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 extracellular regulatory molecules such as glucagon and vasopressin triggering specific hepatocyte receptors to activate the cAMP or phosphoinositide signal transduction pathways, respectively. We now show that the 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 phosphoinositide 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 phosphoinositide pathway, resulting in a sustained rise in blood glucose. It should be possible to use this general strategy to modulate the differentiated functions of target organs in a wide variety of pathologic states.
Wolff
G
G
Division of Pulmonary and Critical Care Medicine, Cornell University Medical College, New York, New York 10021, USA.
Mastrangeli
A
A
Heinflink
M
M
Falck-Pedersen
E
E
Gershengorn
M C
MC
Crystal
R G
RG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008099:Liver / Q000502:physiology*; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018025:Receptors, Thyrotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013973:Thyrotropin-Releasing Hormone / Q000502:physiology*
D001786:Blood Glucose; D010716:Phosphatidylinositols; D018025:Receptors, Thyrotropin-Releasing Hormone; D011993:Recombinant Fusion Proteins; D013973:Thyrotropin-Releasing Hormone