title: Regulation of the PI3K/AKT Pathway and Fuel Utilization During Primate Torpor in the Gray Mouse Lemur, Microcebus murinus.
abstract: Gray mouse lemurs (Microcebus murinus) from Madagascar present an excellent model for studies of torpor regulation in a primate species. In the present study, we analyzed the response of the insulin signaling pathway as well as controls on carbohydrate sparing in six different tissues of torpid versus aroused gray mouse lemurs. We found that the relative level of phospho-insulin receptor substrate (IRS-1) was significantly increased in muscle, whereas the level of phospho-insulin receptor (IR) was decreased in white adipose tissue (WAT) of torpid animals, both suggesting an inhibition of insulin/insulin-like growth factor-1 (IGF-1) signaling during torpor in these tissues. By contrast, the level of phospho-IR was increased in the liver. Interestingly, muscle, WAT, and liver occupy central roles in whole body homeostasis and each displays regulatory controls operating at the plasma membrane. Changes in other tissues included an increase in phospho-glycogen synthase kinase 3α (GSK3α) and decrease in phospho-ribosomal protein S6 (RPS6) in the heart, and a decrease in phospho-mammalian target of rapamycin (mTOR) in the kidney. Pyruvate dehydrogenase (PDH) that gates carbohydrate entry into mitochondria is inhibited via phosphorylation by pyruvate dehydrogenase kinase (e.g., PDK4). In the skeletal muscle, the protein expression of PDK4 and phosphorylated PDH at Ser 300 was increased, suggesting inhibition during torpor. In contrast, there were no changes in levels of PDH expression and phosphorylation in other tissues comparing torpid and aroused animals. Information gained from these studies highlight the molecular controls that help to regulate metabolic rate depression and balance energetics during primate torpor.
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Surgery & Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Tessier
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Chemistry and Chemical Engineering Department, Royal Military College of Canada, Kingston, ON K7K 7B4, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Biochemistry Department, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Biggar
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada; Department of Biology, Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Wu
authors.affiliation: UMR 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy 91800, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Pifferi
authors.affiliation: UMR 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Brunoy 91800, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Perret
authors.affiliation: Institute of Biochemistry & Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: kenneth_storey@carleton.ca.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Storey
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D016565:Cheirogaleidae / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D064348:Torpor
chemical_list: D038362:Glycogen Synthase Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D058570:TOR Serine-Threonine Kinases; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; C546842:MTOR protein, human; C448021:glycogen synthase kinase 3 alpha
keywords: GSK3; Insulin signaling pathway; Metabolic rate depression; PI3K/AKT; Pyruvate dehydrogenase; mTOR