Metabolic Crosstalk: molecular links between glycogen and lipid metabolism in obesity
- Binbin Lu1,
- Dave Bridges1,
- Yemen Yang1,
- Kaleigh Fisher1,
- Alan Cheng1,
- Louise Chang1,
- Zhuoxian Meng1,
- Jiandie Lin1,
- Michael Downes2,
- Ruth T. Yu2,
- Christopher Liddle2,3,
- Ronald M. Evans2 and
- Alan R. Saltiel1⇑
- 1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
- 2Salk Institute for Biological Sciences, La Jolla, CA 92037, USA
- 3Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia
- Corresponding Author: A.R. Saltiel, E-mail:
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.
- © 2014 by the American Diabetes Association.
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