Department of Experimental Medical Science, Lund University, Lund, Sweden.
The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Obesity (Silver Spring). 2023 Oct;31(10):2515-2529. doi: 10.1002/oby.23858. Epub 2023 Aug 22.
Salt-inducible kinase 2 (SIK2) is abundantly expressed in adipocytes and downregulated in adipose tissue from individuals with obesity or insulin resistance. The main aims of this work were to investigate the involvement of SIKs in the regulation of glucose uptake in primary mature human adipocytes and to identify mechanisms underlying this regulation.
Primary mature adipocytes were isolated from human, rat, or mouse adipose tissue and treated with pan-SIK inhibitors. Adipocytes isolated from wild type, ob/ob, and SIK2 knockout mice were also used. Glucose uptake was examined by glucose tracer assay. The insulin signaling pathway was monitored by Western blotting, co-immunoprecipitation, and total internal reflection fluorescence microscopy.
This study demonstrates that SIK2 is downregulated in obese ob/ob mice and that SIK activity is required for intact glucose uptake in primary human and mouse adipocytes. The underlying mechanism involves direct effects on the insulin signaling pathway, likely at the level of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generation or breakdown. Moreover, lack of SIK2 alone is sufficient to attenuate glucose uptake in mouse adipocytes.
SIK2 is required for insulin action in human adipocytes, and the mechanism includes direct effects on the insulin signaling pathway.
盐诱导激酶 2（SIK2）在脂肪细胞中大量表达，在肥胖或胰岛素抵抗个体的脂肪组织中表达下调。本研究的主要目的是研究 SIK 在调节原代成熟人脂肪细胞葡萄糖摄取中的作用，并确定这种调节的机制。
从人、鼠或鼠脂肪组织中分离原代成熟脂肪细胞，并使用泛 SIK 抑制剂进行处理。还使用了来自野生型、ob/ob 和 SIK2 敲除小鼠的脂肪细胞。通过葡萄糖示踪剂测定法检查葡萄糖摄取。通过 Western blot、共免疫沉淀和全内反射荧光显微镜监测胰岛素信号通路。
本研究表明，SIK2 在肥胖的 ob/ob 小鼠中下调，SIK 活性对于原代人脂肪细胞和鼠脂肪细胞中完整的葡萄糖摄取是必需的。潜在机制涉及对胰岛素信号通路的直接影响，可能在磷脂酰肌醇（3,4,5）-三磷酸（PIP3）生成或分解的水平上。此外，单独缺乏 SIK2 足以减弱鼠脂肪细胞中的葡萄糖摄取。
SIK2 是人类脂肪细胞中胰岛素作用所必需的，其机制包括对胰岛素信号通路的直接影响。
