Rab GAPs AS160 and Tbc1d1 play nonredundant roles in the regulation of glucose and energy homeostasis in mice

The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160−/−/Tbc1d1−/− mice). Herein, we describe abnormalities in male and female AS160−/−/Tbc1d1−/− mice on another strain background. We confirm the earlier observation that GLUT4 expression and glucose uptake defects of single-knockout mice join in AS160−/−/Tbc1d1−/− mice to affect all skeletal muscle and adipose tissues. In large mixed fiber-type skeletal muscles, changes in relative basal GLUT4 plasma membrane association in AS160−/− and Tbc1d1−/− mice also combine in AS160−/−/Tbc1d1−/− mice. However, we found different glucose uptake abnormalities in isolated skeletal muscles and adipocytes than reported previously, resulting in different interpretations of how AS160 and Tbc1d1 regulate GLUT4 translocation to the cell surface. In support of a larger role for AS160 in glucose homeostasis, in contrast with the previous study, we find similarly impaired glucose and insulin tolerance in AS160−/−/Tbc1d1−/− and AS160−/− mice. However, in vivo glucose uptake abnormalities in AS160−/−/Tbc1d1−/− skeletal muscles differ from those observed previously in AS160−/− mice, indicating additional defects due to Tbc1d1 deletion. Similar to AS160- and Tbc1d1-deficient mice, AS160−/−/Tbc1d1−/− mice show sex-specific abnormalities in glucose and energy homeostasis. In conclusion, our study supports nonredundant functions for AS160 and Tbc1d1.

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Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00007.2015 ◽

2015 ◽

Vol 309 (3) ◽

pp. E233-E245 ◽

Cited By ~ 16

Author(s):

Stefan R. Hargett ◽

Natalie N. Walker ◽

Syed S. Hussain ◽

Kyle L. Hoehn ◽

Susanna R. Keller

Keyword(s):

Skeletal Muscle ◽

Cell Surface ◽

Glucose Uptake ◽

Skeletal Muscles ◽

Energy Homeostasis ◽

Glucose Transporter ◽

Whole Body ◽

Acid Oxidation ◽

Dependent Manner ◽

Male And Female

Tbc1d1 is a Rab GTPase-activating protein (GAP) implicated in regulating intracellular retention and cell surface localization of the glucose transporter GLUT4 and thus glucose uptake in a phosphorylation-dependent manner. Tbc1d1 is most abundant in skeletal muscle but is expressed at varying levels among different skeletal muscles. Previous studies with male Tbc1d1-deficient (Tbc1d1−/−) mice on standard and high-fat diets established a role for Tbc1d1 in glucose, lipid, and energy homeostasis. Here we describe similar, but also additional abnormalities in male and female Tbc1d1−/− mice. We corroborate that Tbc1d1 loss leads to skeletal muscle-specific and skeletal muscle type-dependent abnormalities in GLUT4 expression and glucose uptake in female and male mice. Using subcellular fractionation, we show that Tbc1d1 controls basal intracellular GLUT4 retention in large skeletal muscles. However, cell surface labeling of extensor digitorum longus muscle indicates that Tbc1d1 does not regulate basal GLUT4 cell surface exposure as previously suggested. Consistent with earlier observations, female and male Tbc1d1−/− mice demonstrate increased energy expenditure and skeletal muscle fatty acid oxidation. Interestingly, we observe sex-dependent differences in in vivo phenotypes. Female, but not male, Tbc1d1−/− mice have decreased body weight and impaired glucose and insulin tolerance, but only male Tbc1d1−/− mice show increased lipid clearance after oil gavage. We surmise that similar changes at the tissue level cause differences in whole-body metabolism between male and female Tbc1d1−/− mice and between male Tbc1d1−/− mice in different studies due to variations in body composition and nutrient handling.

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Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00189.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. E124-E133 ◽

Cited By ~ 85

Author(s):

Rodrigo P. A. Barros ◽

Chiara Gabbi ◽

Andrea Morani ◽

Margaret Warner ◽

Jan-Åke Gustafsson

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

White Adipose Tissue ◽

Glucose Transporter ◽

Wild Type ◽

Glut4 Expression ◽

Glucose Challenge ◽

Fasting Hypoglycemia

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.

