TY - JOUR
T1 - Rac1 muscle knockout exacerbates the detrimental effect of high-fat diet on insulin-stimulated muscle glucose uptake independently of Akt
AU - Raun, Steffen Henning
AU - Ali, Mona Sadek
AU - Kjøbsted, Rasmus
AU - Møller, Lisbeth Liliendal Valbjørn
AU - Federspiel, Morten Andreas
AU - Richter, Erik
AU - Jensen, Thomas Elbenhardt
AU - Sylow, Lykke
N1 - CURIS 2018 NEXS 163
PY - 2018/6/15
Y1 - 2018/6/15
N2 - Key points: The actin cytoskeleton regulating GTPase, Rac1, is a novel player in insulin-stimulated glucose uptake in muscle in vivo. High-fat diet (HFD) exacerbates muscle insulin resistance in Rac1 muscle knockout (mKO) mice. Muscle Rac1 KO protects against HFD-induced insulin resistance in fat tissue indicating tissue cross-talk. A fatty diet markedly reduces insulin clearance in mice. Abstract: Insulin resistance and perturbations in glucose metabolism underpin common lifestyle diseases such as type 2 diabetes and obesity. Insulin resistance in muscle is characterized by compromised activity of the GTPase, Ras-related C3 Botulinum toxin substrate 1 (Rac1), yet the role of Rac1 in insulin-stimulated glucose uptake in vivo and diet-induced insulin resistance is unknown. Inducible muscle-specific Rac1 knockout (Rac1 mKO) and wild type (WT) littermate mice were either fed a chow or a 60% high-fat diet (HFD). Insulin-stimulated 2-deoxy-glucose uptake, intracellular signalling, protein expression, substrate utilization, and glucose and insulin tolerance were assessed. In chow-fed mice, in vivo insulin-stimulated glucose uptake was reduced in triceps, soleus and gastrocnemius muscles from Rac1 mKO mice. HFD-induced whole body insulin resistance was exacerbated by the lack of muscle Rac1 and glucose uptake was reduced in all muscles, except for soleus. Muscle Akt (also known as protein kinase B) signalling was unaffected by diet or genotype. In adipose tissue, Rac1 mKO mice were protected from HFD-induced insulin resistance (with respect to both glucose uptake and phosphorylated-Akt), rendering their whole body glucose tolerance comparable to WT mice on HFD. Our findings show that lack of Rac1 exacerbates HFD-induced insulin resistance in skeletal muscle. Whole body glucose tolerance, however, was largely unaffected in Rac1 mKO mice, likely due to improved insulin-stimulated glucose uptake in adipose tissue. We conclude that lack of Rac1 in the context of obesity is detrimental to insulin-stimulated muscle glucose uptake in muscle independently of Akt signalling.
AB - Key points: The actin cytoskeleton regulating GTPase, Rac1, is a novel player in insulin-stimulated glucose uptake in muscle in vivo. High-fat diet (HFD) exacerbates muscle insulin resistance in Rac1 muscle knockout (mKO) mice. Muscle Rac1 KO protects against HFD-induced insulin resistance in fat tissue indicating tissue cross-talk. A fatty diet markedly reduces insulin clearance in mice. Abstract: Insulin resistance and perturbations in glucose metabolism underpin common lifestyle diseases such as type 2 diabetes and obesity. Insulin resistance in muscle is characterized by compromised activity of the GTPase, Ras-related C3 Botulinum toxin substrate 1 (Rac1), yet the role of Rac1 in insulin-stimulated glucose uptake in vivo and diet-induced insulin resistance is unknown. Inducible muscle-specific Rac1 knockout (Rac1 mKO) and wild type (WT) littermate mice were either fed a chow or a 60% high-fat diet (HFD). Insulin-stimulated 2-deoxy-glucose uptake, intracellular signalling, protein expression, substrate utilization, and glucose and insulin tolerance were assessed. In chow-fed mice, in vivo insulin-stimulated glucose uptake was reduced in triceps, soleus and gastrocnemius muscles from Rac1 mKO mice. HFD-induced whole body insulin resistance was exacerbated by the lack of muscle Rac1 and glucose uptake was reduced in all muscles, except for soleus. Muscle Akt (also known as protein kinase B) signalling was unaffected by diet or genotype. In adipose tissue, Rac1 mKO mice were protected from HFD-induced insulin resistance (with respect to both glucose uptake and phosphorylated-Akt), rendering their whole body glucose tolerance comparable to WT mice on HFD. Our findings show that lack of Rac1 exacerbates HFD-induced insulin resistance in skeletal muscle. Whole body glucose tolerance, however, was largely unaffected in Rac1 mKO mice, likely due to improved insulin-stimulated glucose uptake in adipose tissue. We conclude that lack of Rac1 in the context of obesity is detrimental to insulin-stimulated muscle glucose uptake in muscle independently of Akt signalling.
KW - Faculty of Science
KW - Diet-induced obesity
KW - Rac1
KW - Glucose uptake
KW - Muscle
KW - Adipose tissue
KW - Glucose homeostasis
U2 - 10.1113/jp275602
DO - 10.1113/jp275602
M3 - Journal article
C2 - 29749029
SN - 0022-3751
VL - 596
SP - 2283
EP - 2299
JO - The Journal of Physiology
JF - The Journal of Physiology
IS - 12
ER -
