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TBC1D1 Regulates Insulin- and Contraction-Induced Glucose Transport in Mouse Skeletal Muscle Ding An,1 Taro Toyoda,1 Eric B

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TBC1D1 Regulates Insulin- and Contraction-Induced Glucose Transport in Mouse Skeletal Muscle Ding An,1 Taro Toyoda,1 Eric B ORIGINAL ARTICLE TBC1D1 Regulates Insulin- and Contraction-Induced Glucose Transport in Mouse Skeletal Muscle Ding An,1 Taro Toyoda,1 Eric B. Taylor,1 Haiyan Yu,1 Nobuharu Fujii,1 Michael F. Hirshman,1 and Laurie J. Goodyear1,2 OBJECTIVE—TBC1D1 is a member of the TBC1 Rab-GTPase through a phosphatidylinositol 3 kinase (PI 3-kinase)– family of proteins and is highly expressed in skeletal muscle. dependent mechanism and the exercise effect may involve Insulin and contraction increase TBC1D1 phosphorylation on multiple molecules including the AMP-activated protein phospho-Akt substrate motifs (PASs), but the function of kinase (AMPK) family of protein kinases, an important TBC1D1 in muscle is not known. Genetic linkage analyses show goal in this field has been to elucidate the mechanisms that a TBC1D1 R125W missense variant confers risk for severe connect the proximal insulin and exercise signals to obesity in humans. The objective of this study was to determine whether TBC1D1 regulates glucose transport in skeletal muscle. GLUT4 translocation. Recent studies have identified two molecules, the Akt substrate of 160 kDa (AS160/TBC1D4) RESEARCH DESIGN AND METHODS—In vivo gene injection and its paralog, TBC1D1, as potential molecular links and electroporation were used to overexpress wild-type and among multiple signaling pathways converging on GLUT4 several mutant TBC1D1 proteins in mouse tibialis anterior mus- translocation in skeletal muscle (5–12). cles, and glucose transport was measured in vivo. AS160 was first shown to modulate GLUT4 trafficking in RESULTS—Expression of the obesity-associated R125W mutant insulin-sensitive 3T3-L1 adipocytes (13). A striking struc- significantly decreased insulin-stimulated glucose transport in tural feature of AS160 is that the molecule harbors a the absence of changes in TBC1D1 PAS phosphorylation. Simul- Rab-GTPase (GAP) domain and its activity controls Rab- taneous expression of an inactive Rab-GTPase (GAP) domain of GTP loading and regulation of Rab function (11). AS160 TBC1D1 in the R125W mutant reversed this decrease in glucose contains at least six amino acids that can be phosphory- transport caused by the R125W mutant. Surprisingly, expression of TBC1D1 mutated to Ala on four conserved Akt and/or AMP- lated in response to insulin by Akt (14), and these sites can activated protein kinase predicted phosphorylation sites (4P) be detected in aggregate with an antibody directed against had no effect on insulin-stimulated glucose transport. In contrast, a phospho-Akt substrate motif (PAS). Insulin, exercise, and expression of the TBC1D1 4P mutant decreased contraction- the AMPK activator 5Ј-aminoimidazole-4-carboxymide-1-␤-D- stimulated glucose transport, an effect prevented by concomitant ribofuranoside (AICAR) all cause phosphorylation of disruption of TBC1D1 Rab-GAP activity. There was no effect of the AS160 on PAS sites in skeletal muscle (5,7,10), and there is R125W mutation on contraction-stimulated glucose transport. good evidence that phosphorylation of these sites inhibits CONCLUSIONS—TBC1D1 regulates both insulin- and contrac- AS160 activity, leading to trafficking of GLUT4 vesicles to tion-stimulated glucose transport, and this occurs via distinct the cell surface and glucose transport (8,15). However, mechanisms. The R125W mutation of TBC1D1 impairs skeletal ablation of AS160 phosphorylation at PAS sites only muscle glucose transport, which could be a mechanism for the partially inhibits insulin- and contraction-stimulated glu- obesity associated with this mutation. Diabetes 59:1358–1365, cose transport (8,15). Furthermore, a preliminary report 2010 suggests that whole-body knockout of AS160 does not result in a significant increase in glucose transport in muscle (16). Taken together, these findings suggest that there may be one or more additional Rab-GAP proteins nsulin and exercise are the most physiologically expressed in skeletal muscle that also function to regulate relevant stimulators of glucose transport in skeletal glucose transport. muscle, and in patients with type 2 diabetes, insulin- TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family mem- Ibut not exercise-stimulated glucose transport can be ber 1) is a member of the TBC1 Rab-GAP family of severely impaired (1–4). GLUT4 translocation from an proteins. TBC1D1 and AS160 are 47% identical overall and intracellular location to the sarcolemma and transverse have several comparable structural features. Both proteins tubules is the major mechanism through which both contain two full or partial NH2-terminal phosphotyrosine insulin and exercise increase glucose transport in muscle binding domains, a splice exon, and a putative calmodulin- (1,2). Although it is well established that insulin works binding domain. The COOH-terminal Rab-GAP domains of TBC1D1 and AS160 