Metabolic Crosstalk: molecular links between glycogen and lipid metabolism in obesity

  1. Alan R. Saltiel1
  1. 1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
  2. 2Salk Institute for Biological Sciences, La Jolla, CA 92037, USA
  3. 3Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia
  1. Corresponding Author: A.R. Saltiel, E-mail: Saltiel{at}


Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we demonstrate that feeding mice a high fat diet (HFD) increased hepatic glycogen, due to increased expression of the glycogenic scaffolding protein PTG/R5. PTG promoter activity was increased and glycogen levels were augmented in mice and cells after activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target sterol regulatory element binding protein 1 (SREBP1). Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Surprisingly, PTG deletion also blocked hepatic steatosis in HFD-fed mice, and reduced the expression of numerous lipogenic genes. Additionally, PTG deletion reduced fasting glucose and insulin levels in obese mice, while improving insulin sensitivity, a result of reduced hepatic glucose output. This metabolic crosstalk was due to decreased mTORC1 and SREBP activity in PTG knockout mice or knockdown cells, suggesting a positive feedback loop in which once accumulated, glycogen stimulates the mTORC1/SREBP1 pathway to shift energy storage to lipogenesis. Together, these data reveal a previously unappreciated broad role for glycogen in the control of energy homeostasis.

  • Received October 4, 2013.
  • Accepted April 2, 2014.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.