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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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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. |
format | Online Article Text |
id | pubmed-7949114 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
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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