Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2.
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.
From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Meghan F
MF
Hogan
From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Kim
K
Ravnskjaer
From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto, 606-8502, Japan, and.
Shigenobu
S
Matsumura
From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, California 95616.
Mark O
MO
Huising
Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Rebecca L
RL
Hull
Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108.
Steven E
SE
Kahn
From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, montminy@salk.edu.
Marc
M
Montminy
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D001786:Blood Glucose; C504923:Crtc2 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D014157:Transcription Factors
cAMP response element-binding protein (CREB); gluconeogenesis; insulin resistance; protein phosphorylation; transcriptional coactivator