RGS/G‐protein control of liver carbohydrate and fatty acid metabolism

Abstract

G protein coupled receptor (GPCR) pathways regulate glucose and fatty acid metabolism and the onset of obesity and diabetes. Regulators of G protein Signaling (RGS) proteins are Gα‐GAPs that control the intensity and duration of G protein signaling. One RGS gene, Rgs16, is up regulated 20‐fold in liver during fasting and rapidly down regulated by feeding. Rgs16 mRNA expression is restricted to the periportal hepatocytes which preferentially oxidize fatty acids and produce glucose during fasting. Interestingly, dietary saccharides induce Rgs16 mRNA up to 300‐fold and expression expands to all hepatocytes. The bHLH transcription factor ChREBP is required for glucose‐dependent induction of Rgs16 transcription in mice and cultured liver slices. Transgenic mice that express Rgs16 protein specifically in liver have reduced expression of hepatic genes that promote fatty acid oxidation, lower rates of fatty acid oxidation in liver extracts, and lower plasma β‐ketone levels compared to wild type littermates. By contrast, Rgs16 knockout mice exhibit the reciprocal phenotypes. In summary, Rgs16 is a glucose‐responsive inhibitor of fatty acid oxidation in liver. We are investigating broader roles of Rgs16 in glucose and fatty acid metabolism in healthy, obese and diabetic conditions. Research support: NIH & Welch Foundation.