Periphere und zentralnervöse Wirkungen einer Protein-Tyrosin-Phosphatase 1B Hemmung auf den Glukose- und Fettstoffwechsel bei Menschen und Mäusen
Final Report Abstract
The Indy (Indy = I am not dead yet) gene encodes for a transporter that passes specific energetic substrates (di- and tricarboxylates) from the circulation into cells. It’s major sites of expression are sinusoidal plasma membranes of liver cells. The significance of INDY for mammalian energy balance is unknown. Deletion of the Indy gene in flies led to increased lifespan and shared many features of calorie restricted flies. Here, we deleted the Indy gene for the first time in a mammalian mouse model (mINDY-/- mouse). Deletion of the Indy gene in mice promoted energy expenditure and reduced adiposity when mice were fed a high calorie diet and during aging. It also protected from insulin resistance in these settings. On the cellular level, loss of Indy increased the density of mitochondria and the capacity to oxidize fat as a source of biochemical energy. These traits resemble the effects of caloric restriction, which is the most effective intervention to promote health- and life span in all species studied so far. Our data demonstrate that the mammalian Indy gene functions as a novel regulator of cellular energy metabolism and suggest that Indy is a promising therapeutic target for the treatment of obesity and type 2 diabetes. At the 70th American Diabetes Association Scientific Sessions 2010, the world’s most important conference on diabetes, the Indy-project was designated a Young Investigator Award. These awards are published in Diabetes 2010, 59, Suppl. 1, and they are given for the 30 top scoring abstracts accepted for presentation.
Publications
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Diabetes 2009; Suppl. 1 SGLT2 knockout improves glucose tolerance in lean and fat-fed mice. Abstract at the American Diabetes Association Sessions 2009
Jurczak MJ, Birkenfeld AL, Frederick DW, Lee HY, Samuel VT, Whaley JM, Shulman GI, Kibbey RG
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Liver Specific Inhibition of the eIF2α Mediated ER Stress Response Pathway Improves Hepatic Insulin Action but Impairs Peripheral Insulin Sensitivity in Mice. Diabetes 2009; Suppl. 1. Abstract at the American Diabetes Association Sessions
Birkenfeld AL, Lee HY, Frederick DW, Jurczak MJ, Jornayvaz FR, Oyadomari S, Samuel VT, Ron D, Shulman GI
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Pigment Epithelium- Derived Factor Deficiency Deteriorates Lipid and Glucose Metabolism. Diabetes 2009; Suppl. 1 Abstract at the American Diabetes Association Sessions 2009
Birkenfeld AL, Chung CC, Lee HY, Jurczak MJ, Frederick DW, Jornayvaz FR, Gattu A, Shugrue C, Gorelick F, Crawford S, Shulman GI, Samuel VT
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Deletion of the apha-Arrestin Protein Txnip in Mice Promotes Adiposity and Adipogenesis While Preserving Insulin Sensitivity. Diabetes 2010; 59(6):1424-34
Chutkow WA, Birkenfeld AL, Brown JD, Lee HJ, Frederick DW, Yoshioka J, Patwari P, Kursawe R, Cushman SW, Plutzky J, Shulman GI, Samuel VT, Lee RT
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Deletion of the Mammalian INDY Homologue in Mice Promotes Increased Energy Expenditure and Protects Against Diet and Age-Induced Adiposity and Insulin Resistance. Diabetes 2010;59 Suppl. 1. Abstract at the American Diabetes Association Sessions 2010
Birkenfeld AL, Lee HY, Jurzcak MJ, Jornayvaz FR, Frederick DW, Alves T, Kahn M, Zhang D, Hsiao JJ, Guigni B, Carmean CM, Weisman D, Knauf F, Irusta PM, De Cabo R, Helfand SL, Samuel VT, Shulman GI
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Targeted Expression of Catalase to Mitochondria Prevents Age-Associated Reductions in Mitochondrial Function and Insulin Resistance. Cell Metab 2010; 12: 676–682
Lee HY, Choi CS, Birkenfeld AL, Frederick DW, Shadel G, Ladiges W, Rabinovitch PS, Petersen KF, Samuel VT, Shulman GI
