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Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake.

Habtemichael EN, Li DT, Camporez JP, Westergaard XO, Sales CI, Liu X, López-Giráldez F, DeVries SG, Li H, Ruiz DM
Nat Metab 2021
Open on PubMed

1. Nat Metab. 2021 Mar;3(3):378-393. doi: 10.1038/s42255-021-00359-x. Epub 2021 Mar 8. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. Habtemichael EN(#)(1)(2), Li DT(#)(1)(3), Camporez JP(1)(4), Westergaard XO(1)(5), Sales CI(1), Liu X(3), López-Giráldez F(6), DeVries SG(1), Li H(1)(7), Ruiz DM(1), Wang KY(1), Sayal BS(1), González Zapata S(1), Dann P(1), Brown SN(1), Hirabara S(1)(8), Vatner DF(1), Goedeke L(1), Philbrick W(1), Shulman GI(1)(9), Bogan JS(10)(11). Author information: (1)Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. (2)Evelo Biosciences, Inc., Cambridge, MA, USA. (3)Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA. (4)University of São Paulo, São Paulo, Brazil. (5)Columbia University, New York, NY, USA. (6)Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA. (7)Zhejiang University of Technology, Hangzhou, China. (8)Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, São Paulo, Brazil. (9)Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. (10)Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. jonathan.bogan@yale.edu. (11)Department of Cell Biology, Yale School of Medicine, New Haven, CT, USA. jonathan.bogan@yale.edu. (#)Contributed equally TUG tethering proteins bind and sequester GLUT4 glucose transporters intracellularly, and insulin stimulates TUG cleavage to translocate GLUT4 to the cell surface and increase glucose uptake. This effect of insulin is independent of phosphatidylinositol 3-kinase, and its physiological relevance remains uncertain. Here we show that this TUG cleavage pathway regulates both insulin-stimulated glucose uptake in muscle and organism-level energy expenditure. Using mice with muscle-specific Tug (Aspscr1)-knockout and muscle-specific constitutive TUG cleavage, we show that, after GLUT4 release, the TUG C-terminal cleavage product enters the nucleus, binds peroxisome proliferator-activated receptor (PPAR)γ and its coactivator PGC-1α and regulates gene expression to promote lipid oxidation and thermogenesis. This pathway acts in muscle and adipose cells to upregulate sarcolipin and uncoupling protein 1 (UCP1), respectively. The PPARγ2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The ATE1 arginyltransferase, which mediates a specific protein degradation pathway and controls thermogenesis, regulates the stability of the TUG product. We conclude that insulin-stimulated TUG cleavage coordinates whole-body energy expenditure with glucose uptake, that this mechanism might contribute to the thermic effect of food and that its attenuation could promote obesity. DOI: 10.1038/s42255-021-00359-x PMCID: PMC7990718 PMID: 33686286 [Indexed for MEDLINE] Conflict of interest statement: Competing interests The authors declare no competing interests.

16 Figures Extracted
Extended Data Fig. 1.
Extended Data Fig. 1. PMC
Characterization of glucose homeostasis in MTKO mice. a,b, Relative TUG abundance was quantified in quadriceps ( a ) and heart ( b ) using densitomet...
Extended Data Fig. 2.
Extended Data Fig. 2. PMC
Characterization of energy expenditure in MTKO mice. a–d, The indicated parameters were measured in 17-week old WT and MTKO mice in metabolic cages. ...
Extended Data Fig. 3.
Extended Data Fig. 3. PMC
MTKO mice are susceptible to obesity and have reduced energy expenditure on a high-fat diet. a, Mice were fed a high-fat diet (HFD) beginning at 15 w...
Extended Data Fig. 4.
Extended Data Fig. 4. PMC
a, Body weights were measured in male MTKO and WT mice housed at 30° C from weaning. All mice were maintained on regular chow. N = 11 WT and 9 MTKO m...
Extended Data Fig. 5.
Extended Data Fig. 5. PMC
Expression of specific genes involved in energy expenditure is reduced in MTKO mice and increased in UBX mice. a–e, RNA was prepared from quadriceps ...
Extended Data Fig. 6.
Extended Data Fig. 6. PMC
The TUG C-terminal product enters the nucleus and binds PPARγ and PGC-1α. a, Nuclear fractions were prepared from quadriceps of WT, UBX, and MTKO mic...
Extended Data Fig. 7.
Extended Data Fig. 7. PMC
TUG controls PGC-1α protein abundance. a, WT and MTKO mice were treated by IP injection of insulin-glucose, or saline control, then sacrificed at the...
Extended Data Fig. 8.
Extended Data Fig. 8. PMC
TUG regulates mitochondrial function and morphology and has no large effect on muscle fiber type. a, WT and MTKO soleus muscles from mice that had be...
Extended Data Fig. 9.
Extended Data Fig. 9. PMC
Sarcolipin abundance is regulated by TUG and is decreased in diet-induced insulin resistance. a, WT and MTKO mice were housed at 30° C from the time ...
Fig. 1.
Fig. 1. PMC
TUG deletion in muscle causes GLUT4 translocation and increased glucose uptake during fasting, without affecting energy expenditure, in mice fed regul...
Fig. 2.
Fig. 2. PMC
On a high-fat diet, muscle TUG knockout mice have increased weight gain and reduced energy expenditure, which is opposite to effects in mice with cons...
Fig. 3.
Fig. 3. PMC
The TUG C-terminal cleavage product acts with PPARγ and PGC-1α to control oxidative metabolism. a, RNA-seq was used to analyze transcriptomes in quad...
Fig. 4.
Fig. 4. PMC
Insulin acts through TUG to enhance production of the thermogenic protein, sarcolipin. a, Mice were treated with IP insulin-glucose, or saline contro...
Fig. 5.
Fig. 5. PMC
Insulin acts through TUG to enhance production of Ucp1 in adipocytes. a, Subcellular fractions from basal and insulin-treated 3T3-L1 adipocytes were ...
Fig. 6.
Fig. 6. PMC
The TUG C-terminal cleavage product stabilizes PGC-1α and is degraded by an Ate1-dependent mechanism. a, A diagram is shown to indicate how the TUG C...
Fig. 7.
Fig. 7. PMC
A model for the coordinated regulation of glucose uptake and energy expenditure. Insulin acts through a phosphaditylinositol-3-kinase -independent pat...
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