Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

Meghan F Hogan,Kim Ravnskjaer,Shigenobu Matsumura,Mark O Huising,Rebecca L Hull,Steven E Kahn,Marc Montminy

doi:10.1074/jbc.m115.679266

Abstract

Under fasting conditions, increases in circulating concentrations of glucagon maintain glucose homeostasis via the induction of hepatic gluconeogenesis. Triggering of the cAMP pathway in hepatocytes stimulates the gluconeogenic program via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where it contributes to the attendant hyperglycemia. Whether selective activation of the hepatic CREB/CRTC pathway is sufficient to trigger metabolic changes in other tissues is unclear, however. Modest hepatic expression of a phosphorylation-defective and therefore constitutively active CRTC2S171,275A protein increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S171,275A-expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S171,275A mice, demonstrating that chronic increases in CRTC2 activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis.

Highlights

Loss of CRTC2 improves insulin sensitivity, but it is unknown if chronic CRTC2 activity causes hepatic insulin resistance
Hepatic gluconeogenesis is increased in insulin resistance where it contributes to the attendant hyperglycemia
Insulin resistance is a major risk factor for the development of type 2 diabetes, which is characterized by an inability for insulin to promote glucose uptake into muscle and to inhibit glucose production by the liver

Summary

Background

Loss of CRTC2 improves insulin sensitivity, but it is unknown if chronic CRTC2 activity causes hepatic insulin resistance. Despite accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S171,275A mice, demonstrating that chronic increases in CRTC2 activity in the liver are sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis. Recognizing the importance of the CREB/CRTC2 pathway in the fasting adaptation, we wondered whether modest expression of an active form of CRTC2 in the liver would be sufficient to increase hepatic gluconeogenesis and promote insulin resistance in peripheral tissues. We found that selective expression of a constitutively active form of CRTC2 in liver for a period of up to 5 weeks increases the set point for circulating concentrations of glucose This stable rise in blood glucose levels promotes compensatory increases in pancreatic islet mass and insulin secretion. The results point to an important role for hepatic CRTC2 in glucose homeostasis and in the development of hepatic insulin resistance

Experimental Procedures

Results

Discussion