The role of PAS kinase in regulating energy metabolism.

Metabolic disorders, such as diabetes and obesity, are fundamentally caused by cellular energy imbalance and dysregulation. Therefore, understanding the regulation of cellular fuel and energy metabolism is of great importance to develop effective therapies for metabolic disease. The cellular nutrient and energy sensors, AMPK and TOR, play a key role in maintaining cellular energy homeostasis. Like AMPK and TOR, PAS kinase (PASK) is also a nutrient responsive protein kinase. In yeast, PAS kinase phosphorylates the enzyme Ugp1 and thereby shifts glucose partitioning toward cell wall glucan synthesis at the expense of glycogen synthesis. Consistent with this function, yeast PAS kinase is activated by both cell integrity stress and growth in non-fermentative carbon sources. PASK is also important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. In cultured pancreatic beta-cells, PASK is activated by elevated glucose concentrations and is required for glucose-stimulated transcription of the insulin gene. PASK knockdown in cultured myoblasts causes increased glucose oxidation and elevated cellular ATP levels. Mice lacking PASK exhibit increased metabolic rate and resistance to diet-induced obesity. Interestingly, PGC-1 expression and AMPK and TOR activity were not affected in PASK deficient mice, suggesting PASK may exert its metabolic effects through a new mechanism. We propose that PASK plays a significant role in nutrient sensing, metabolic regulation, and energy homeostasis, and is a potential therapeutic target for metabolic disease.