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Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00297.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. C377-C385 ◽

Cited By ~ 67

Author(s):

Jonas T. Treebak ◽

Eric B. Taylor ◽

Carol A. Witczak ◽

Ding An ◽

Taro Toyoda ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Uptake ◽

Glucose Transporter ◽

Vastus Lateralis ◽

Phosphorylation Site ◽

Rab Gtpase ◽

Vastus Lateralis Muscle ◽

Phosphorylation Sites ◽

Amp Activated Protein Kinase

TBC1D4 (also known as AS160) regulates glucose transporter 4 (GLUT4) translocation and glucose uptake in adipocytes and skeletal muscle. Its mode of action involves phosphorylation of serine (S)/threonine (T) residues by upstream kinases resulting in inactivation of Rab-GTPase-activating protein (Rab-GAP) activity leading to GLUT4 mobilization. The majority of known phosphorylation sites on TBC1D4 lie within the Akt consensus motif and are phosphorylated by insulin stimulation. However, the 5′-AMP-activated protein kinase (AMPK) and other kinases may also phosphorylate TBC1D4, and therefore we hypothesized the presence of additional phosphorylation sites. Mouse skeletal muscles were contracted or stimulated with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), and muscle lysates were subjected to mass spectrometry analyses resulting in identification of novel putative phosphorylation sites on TBC1D4. The surrounding amino acid sequence predicted that S711 would be recognized by AMPK. Using a phosphospecific antibody against S711, we found that AICAR and contraction increased S711 phosphorylation in mouse skeletal muscle, and this increase was abolished in muscle-specific AMPKα2 kinase-dead transgenic mice. Exercise in human vastus lateralis muscle also increased TBC1D4 S711 phosphorylation. Recombinant AMPK, but not Akt1, Akt2, or PKCζ, phosphorylated purified muscle TBC1D4 on S711 in vitro. Interestingly, S711 was also phosphorylated in response to insulin in an Akt2- and rapamycin-independent, but a wortmannin-sensitive, manner, suggesting this site is regulated by one or more additional upstream kinases. Despite increased S711 phosphorylation with AICAR, contraction, and insulin, mutation of S711 to alanine did not alter glucose uptake in response to these stimuli. S711 is a novel TBC1D4 phosphorylation site regulated by AMPK in skeletal muscle.

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MicroRNAs-Mediated Regulation of Skeletal Muscle GLUT4 Expression and Translocation in Insulin Resistance

Journal of Diabetes Research ◽

10.1155/2017/7267910 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 35

Author(s):

João Victor Esteves ◽

Francisco Javier Enguita ◽

Ubiratan Fabres Machado

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glycemic Control ◽

Glucose Uptake ◽

Glucose Transporter ◽

Regulation Of Gene Expression ◽

Glut4 Translocation ◽

Therapeutic Approaches ◽

Glut4 Expression ◽

Solute Carrier

The solute carrier family 2 facilitated glucose transporter member 4 (GLUT4) plays a key role in the insulin-induced glucose uptake by muscle and adipose tissues. In prediabetes and diabetes, GLUT4 expression/translocation has been detected as reduced, participating in mechanisms that impair glycemic control. Recently, a class of short endogenous noncoding RNAs named microRNAs (miRNAs) has been increasingly described as involved in the posttranscriptional epigenetic regulation of gene expression. The present review focuses on miRNAs potentially involved in the expression of GLUT4 expression, and proteins related to GLUT4 and translocation in skeletal muscle, seeking to correlate them with insulin resistance and diabetes. So far, miR-21a-5p, miR-29a-3p, miR-29c-3p, miR-93-5p, miR-106b-5p, miR-133a-3p, miR-133b-3p, miR-222-3p, and miR-223-3p have been reported to directly and/or indirectly regulate the GLUT4 expression; and their expression is altered under diabetes-related conditions. Besides, some miRNAs that have been linked to the expression of proteins involved in GLUT4 translocation machinery in muscle could also impact glucose uptake. That makes these miRNAs promising targets for preventive and/or therapeutic approaches, which could improve glycemic control, thus deserving future new investigations.