are 79% identical and exhibit similar From the 1Research Division, Joslin Diabetes Center, Boston, Massachusetts; Rab specificities in vitro (6). Both proteins are detected at and the 2Department of Medicine, Brigham and Women’s Hospital and a molecular weight of ϳ150–160 kDa upon SDS-PAGE, Harvard Medical School, Boston, Massachusetts. and both can be detected using the PAS antibody. Al- Corresponding author: Laurie J. Goodyear, [email protected]. Received 26 August 2009 and accepted 2 March 2010. Published ahead of print though there are several similarities between TBC1D1 and at http://diabetes.diabetesjournals.org on 18 March 2010. DOI: 10.2337/ AS160, there are also clear differences in tissue distribu- db09-1266. tion and protein phosphorylation. For example, whereas © 2010 by the American Diabetes Association. Readers may use this article as AS160 is expressed in multiple tissues at similar levels, long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by TBC1D1 is several-fold higher in skeletal muscle com- -nc-nd/3.0/ for details. pared with other tissues (12). Another key difference The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance between TBC1D1 and AS160 relates to the phosphoryla- with 18 U.S.C. Section 1734 solely to indicate this fact. tion status of the proteins. Insulin increases the phosphor- 1358 DIABETES, VOL. 59, JUNE 2010 diabetes.diabetesjournals.org D. AN AND ASSOCIATES ylation of five of six Akt substrate motifs in AS160, TBC1D1 mutated to Lys at Arg941 within its Rab-GAP domain to eliminate whereas only one of these insulin-stimulated sites is TBC1D1 GAP activity (R/K); 4) TBC1D1 double mutant containing both the 4P conserved in TBC1D1 (6,12,13). and R/K mutations; and 5) TBC1D1 double mutant containing both the R125W and R/K mutations. TBC1D1 cDNA constructs were sequenced to confirm A recent report has shown that a mouse genetic model accuracy, using the high-throughput DNA sequencing service at Brigham and resulting in a truncation mutation of TBC1D1 that includes Women’s Hospital. Plasmid DNA was amplified in E. coli Top10 cells the Rab-GAP domain of the protein, as well as knockdown (Invitrogen), extracted using an endotoxin-free Plasmid Mega Kit (Qiagen), of TBC1D1 in C2C12 muscle cells, lead to increased fatty and suspended in saline at 4 ␮g/␮l. TBC1D1 plasmids (100 ␮g) were injected acid oxidation (17). Other studies have identified a genetic into mouse tibialis anterior muscles using our protocol (22), modified to that variation in TBC1D1 that confers risk for severe obesity in originally described by Aihara and Miyazaki (23), and mice were studied 7 Caucasian U.S. and French pedigrees (18,19). This R125W days later. Contraction, glucose, and insulin treatment in the study of PAS missense variant occurs in a phosphotyrosine-binding phosphorylation. Mice were anesthetized with intraperitoneal administra- domain of TBC1D1, but how this mutation leads to meta- tion of pentobarbital sodium (90 mg/kg of body wt). Peroneal nerves from bolic dysfunction and obesity is not known. both legs were surgically exposed for electrode placement. One leg was left Using mass spectrometry, we have identified novel unstimulated (basal/sham control) and the other leg was subjected to electri- phosphorylation sites on TBC1D1 (12), and we and other cal stimulation using a Grass S88 pulse generator for 15 min of contractions laboratories have shown that one or more of these sites (train rate 1/s; train duration 500 ms; pulse rate 100 Hz; duration 0.1 ms at 2–7 can be regulated by insulin, contraction, and/or AICAR in V), as we have previously described (5). To study insulin-activated PAS skeletal muscle (12,14,20,21). The function of these phos- signaling, we injected mice with either a bolus of glucose that resulted in a physiological increase in plasma insulin concentrations (8) or an insulin bolus. phorylation sites is not known. However, given that these For the glucose treatment, mice were anesthetized and administered a 20% stimuli are potent regulators of glucose transport, that glucose bolus (1.0 g of glucose/kg of body wt). For the insulin treatment, mice TBC1D1 is highly expressed in skeletal muscle, and that were anesthetized and injected with insulin (10 mU/g). Immediately after R125W mutation of TBC1D1 is associated with obesity, we contraction, 15 min after glucose administration, or 6 min after insulin hypothesized TBC1D1 regulates glucose transport in skel- stimulation, tibialis anterior muscles were dissected and frozen in liquid etal muscle. We found distinct mutations of TBC1D1 nitrogen. differentially decrease insulin- and contraction-stimulated Protein extraction, immunoprecipitation, and immunoblotting. Frozen muscle tissue was homogenized with a Polytron (Brinkman Instruments) in glucose transport in skeletal muscle, and this occurs in a lysis buffer, as described previously (12). Homogenates were centrifuged at Rab-GAP domain–dependent manner. Our findings dem- 14,000g for 10 min and supernatants were collected. Protein concentrations onstrate that TBC1D1 functions as a Rab-GAP protein, were determined by the Bradford assay.
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