Novel mouse models to probe the function of hepatic Gi signaling in maintaining glucose homeostasis

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NIDDK	MOLBIO-17

* FARE Award Winner

Authors

• M. Rossi
• L. Zhu
• S.M. McMillin
• Y. Cui
• O. Gavrilova
• S. Coughlin
• M.J. Birnbaum
• J. Wess

Abstract

Type 2 Diabetes (T2D) is a major metabolic disorder characterized by high blood glucose levels. One of the key features of T2D is enhanced hepatic glucose production (HGP). Increased signaling through hepatic glucagon receptors has been implicated in maintaining unphysiologically high HGP in T2D. Glucagon receptors couple to the stimulatory G protein, Gs, thus promoting glycogen breakdown and gluconeogenesis in hepatocytes. However, hepatocytes express other G protein-coupled receptors (GPCRs) that preferentially couple to G proteins of the Gq or Gi family. At present little is known about the physiological relevance of Gi-coupled GPCRs in regulating HGP. To address this issue, we generated two novel mouse models, Hep-Ri and Hep-Gi-KO mice. The Hep-Ri mice express a Gi-coupled designer GPCR (Ri) specifically in hepatocytes that can only be activated by a synthetic compound (CNO) that is otherwise pharmacologically inert. On the other hand, the Hep-Gi-KO mice lack functional Gi proteins specifically in hepatocytes. Interestingly, in the Hep-Ri mice CNO-induced Ri activation led to increased blood glucose levels, impaired glucose tolerance, and enhanced gluconeogenesis, while Hep-Gi-KO mice showed the opposite phenotype. Taken together, these data suggest that Gi-coupled GPCRs endogenously expressed by hepatocytes may represent potential targets for developing new anti-diabetic treatments.

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