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Jonathan Bogan, MD

Work in my laboratory focuses on understanding cell biological processes that regulate metabolism in fat and muscle. A particular interest has been how insulin stimulates glucose uptake, by causing the exocytic translocation of GLUT4 glucose transporters to the plasma membrane. We discovered that, in unstimulated cells, GLUT4 is retained intracellularly by the action of TUG proteins. Data support a model in which TUG links insulin-responsive “GLUT4 Storage Vesicles” (GSVs) to the Golgi matrix, trapping them intracellularly to sequester GLUT4 away from the plasma membrane. To mobilize these vesicles, and thus to stimulate glucose uptake, insulin triggers acute, site-specific endoproteolytic TUG cleavage. Current studies seek to understand the GSVs: how do they originate, and from what membranes? How are they affected by membrane lipids and in insulin resistance? Why do these vesicles accumulate in fat and muscle cells, but not in most other cell types? Insulin acts by a non-canonical signaling pathway to cause TUG cleavage and GLUT4 translocation. What is the mechanism by which this is regulated? How is TUG cleaved in response to other signals, to cause insulin-independent glucose uptake?

We observed, unexpectedly, that the proteolytic mechanism we discovered controls other physiologic effects, in addition to glucose uptake. The GSVs contain only a handful of cargo proteins. Yet, vesicle cargos other than GLUT4 contribute to the regulation of vasopressin action and, possibly, lipid metabolism. We hypothesize that effects on vasopressin contribute to hypertension in the setting of insulin resistance. More broadly, we want to understand whether distinct components of the metabolic syndrome result, at least in part, from altered intracellular targeting of distinct GSV cargoes. A related area of interest is whether other physiologically-important membrane proteins are regulated by variations on this translocation pathway, possibly in other cell types.

How the TUG proteolytic pathway regulates energy expenditure is another major focus of our work. After TUG cleavage, the C-terminal cleavage product enters the nucleus and acts with transcriptional regulators to promote thermogenesis. Because the TUG product has a limited half-life, this is a transient effect. We hypothesize that it contributes to the thermic effect of food, and that common genetic polymorphisms modulate this thermogenic effect to modify diabetes risk. Ongoing studies focus on how the stability of the TUG product is regulated and seek to understand downstream effects on fatty acid oxidation and thermogenesis. These studies may lead to new approaches for the prevention and treatment of metabolic disease.