TBC1D4-S711 controls skeletal muscle insulin sensitization after exercise and contraction
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TBC1D4-S711 controls skeletal muscle insulin sensitization after exercise and contraction. / Kjøbsted, Rasmus; Kristensen, Jonas Møller; Eskesen, Nicolas Oldenburg; Kido, Kohei; Fjorder, Klara; Damgaard, Ditte F; Larsen, Jeppe Kjærgaard; Andersen, Nicoline Resen; Birk, Jesper Bratz; Gudiksen, Anders; Treebak, Jonas Thue; Schjerling, Peter; Pilegaard, Henriette; Wojtaszewski, Jørgen.
In: Diabetes, Vol. 72, No. 7, 2023, p. 857-871.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - TBC1D4-S711 controls skeletal muscle insulin sensitization after exercise and contraction
AU - Kjøbsted, Rasmus
AU - Kristensen, Jonas Møller
AU - Eskesen, Nicolas Oldenburg
AU - Kido, Kohei
AU - Fjorder, Klara
AU - Damgaard, Ditte F
AU - Larsen, Jeppe Kjærgaard
AU - Andersen, Nicoline Resen
AU - Birk, Jesper Bratz
AU - Gudiksen, Anders
AU - Treebak, Jonas Thue
AU - Schjerling, Peter
AU - Pilegaard, Henriette
AU - Wojtaszewski, Jørgen
N1 - © 2023 by the American Diabetes Association.
PY - 2023
Y1 - 2023
N2 - The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact wholebody glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.
AB - The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact wholebody glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.
KW - Faculty of Science
KW - AS160
KW - AMPK
KW - Exercise
KW - Glucose uptake
KW - Insulin sensitivity
U2 - 10.2337/db22-0666
DO - 10.2337/db22-0666
M3 - Journal article
C2 - 37074686
VL - 72
SP - 857
EP - 871
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 7
ER -
ID: 344644780