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ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes

Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling m...

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Autores principales: Beg, Muheeb, Zhang, Wei, McCourt, Andrew C., Enerbäck, Sven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949114/
https://www.ncbi.nlm.nih.gov/pubmed/33508319
http://dx.doi.org/10.1016/j.jbc.2021.100332
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author Beg, Muheeb
Zhang, Wei
McCourt, Andrew C.
Enerbäck, Sven
author_facet Beg, Muheeb
Zhang, Wei
McCourt, Andrew C.
Enerbäck, Sven
author_sort Beg, Muheeb
collection PubMed
description Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.
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spelling pubmed-79491142021-03-19 ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes Beg, Muheeb Zhang, Wei McCourt, Andrew C. Enerbäck, Sven J Biol Chem Research Article Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake. American Society for Biochemistry and Molecular Biology 2021-01-27 /pmc/articles/PMC7949114/ /pubmed/33508319 http://dx.doi.org/10.1016/j.jbc.2021.100332 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Beg, Muheeb
Zhang, Wei
McCourt, Andrew C.
Enerbäck, Sven
ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
title ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
title_full ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
title_fullStr ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
title_full_unstemmed ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
title_short ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
title_sort atgl activity regulates glut1-mediated glucose uptake and lactate production via txnip stability in adipocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949114/
https://www.ncbi.nlm.nih.gov/pubmed/33508319
http://dx.doi.org/10.1016/j.jbc.2021.100332
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AT mccourtandrewc atglactivityregulatesglut1mediatedglucoseuptakeandlactateproductionviatxnipstabilityinadipocytes
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