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AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00460.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. E931-E939 ◽

Cited By ~ 6

Author(s):

Jin-Ho Koh ◽

Chad R. Hancock ◽

Dong-Ho Han ◽

John O. Holloszy ◽

K. Sreekumaran Nair ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Glucose Uptake ◽

Glucose Transporter ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Glut4 Expression ◽

Amp Activated Protein Kinase ◽

Response To Exercise ◽

Glucose Transporter Type 4

The objective of this study is to determine whether AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), or peroxisome proliferator-activated receptor β (PPARβ) can independently mediate the increase of glucose transporter type 4 (GLUT4) expression that occurs in response to exercise training. We found that PPARβ can regulate GLUT4 expression without PGC-1α. We also found AMPK and PPARβ are important for maintaining normal physiological levels of GLUT4 protein in the sedentary condition as well following exercise training. However, AMPK and PPARβ are not essential for the increase in GLUT4 protein expression that occurs in response to exercise training. We discovered that AMPK activation increases PPARβ via myocyte enhancer factor 2A (MEF2A), which acted as a transcription factor for PPARβ. Furthermore, exercise training increases the cooperation of AMPK and PPARβ to regulate glucose uptake. In conclusion, cooperation between AMPK and PPARβ via NRF-1/MEF2A pathway enhances the exercise training mediated adaptive increase in GLUT4 expression and subsequent glucose uptake in skeletal muscle.

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Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00466.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. E223-E230 ◽

Cited By ~ 13

Author(s):

Carlos M. Castorena ◽

Edward B. Arias ◽

Naveen Sharma ◽

Jonathan S. Bogan ◽

Gregory D. Cartee

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Transporter ◽

Fiber Type ◽

Fiber Types ◽

Rat Skeletal Muscle ◽

Single Fibers ◽

Mhc Iia ◽

Mhc Iib ◽

Filamin C

To fully understand skeletal muscle at the cellular level, it is essential to evaluate single muscle fibers. Accordingly, the major goals of this study were to determine if there are fiber type-related differences in single fibers from rat skeletal muscle for: 1) contraction-stimulated glucose uptake and/or 2) the abundance of GLUT4 and other metabolically relevant proteins. Paired epitrochlearis muscles isolated from Wistar rats were either electrically stimulated to contract (E-Stim) or remained resting (No E-Stim). Single fibers isolated from muscles incubated with 2-deoxy-d-[3H]glucose (2-DG) were used to determine fiber type [myosin heavy chain (MHC) isoform protein expression], 2-DG uptake, and abundance of metabolically relevant proteins, including the GLUT4 glucose transporter. E-Stim, relative to No E-Stim, fibers had greater ( P < 0.05) 2-DG uptake for each of the isolated fiber types (MHC-IIa, MHC-IIax, MHC-IIx, MHC-IIxb, and MHC-IIb). However, 2-DG uptake for E-Stim fibers was not significantly different among these five fiber types. GLUT4, tethering protein containing a UBX domain for GLUT4 (TUG), cytochrome c oxidase IV (COX IV), and filamin C protein levels were significantly greater ( P < 0.05) in MHC-IIa vs. MHC-IIx, MHC-IIxb, or MHC-IIb fibers. TUG and COX IV in either MHC-IIax or MHC-IIx fibers exceeded values for MHC-IIxb or MHC-IIb fibers. GLUT4 levels for MHC-IIax fibers exceeded MHC-IIxb fibers. GLUT4, COX IV, filamin C, and TUG abundance in single fibers was significantly ( P < 0.05) correlated with each other. Differences in GLUT4 abundance among the fiber types were not accompanied by significant differences in contraction-stimulated glucose uptake.

