PASK-dependent Signaling

Integrated Control of Metabolism by PASK-dependent Signaling

We have a growing but incomplete understanding of the mechanisms whereby the body senses its nutrient status and responds to adapt cellular and organismal behavior accordingly. The resulting energetic efficiencies are of obvious evolutionary importance as organisms faced a variety of challenging environmental situations, including prolonged exertion, episodic food shortage and competition for resources. In modern human societies, however, these adaptations often have negative health consequences. One clear example is the propensity of most mammals to store excess ingested calories, primarily as fat, in anticipation of an ensuing period of food scarcity. That period rarely comes in our society today and the result is obesity, with all of its attendant comorbidities.

We are interested in the functions of PASK, an evolutionarily conserved serine/threonine kinase, in coupling nutrient status with metabolic state, energy storage and growth. PASK-/- mice were resistant to high-fat diet induced obesity, hepatic steatosis and insulin resistance. This phenotype appears to be due to hypermetabolism in PASK-/- mice in vivo as measured by indirect calorimetry and in isolated skeletal muscle. These findings suggest an important physiological role of PASK in regulating metabolism and controlling energy balance in mammals (Hao, et al. 2007).

A major focus of our lab is to understand the mechanisms by which PASK controls both cellular and organismal energy metabolism. Specifically, we are working to understand how PASK regulates mitochondrial metabolism in skeletal muscle (and probably in many cell types). We are also working to understand how PASK controls hepatic lipid metabolism (as described in Hao, et al. 2007). We have strong in vivo data, using genetics and pharmacology, that PASK plays a key role in mediating the effects of a Western diet to promote dyslipidemia and disease.