The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

Stöckli, Jacqueline; Meoli, Christopher C.; Hoffman, Nolan J.; Fazakerley, Daniel J.; Pant, Himani; Cleasby, Mark E.; Ma, Xiuquan; Kleinert, Maximilian; Brandon, Amanda E.; Lopez, Jamie A.; Cooney, Gregory J.; James, David E.

doi:10.2337/db13-1489

Cited by 55 publications

(74 citation statements)

References 45 publications

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“…5E-G). Normal GLUT4 expression and glucose uptake in EDL muscle of the AS160 R917K knockin or AS160 KO mice (14)(15)(16)(17) are most likely a result of the presence of TBC1D1, which regulates GLUT4 expression in white skeletal muscle (32)(33)(34). The AS160 R917K knockin mice displayed significant insulin resistance and exhibited intolerance to glucose administration (Fig.…”

Section: Gap Deficiency Of As160 Caused Insulin Resistance and Postprmentioning

confidence: 91%

The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Xie

Chen

et al. 2016

Diabetes

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The AS160 (Akt substrate of 160 kDa) is a Rab-GTPase activating protein (RabGAP) with several other functional domains, and its deficiency in mice or human patients lowers GLUT4 protein levels and causes severe insulin resistance. How its deficiency causes diminished GLUT4 proteins remains unknown. We found that the deletion of AS160 decreased GLUT4 levels in a cell/ tissue-autonomous manner. Consequently, skeletal muscle-specific deletion of AS160 caused postprandial hyperglycemia and hyperinsulinemia. The pathogenic effects of AS160 deletion are mainly, if not exclusively, due to the loss of its RabGAP function since the RabGAP-inactive AS160 R917K mutant mice phenocopied the AS160 knockout mice. The inactivation of RabGAP of AS160 promotes lysosomal degradation of GLUT4, and the inhibition of lysosome function could restore GLUT4 protein levels. Collectively, these findings demonstrate that the RabGAP activity of AS160 maintains GLUT4 protein levels in a cell/tissue-autonomous manner and its inactivation causes lysosomal degradation of GLUT4 and postprandial hyperglycemia and hyperinsulinemia.

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Section: Gap Deficiency Of As160 Caused Insulin Resistance and Postprmentioning

confidence: 91%

The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Xie

Chen

et al. 2016

Diabetes

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“…A treadmill running test was performed on a TMW‐4 mouse treadmill (MELQUEST) (Stockli et al., 2015). To evaluate exercise capacity, mice were subjected to running at 10 m/min for 10 min, followed by an increase in running speed of 1 m/min every 15 min.…”

Section: Methodsmentioning

confidence: 99%

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

et al. 2018

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SummaryExtending healthy lifespan is an emerging issue in an aging society. This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)‐induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age‐related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age‐dependent decrease in slow‐twitch muscle fiber function but reduced absolute fast‐twitch muscle fiber function. DR‐induced fast‐twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum‐fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet‐restricted aged mice, which were accompanied by a recovery in H2S production capacity and lower oxidative stress. These data imply that a dietary approach could combat kidney aging and prolong lifespan, while preventing muscle weakness, and suggest that renal methionine metabolism and the trans‐sulfuration pathway could be therapeutic targets for preventing kidney aging and subsequently promoting healthy aging.

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“…Clearly, TBC1D1 has other functions, and regulates GLUT4 expression and fatty acid oxidation in skeletal muscle (8,9,11). TBC1D1 can be phosphorylated on multiple sites besides Ser 231 (12), and electroporation of a TBC1D1-4P mutant (in which Ser 231 , Thr 499 , Thr 590 , and Ser 621 are mutated to Ala) into skeletal muscle decreases contraction-stimulated glucose uptake (10).…”

Section: Discussionmentioning

confidence: 99%

“…A truncation or KO of TBC1D1 confers leanness to mice fed on high fat diet with increased fatty acid oxidation in skeletal muscle (8,9). TBC1D1 has also been implicated in regulating muscle glucose uptake (10), whereas its deficiency causes a decreased expression level of GLUT4 in skeletal muscle (8,9,11).We previously identified TBC1D1 as an AMPK substrate that is phosphorylated on Ser 231 by AMPK and interacts with 14-3-3 proteins on Ser 231 phosphorylation (12). However, the physiological role of this AMPK-TBC1D1 signal nexus remains elusive.…”

mentioning

confidence: 99%

Disruption of the AMPK–TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion

Chen

Xie

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser 231 by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1 Ser231Ala knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet. Mechanistically, TBC1D1 is located on insulin-like growth factor 1 (IGF1) storage vesicles, and the KI mutation increases endocrinal and paracrinal/autocrinal IGF1 secretion in an Rab8a-dependent manner. Hypersecretion of IGF1 causes increased expression of lipogenic genes via activating the protein kinase B (PKB; also known as Akt)-mammalian target of rapamycin (mTOR) pathway in adipose tissues, which contributes to the development of obesity, diabetes, and hepatic steatosis as the KI mice age. Collectively, these findings demonstrate that the AMPK-TBC1D1 signaling nexus interacts with the PKB-mTOR pathway via IGF1 secretion, which consequently controls expression of lipogenic genes in the adipose tissue. These findings also have implications for drug discovery to combat obesity.D ue to changes in diet and lifestyle, metabolic syndrome including obesity, type 2 diabetes, and nonalcoholic fatty liver disease is increasing in prevalence worldwide, putting a huge burden on modern society and motivating us to get better understanding of these diseases and how to combat them.High energy intake and lack of physical activity can result in imbalances of energy metabolism and changed energy status of the body, which is monitored by the energy-sensing kinase AMPactivated protein kinase (AMPK) (1). The AMPK holoenzyme is a heterotrimer, consisting of catalytic α (α1 and α2), regulatory β (β1 and β2), and γ (γ1, γ2 and γ3) subunits (1). AMPK is mainly activated through Thr 172 phosphorylation in its catalytic domain by the upstream liver kinase B1 (LKB1) under energy stress conditions that increase the cellular AMP:ATP ratio (2, 3). AMPK can regulate both glucose and lipid metabolism by its phosphorylation of multiple substrates (4). For instance, acetyl-CoA carboxylase (ACC), an enzyme important for fatty acid synthesis and oxidation, is regulated through an inhibitory phosphorylation by AMPK, which is essential for the control of lipid metabolism (5). The LKB1-AMPK pathway can also control glucose uptake into skeletal muscle by promoting translocation of the glucose transporter 4 (GLUT4) from its intracellular storage sites onto plasma membrane in response to a pharmacological AMPK activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), or muscle contraction (6). However, the mechanism by which AMPK promotes translocation of GLUT4 onto plasma membrane is not well understood.Tre-2/USP6, BUB2, cdc16 domain family member 1 [the TBC domain is the GTPase activating protein (GAP) domain] (TBC1D1) is an R...

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The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

Cited by 55 publications

References 45 publications

The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged mice

Disruption of the AMPK–TBC1D1 nexus increases lipogenic gene expression and causes obesity in mice via promoting IGF1 secretion

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