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Exercise, GLUT4, and Skeletal Muscle Glucose Uptake

Physiological Reviews ◽

10.1152/physrev.00038.2012 ◽

2013 ◽

Vol 93 (3) ◽

pp. 993-1017 ◽

Cited By ~ 485

Author(s):

Erik A. Richter ◽

Mark Hargreaves

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Glucose Uptake ◽

Nuclear Export ◽

Glucose Transporter ◽

Glucose Disposal ◽

Facilitated Diffusion ◽

Molecular Signaling ◽

Glut4 Translocation ◽

Glut4 Expression

Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca2+, and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.

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Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00316.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. E1273-E1286 ◽

Cited By ~ 64

Author(s):

Melissa N. Lansey ◽

Natalie N. Walker ◽

Stefan R. Hargett ◽

Joseph R. Stevens ◽

Susanna R. Keller

Keyword(s):

Cell Surface ◽

Glucose Uptake ◽

Glucose Homeostasis ◽

Skeletal Muscles ◽

Plasma Membranes ◽

Glucose Transporter ◽

Cultured Cells ◽

In Vivo Studies ◽

Glucose Disposal ◽

Normal Male

Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160−/−) mice. We observed increased and normal basal glucose uptake in isolated AS160−/− adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160−/− extensor digitorum longus muscles. In plasma membranes isolated from AS160−/− adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160−/− adipocytes and normal in AS160−/− soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160−/− skeletal muscles and liver but not in AS160−/− adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis.

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Glucose-transporter (GLUT4) protein content in oxidative and glycolytic skeletal muscles from calf and goat

Biochemical Journal ◽

10.1042/bj3050465 ◽

1995 ◽

Vol 305 (2) ◽

pp. 465-470 ◽

Cited By ~ 37

Author(s):

J F Hocquette ◽

F Bornes ◽

M Balage ◽

P Ferre ◽

J Grizard ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Transport ◽

Skeletal Muscles ◽

Glucose Transporter ◽

Transporter Protein ◽

Rat Muscle ◽

Glucose Transporter Glut4

It is well accepted that skeletal muscle is a major glucose-utilizing tissue and that insulin is able to stimulate in vivo glucose utilization in ruminants as in monogastrics. In order to determine precisely how glucose uptake is controlled in various ruminant muscles, particularly by insulin, this study was designed to investigate in vitro glucose transport and insulin-regulatable glucose-transporter protein (GLUT4) in muscle from calf and goat. Our data demonstrate that glucose transport is the rate-limiting step for glucose uptake in bovine fibre strips, as in rat muscle. Insulin increases the rate of in vitro glucose transport in bovine muscle, but to a lower extent than in rat muscle. A GLUT4-like protein was detected by immunoblot assay in all insulin-responsive tissues from calf and goat (heart, skeletal muscle, adipose tissue) but not in liver, brain, erythrocytes and intestine. Unlike the rat, bovine and goat GLUT4 content is higher in glycolytic and oxido-glycolytic muscles than in oxidative muscles. In conclusion, using both a functional test (insulin stimulation of glucose transport) and an immunological approach, this study demonstrates that ruminant muscles express GLUT4 protein. Our data also suggest that, in ruminants, glucose is the main energy-yielding substrate for glycolytic but not for oxidative muscles, and that insulin responsiveness may be lower in oxidative than in other skeletal muscles.

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Compound- and fiber type-selective requirement of AMPKγ3 for insulin-independent glucose uptake in skeletal muscle

10.1101/2021.03.05.433354 ◽

2021 ◽

Author(s):

Philipp Rhein ◽

Eric M Desjardins ◽

Ping Rong ◽

Danial Ahwazi ◽

Nicolas Bonhoure ◽

...

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Oxygen Consumption ◽

Blood Glucose ◽

Glucose Uptake ◽

Glucose Homeostasis ◽

Ex Vivo ◽

Fiber Type ◽

Whole Body ◽

Glucose Clearance

Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and also potentially in BAT. Here, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed if γ3 plays a role in adipose thermogenesis and browning. Methods: Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo, as well as blood glucose clearance in response to small molecule AMPK activators that target nucleotide-binding domain of γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics and function. Results: Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and integrity, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose lowering in vivo and glucose uptake specifically in glycolytic muscles ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice. Conclusions: These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for thermogenesis and browning of iWAT.

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