Case Western Reserve University

Richard W. Hanson, Ph.D.

Professor

Research Interests

My research over the past 30 years has focused on the interface between molecular genetics and metabolic regulation. In the 1980’s I began to use molecular biology as a tool for the study of metabolism. This interest has evolved into the use mouse genetics to study the impact of gene modification on metabolism.

There are currently four major themes in my research program:

• (1) The dietary and hormonal regulation of transcription of the gene for the cytosolic form of P-enolpyruvate carboxykinase (PEPCK-C) and the factors that regulate its transcription in liver adipose tissue and the kidney cortex. The regulation of PEPCK-C gene transcription is now among the best understood of any mammalian gene. We are currently assessing the role of SERT-1 and the role of acetylation of specific transcription factors (i.e. HNF4a) in controlling the transcription of the gene for PEPCK-C in the liver and adipose tissue.
• (2) The physiological role of PEPCK in animal tissues. This research involves determining the role of the isoforms of PEPCK in animals and the metabolic function of PEPCK in non-gluconeogenic tissues such as adipose tissue. In 1968, my colleagues and I proposed a pathway termed glyceroneogenesis, an abbreviated version of gluconeogenesis that synthesizes glyceride-glycerol from precursors other than glucose and glycerol. This pathway is now recognized as a key step in diabetes and a major route for the generation of 3-glycerol phosphate for triglyceride synthesis. We are studying the important role of glyceroneogenesis in a variety of organisms under different dietary and hormonal condition.
• (3) The metabolism of the PEPCK-Cmus mouse We are studying the metabolic basis for the hyper-activity, increased life span and reproductive capacity noted with the PEPCK-Cmus mouse. These animals have a greatly enhanced capacity for exercise and live longer than control littermates. The metabolic basis for this remarkable alteration in capacity is not clear and is currently under investigation. We are also assessing of the effect of hyper-activity on the progression of colon cancer in the Mon+/- mouse model.
• (4) The metabolic role of the mitochondrial form of PEPCK (PEPCK-M) The major emphasis of research on the metabolic role of PEPCK involves studies of PEPCK-C. this isoform of PEPCK is inducible by diet and hormones and is required for gluconeogenesis and glyceroneogenesis from diverse compounds such as amino acids. However, all species studied to date have agene for PEPCK-M; in most mammals, including humans, there is an equal activity of the two isofoms of PEPCK in the liver. Despite this, the role of PEPCK-M in metabolism has been virtually ignored. This is due, in large part, to the fact that the widely studied rodent species, the mouse and rat, have only 5% total PEPCK-M activity. A major goal of our current research is to create mouse models that over express PEPCK-M in the skeletal muscle and in the same tissues that express the gene for PEPCK-C and to then determine the metabolic consequences.

Selected References