNK 4在小鼠脂肪组织和3T3-L1脂肪细胞中表达。在小鼠原代前脂肪细胞和3T3-L1脂肪细胞中，WNK 4在脂肪细胞分化的早期阶段被显著诱导。WNK 4的表达先于关键转录因子PPAR γ和C/EBP α的表达。WNK 4-siRNA转染的3T3-L1细胞和人骨髓间充质干细胞显示PPAR γ和C/EBP α的表达减少以及脂质积聚。WNK 4蛋白影响C/EBP β的DNA结合能力，从而降低了PPAR γ的表达。在WNK 4 −/−小鼠中，脂肪组织中的PPAR γ和C/EBP α表达减少，小鼠对高脂饮食诱导的肥胖表现出部分抵抗力。这些数据表明，WNK 4可能是一个促脂肪形成因子，并提供了WNK和能量代谢之间的关系的见解。WNK 4调节小鼠和人前脂肪细胞中的脂肪细胞分化。WNK 4 −/−小鼠表现出肥胖减少和胰岛素敏感性增加。WNK 4可能是治疗饮食诱导的肥胖和盐敏感性高血压的药物靶点。无赖氨酸激酶（WNK）4基因是遗传性高血压病--假性醛固酮减少症II型的致病基因。虽然WNK在体内广泛表达，并参与高血压的发病机制，但其代谢功能和肾外作用尚不清楚。这项研究证明了WNK 4对脂肪形成的核心转录因子的调节的贡献，并且它的消耗表明高脂肪饮食对肥胖有一些有益的影响。这项研究表明，引起高血压的WNK 4作为前脂肪形成因子的作用，并提供了WNK和能量代谢之间的关系的见解。
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. WNK4 regulates adipocyte differentiation in mouse and human preadipocytes. WNK4−/− mice exhibit reduced adiposity and increased insulin sensitivity. WNK4 may be a drug target for diet-induced obesity and salt-sensitive hypertension. The with-no-lysine kinase (WNK) 4 gene is a causative gene in pseudohypoaldosteronism type II, a hereditary hypertensive disease. Although WNKs are widely expressed in the body and are involved in the pathogenesis of hypertension, neither their metabolic functions nor their extrarenal role is clear. This study demonstrated a contribution of WNK4 to the regulation of core transcriptional factors for adipogenesis and that its depletion indicates some beneficial effects for obesity by a high-fat diet. This study suggests a role of hypertension-causing WNK4 as a proadipogenic factor and offers insights into the relationship between WNKs and energy metabolism.