Hao Huai-Xiang, Cardon Caleb M, Swiatek Wojtek, Cooksey Robert C, Smith Tammy L, Wilde James, Boudina Sihem, Abel E Dale, McClain Donald A, Rutter Jared
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15466-71. doi: 10.1073/pnas.0705407104. Epub 2007 Sep 18.
The metabolic syndrome, a complex set of phenotypes typically associated with obesity and diabetes, is an increasing threat to global public health. Fundamentally, the metabolic syndrome is caused by a failure to properly sense and respond to cellular metabolic cues. We studied the role of the cellular metabolic sensor PAS kinase (PASK) in the pathogenesis of metabolic disease by using PASK(-/-) mice. We identified tissue-specific metabolic phenotypes caused by PASK deletion consistent with its role as a metabolic sensor. Specifically, PASK(-/-) mice exhibited impaired glucose-stimulated insulin secretion in pancreatic beta-cells, altered triglyceride storage in liver, and increased metabolic rate in skeletal muscle. Further, PASK deletion caused nearly complete protection from the deleterious effects of a high-fat diet including obesity and insulin resistance. We also demonstrate that these cellular effects, increased rate of oxidative metabolism and ATP production, occur in cultured cells. We therefore hypothesize that PASK acts in a cell-autonomous manner to maintain cellular energy homeostasis and is a potential therapeutic target for metabolic disease.
代谢综合征是一组通常与肥胖和糖尿病相关的复杂表型，对全球公共卫生构成日益严重的威胁。从根本上讲，代谢综合征是由于无法正确感知和响应细胞代谢信号所致。我们通过使用PASK基因敲除（PASK(-/-)）小鼠研究了细胞代谢传感器PAS激酶（PASK）在代谢疾病发病机制中的作用。我们确定了由PASK缺失引起的组织特异性代谢表型，这与其作为代谢传感器的作用一致。具体而言，PASK(-/-)小鼠在胰腺β细胞中表现出葡萄糖刺激的胰岛素分泌受损，肝脏中甘油三酯储存改变，以及骨骼肌代谢率增加。此外，PASK缺失几乎完全保护小鼠免受高脂饮食的有害影响，包括肥胖和胰岛素抵抗。我们还证明，这些细胞效应，即氧化代谢率和ATP产生增加，在培养细胞中也会出现。因此，我们假设PASK以细胞自主方式发挥作用以维持细胞能量稳态，并且是代谢疾病的潜在治疗靶点。
