Metabolic crosstalk: molecular links between glycogen and lipid metabolism in obesity.
Glycogen and lipids are major storage forms of energy that are tightly regulated by hormones and metabolic signals. We demonstrate that feeding mice a high-fat diet (HFD) increases 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 the mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target SREBP1. Deletion of the PTG gene in mice prevented HFD-induced hepatic glycogen accumulation. Of note, 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.
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Binbin
B
Lu
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Dave
D
Bridges
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Yemen
Y
Yang
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Kaleigh
K
Fisher
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Alan
A
Cheng
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Louise
L
Chang
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Zhuo-Xian
ZX
Meng
Life Sciences Institute, University of Michigan, Ann Arbor, MI.
Jiandie D
JD
Lin
Salk Institute for Biological Sciences, La Jolla, CA.
Michael
M
Downes
Salk Institute for Biological Sciences, La Jolla, CA.
Ruth T
RT
Yu
Salk Institute for Biological Sciences, La Jolla, CA Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, NSW, Australia.
Christopher
C
Liddle
Salk Institute for Biological Sciences, La Jolla, CA.
Ronald M
RM
Evans
Life Sciences Institute, University of Michigan, Ann Arbor, MI saltiel@umich.edu.
Alan R
AR
Saltiel
D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology; D005246:Feedback; D006003:Glycogen / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000172:deficiency*; D050356:Lipid Metabolism; D050155:Lipogenesis; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008112:Liver Glycogen; D046912:Multiprotein Complexes; C104748:Ppp1r3c protein, mouse; D051779:Sterol Regulatory Element Binding Proteins; D006003:Glycogen; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases