Vivo Metabolic Roles of G Proteins of the Gi Family Studied With Novel Mouse Models

G protein-coupled receptors (GPCRs) are the target of similar to 30% to 35% of all US Food and Drug Administration-approved drugs. The individual members of the GPCR superfamily couple to 1 or more functional classes of heterotrimeric G proteins. The physiological outcome of activating a particular GPCR in vivo depends on the pattern of receptor distribution and the type of G proteins activated by the receptor. Based on the structural and functional properties of their alpha-subunits, heterotrimeric G proteins are subclassified into 4 major families: G(s), G(i/o), G(q/11), and G(12/13). Recent studies with genetically engineered mice have yielded important novel insights into the metabolic roles of G(i/o)-type G proteins. For example, recent data indicate that G(i) signaling in pancreatic alpha-cells plays a key role in regulating glucagon release and whole body glucose homeostasis. Receptor-mediated activation of hepatic G(i) signaling stimulates hepatic glucose production, suggesting that inhibition of hepatic G(i) signaling could prove clinically useful to reduce pathologically elevated blood glucose levels. Activation of adipocyte G(i) signaling reduces plasma free fatty acid levels, thus leading to improved insulin sensitivity in obese, glucose-intolerant mice. These new data suggest that G(i)-coupled receptors that are enriched in metabolically important cell types represent potential targets for the development of novel drugs useful for the treatment of type 2 diabetes and related metabolic disorders.

Automated summary

GPCRs are significant targets for drugs approved by the US FDA, where activation of different GPCRs can impact physiological outcomes differently, reflecting the effects of G protein activation from different perspectives.