1605-P: Hepatic Glycogen Directly Regulates Gluconeogenesis in Energy Shortage through AMPK Free

Hierarchical synthesis and breakdown of nutrients in the liver maintain metabolic homeostasis in feeding and fasting cycles. Liver glycogen is the first choice for glucose storage and utilization. Patients with obesity and type 2 diabetes show aberrant hepatic glycogen metabolism, contributing to their increased glucose levels. However, whether and how liver glycogen per se regulates glucose metabolism is unknown. Protein targeting to glycogen (PTG) is the scaffolding protein that controls glycogen metabolism. Here, using a mouse model with liver-specific PTG knockout (LKO), we report that rather than a mere passive reservoir of energy, hepatic glycogen itself senses nutritional and hormonal cues to regulate gluconeogenesis, maintaining sufficient glucose output in energy shortage. Glycogen levels are decreased by 75% in the whole liver and 55% in isolated primary hepatocytes from LKO mice. LKO mice show 40% lower glucose levels in response to short-term fasting because of blunted glycogenolysis. Interestingly, the glucose level is similar in WT and LKO mice after overnight fasting, indicating enhanced gluconeogenesis in LKO mice. In agreement with this, LKO mice show significantly increased glucose production in a pyruvate tolerance test. LKO hepatocytes show increased gene expression of key regulators of gluconeogenesis (Nr4a3, Pgc1a, Pck1) when treated with glucagon or cell-permeable cAMP. Glucose production is also enhanced in LKO hepatocytes with fasting or cAMP treatment. Mechanistically, decreased glycogen levels in LKO hepatocytes increases the activity of AMPK. Pre-treatment of LKO hepatocytes with an AMPK inhibitor abolishes the increase in both gluconeogenic gene expression levels and cellular glucose production. Together, these results reveal a new regulatory role for hepatic glycogen in glucose metabolism, indicating that glycogen is an active molecule that signals the gluconeogenesis pathway through AMPK, to fine tune glucose production during energy shortage.