TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction

TY - JOUR

T1 - TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction

AU - Kjøbsted, Rasmus

AU - Chadt, Alexandra

AU - Jørgensen, Nicolas Oldenburg

AU - Kido, Kohei

AU - Larsen, Jeppe K

AU - de Wendt, Christian

AU - Al-Hasani, Hadi

AU - Wojtaszewski, Jørgen

N1 - CURIS 2019 NEXS 278 © 2019 by the American Diabetes Association.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. We recently demonstrated that AMPK is necessary for AICAR, contraction, and exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization. However, the necessity of TBC1D4 for this phenomenon has not been proven. Thus, the purpose of this study was to determine whether TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. We found that immediately after contraction and AICAR stimulation, phosphorylation of AMPKα-Thr172 and downstream targets were increased similarly in glycolytic skeletal muscle from wild-type and TBC1D4-deficient mice. In contrast, 3 h after contraction or 6 h after AICAR stimulation, enhanced insulin-stimulated glucose uptake was evident in muscle from wild-type mice only. The enhanced insulin sensitivity in muscle fromwild-type mice was associated with improved insulin-stimulated phosphorylation of TBC1D4 (Thr649 and Ser711) but not of TBC1D1. These results provide genetic evidence linking signaling through TBC1D4 to enhanced muscle insulin sensitivity after activation of the cellular energy sensor AMPK.

AB - Muscle insulin sensitivity for stimulating glucose uptake is enhanced in the period after a single bout of exercise. We recently demonstrated that AMPK is necessary for AICAR, contraction, and exercise to enhance muscle and whole-body insulin sensitivity in mice. Correlative observations from both human and rodent skeletal muscle suggest that regulation of the phosphorylation status of TBC1D4 may relay this insulin sensitization. However, the necessity of TBC1D4 for this phenomenon has not been proven. Thus, the purpose of this study was to determine whether TBC1D4 is necessary for enhancing muscle insulin sensitivity in response to AICAR and contraction. We found that immediately after contraction and AICAR stimulation, phosphorylation of AMPKα-Thr172 and downstream targets were increased similarly in glycolytic skeletal muscle from wild-type and TBC1D4-deficient mice. In contrast, 3 h after contraction or 6 h after AICAR stimulation, enhanced insulin-stimulated glucose uptake was evident in muscle from wild-type mice only. The enhanced insulin sensitivity in muscle fromwild-type mice was associated with improved insulin-stimulated phosphorylation of TBC1D4 (Thr649 and Ser711) but not of TBC1D1. These results provide genetic evidence linking signaling through TBC1D4 to enhanced muscle insulin sensitivity after activation of the cellular energy sensor AMPK.

KW - Faculty of Science

KW - AMPK

KW - Exercise

KW - Glucose uptake

KW - AS160

U2 - 10.2337/db18-0769

DO - 10.2337/db18-0769

M3 - Journal article

C2 - 31175100

SN - 0012-1797

VL - 68

SP - 1756

EP - 1766

JO - Diabetes

JF - Diabetes

IS - 9

ER -