Hurov Jonathan B, Huang Mei, White Lynn S, Lennerz Jochen, Choi Cheol Soo, Cho You-Ree, Kim Hyo-Jeong, Prior Julie L, Piwnica-Worms David, Cantley Lewis C, Kim Jason K, Shulman Gerald I, Piwnica-Worms Helen
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5680-5. doi: 10.1073/pnas.0701179104. Epub 2007 Mar 19.
Obesity is a major factor central to the development of insulin resistance and type 2 diabetes. The identification and characterization of genes involved in regulation of adiposity, insulin sensitivity, and glucose uptake are key to the design and development of new drug therapies for this disease. In this study, we show that the polarity kinase Par-1b/MARK2 is required for regulating glucose metabolism in vivo. Mice null for Par-1b were lean, insulin hypersensitive, resistant to high-fat diet-induced weight gain, and hypermetabolic. (18)F-FDG microPET and hyperinsulinemic-euglycemic clamp analyses demonstrated increased glucose uptake into white and brown adipose tissue, but not into skeletal muscle of Par-1b null mice relative to wild-type controls. Taken together, these data indicate that Par-1b is a regulator of glucose metabolism and adiposity in the whole animal and may be a valuable drug target for the treatment of both type 2 diabetes and obesity.
肥胖是胰岛素抵抗和2型糖尿病发展的一个主要核心因素。鉴定和表征参与调节肥胖、胰岛素敏感性和葡萄糖摄取的基因是设计和开发针对该疾病的新药物疗法的关键。在本研究中，我们表明极性激酶Par-1b/MARK2是体内调节葡萄糖代谢所必需的。Par-1b基因敲除小鼠体型瘦、对胰岛素敏感、对高脂饮食诱导的体重增加有抵抗力且代谢亢进。(18)F-FDG微型正电子发射断层扫描（microPET）和高胰岛素-正常血糖钳夹分析表明，相对于野生型对照，Par-1b基因敲除小鼠的白色和棕色脂肪组织中葡萄糖摄取增加，但骨骼肌中未增加。综上所述，这些数据表明Par-1b是整个动物体内葡萄糖代谢和肥胖的调节因子，可能是治疗2型糖尿病和肥胖的有价值的药物靶点。
