Hepatic glycogen directly regulates gluconeogenesis through an AMPK/CRTC2 axis in mice
Bichen Zhang, … , Jeffrey E. Pessin, Alan R. Saltiel
Bichen Zhang, … , Jeffrey E. Pessin, Alan R. Saltiel
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e188363. https://doi.org/10.1172/JCI188363.
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Research Article Cell biology Metabolism

Hepatic glycogen directly regulates gluconeogenesis through an AMPK/CRTC2 axis in mice

Abstract

Glycogenolysis and gluconeogenesis ensure sufficient hepatic glucose production during energy shortages. Here, we report that hepatic glycogen levels control the phosphorylation of a transcriptional coactivator to determine the amplitude of gluconeogenesis. Decreased liver glycogen during fasting promotes gluconeogenic gene expression, while feeding-induced glycogen accumulation suppresses it. Liver-specific deletion of the glycogen scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels, increases the expression of gluconeogenic genes, and promotes glucose production in primary hepatocytes. In contrast, liver glycogen phosphorylase (PYGL) knockdown or inhibition increases glycogen levels and represses gluconeogenic gene expression. These changes in hepatic glycogen levels are sensed by AMP-activated protein kinase (AMPK). AMPK activity is increased when glycogen levels decline, resulting in the phosphorylation and stabilization of CREB-regulated transcriptional coactivator 2 (CRTC2), which is crucial for the full activation of the cAMP-responsive transcriptional factor CREB. High glycogen allosterically inhibits AMPK, leading to CRTC2 degradation and reduced CREB transcriptional activity. Hepatocytes with low glycogen levels or high AMPK activity show higher CRTC2 protein levels, priming the cell for gluconeogenesis through transcriptional regulation. Thus, glycogen plays a regulatory role in controlling hepatic glucose metabolism through the glycogen/AMPK/CRTC2 signaling axis, safeguarding efficient glucose output during fasting and suppressing it during feeding.

Authors

Bichen Zhang, Morgan M. Johnson, Timothy Yuan, Tammy-Nhu Nguyen, Junichi Okada, Fajun Yang, Alus M. Xiaoli, Liana H. Melikian, Songran Xu, Benyamin Dadpey, Jeffrey E. Pessin, Alan R. Saltiel

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Figure 3

Glucose metabolism is regulated by glycogen levels in vivo.

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Glucose metabolism is regulated by glycogen levels in vivo. (A) Glycogen...
(A) Glycogen levels in liver lysates from WT and PTGLKO mice. Mice were fasted 4 hours before sacrifice. (B) Glucose levels in WT and PTGLKO mice. (C) Pyruvate tolerance test (PTT) and quantification of area under the curve (AUC). Mice were injected with 1.5 g sodium pyruvate per kilogram body weight. (D) Gluconeogenic gene expression in fasted and fed WT and PTGLKO mice. (E) Gluconeogenic gene expression in liver lysates from WT and PTGLKO mice. Mice were fasted for 1 hour, injected with 0.5 mg/kg glucagon, and sacrificed 30 minutes after. (F) PTT assay of mice injected with AAV-GFP and AAV-PTG, and quantification of AUC. (G) PTT assay of sgNT and sgPYGL mice and quantification of AUC. n = 3–8 per group. *P < 0.05; **P < 0.01; ***P < 0.001 by unpaired Student’s t test (A–C and E–G) and 2-way ANOVA (D).