Under the tutelage of another supportive mentor, and in a lab full of great colleagues, Hanson first began working on the protein that would become his calling card: phosphoenolpyruvate carboxykinase, better known as “PEPCK.”
The enzyme, which is involved in glucose production, along with the related enzyme pyruvate carboxylase recently had been discovered by Merton F. Utter in the department of biochemistry at Case Western Reserve University School of Medicine— where, in another happy accident, Hanson would end up moving in 1978 to become chairman of the department— and Hanson was examining their role in the initiation of glucose homeostasis in developing rat livers. Along the way, he and colleague John Ballard had, surprisingly, found PEPCK in adipose tissue, which seemed bizarre, as adipocytes do not make glucose.
Soon, together with Gilbert Leveille and their longtime collaborator Lea Reshef, they realized that PEPCK was involved in an abbreviated pathway that converted pyruvate into glycerol-3-phosphate for triglyceride synthesis, which was hence named glyceroneogenesis.
That discovery highlights just one example of the many wonderful collaborations Hanson has had; he likes to note that the numerous excellent scientists he has worked with have given him much more than he has given back. He especially acknowledges Reshef, an Israeli scientist who worked closely with him for more than 30 years, studying the factors that control PEPCK-C gene transcription. “Lea has been a wonderful collaborator; I am not a molecular biologist, so I owe a great deal of my success in studying gene expression to her insights,” he says. “She was full of ideas and always willing to share with me her vision and enthusiasm for studying PEPCK-C.”
Following that 1967 glyceroneogenesis breakthrough, which resulted in a paper in the JBC’s Classics series, Hanson began a fruitful series of studies on the factors that regulate the levels of PEPCK-C in mammalian tissues; he and his colleagues isolated the genes for both the cytosolic (PEPCK-C) and mitochondrial (PEPCK-M) forms of the enzyme and began focusing on the hormonal and dietary factors that affected PEPCK-C gene transcription. He never wavered in his pursuits, even as the prominence of metabolism gave way to the era of molecular biology, though he commented that at times it made funding more difficult to come by.
During the past decade, though, partially spurred by the rise in interest in the causes of obesity and diabetes, metabolism studies have made a very strong comeback. This certainly came as a welcome turn of events to Hanson, at least until he found himself thrust right in the middle of the metabolic resurgence.
Of Mighty Mice and Men
Going back to his graduate school days, Hanson had significant experience with animal models as tools to understand metabolic function and, over the years, had developed strains of mice in which PEPCK was either deleted or overexpressed in specific tissues. For example, in 2002, in collaboration with Reshef and her student Yael Olswang, they found that ablating PEPCK-C gene expression specifically in adipose tissue produced lipodystrophy in many affected mice, validating the enzyme’s central role in adipose-tissue glyceroneogenesis.
As a follow-up, in 2007, Hanson, together with his longtime colleague Parvin Hakimi, decided to generate mice in which PEPCK-C was overexpressed in skeletal muscle, another tissue like adipose tissue that has PEPCK-C activity but does not synthesize glucose. “I didn’t know exactly what to expect,” Hanson says, “but I was pretty sure these mice would only have subtle changes in their metabolic profile; boy, was I in for a shock.”