ECTOPIC EXPRESSION OF THYROTROPIN-RELEASING-HORMONE (TRH) RECEPTORS IN LIVER MODULATES ORGAN FUNCTION TO REGULATE BLOOD-GLUCOSE BY TRH

Maintenance of blood glucose by the liver is normally initiated by ext racellular regulatory molecules such as glucagon and vasopressin trigg ering specific hepatocyte receptors to activate the cAMP or phosphoino sitide signal transduction pathways, respectively. We now show that th e normal ligand-receptor regulators of blood glucose in the liver can be bypassed using an adenovirus vector expressing the mouse pituitary thyrotropin releasing hormone receptor (TRHR) cDNA ectopically in rat liver in vivo. The ectopically expressed TRHR links to the phosphoinos itide pathway, providing a means to regulate liver function with TRH, an extracellular ligand that does not normally affect hepatic function . Administration of TRH to these animals activates the phosphoinositid e pathway, resulting in a sustained rise in blood glucose. It should b e possible to use this general strategy to modulate the differentiated functions of target organs in a wide variety of pathologic states.