Gq alpha mediates metabolic regulation of liver and fat in vivo: analyses in transgenic mice harboring an inducible, tissue-specific transgene for RNA antisense to G alpha q.
Heterotrimeric G-proteins mediate transmembrane signaling from a populous group of cell-surface receptors to a lesser group of effector molecules that includes adenylyl cyclase, phospholipase C and various ion channels. We have already demonstrated that Gi alpha, and Gs alpha play a role in complex biological processes such as growth and development. Little is known about the role of G-protein of the Gq family in vivo. In cell culture, G alpha q has been shown to stimulate PLC. We used a novel approach to the in-vivo study of Gq alpha by creating transgenic mice who harbor a conditional, tissue-specific expression vector capable of producing RNA antisense to Gq alpha. BDF1 mice carrying the pPCK-ASGqalpha transgene were identified by southern analysis. By 4 weeks of age, transgenic mice were visually larger with total body weights 25% greater than control littermates. The liver mass was 30% greater in transgenic mice by 8 weeks of age. Inspection of a wide range of tissues revealed that growth had been increased selectively in target organs only. Histology data from necropsy material revealed that the livers from transgenic animals displayed increased hepatocellular vacuolation of the glycogen type. Glycogen determinations were assessed and proved to be greater than 2 fold in hepatic tissue from transgenic mice at 12 wks, 18 wks, 24 wks and 39 wks. Non-target organs were studied the same way and showed no affect. Insulin and glucose levels were measured in control and transgenic mice and found to be equivalent. Similar findings occurred when the mice were fasted for 24 hrs. Glycogenolysis in the liver is known to operate via a cyclic AMP dependent pathway, however it has been suspected that there may be a cyclic AMP independent pathway operating as well.Our previous studies have shown that Gq alpha is involved in activation of the PLC pathway in vivo. This pathway regulates protein kinase C activity which is necessary for phosphorylation of glycogen synthase. If glycogen synthase is not inactivated by phosphorylation it will continue to make glycogen. These studies demonstrate the potential effect of Gq alpha on protein kinase C. Suppression of Gq alpha in transgenic mice was associated with an altered total body weight and clinically signicant metabolic changes in the liver and fat.
