Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake.
3T3-L1 Cells
Aminoacyltransferases
/ metabolism
Animals
Energy Metabolism
Glucose
/ metabolism
Insulin
/ metabolism
Intracellular Signaling Peptides and Proteins
/ metabolism
Mice
Mice, Knockout
Oxidation-Reduction
PPAR gamma
/ metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ metabolism
Proteolysis
Thermogenesis
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
31
10
2019
accepted:
05
02
2021
pubmed:
10
3
2021
medline:
24
4
2021
entrez:
9
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33686286
doi: 10.1038/s42255-021-00359-x
pii: 10.1038/s42255-021-00359-x
pmc: PMC7990718
mid: NIHMS1671263
doi:
Substances chimiques
Aspscr1 protein, mouse
0
Insulin
0
Intracellular Signaling Peptides and Proteins
0
PPAR gamma
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Ppargc1a protein, mouse
0
Aminoacyltransferases
EC 2.3.2.-
Ate1 protein, mouse
EC 2.3.2.-
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
378-393Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK092661
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK092661
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114793
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116774
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK045735
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL150234
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM136651
Pays : United States
Organisme : NIDDK NIH HHS
ID : F30 DK115037
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK124272
Pays : United States
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