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Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway
OBJECTIVES: Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin s...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193009/ https://www.ncbi.nlm.nih.gov/pubmed/37100238 http://dx.doi.org/10.1016/j.molmet.2023.101723 |
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author | Metz, Matthäus O'Hare, James Cheng, Bob Puchowicz, Michelle Buettner, Christoph Scherer, Thomas |
author_facet | Metz, Matthäus O'Hare, James Cheng, Bob Puchowicz, Michelle Buettner, Christoph Scherer, Thomas |
author_sort | Metz, Matthäus |
collection | PubMed |
description | OBJECTIVES: Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin signaling in regulating lipolysis and defined the intracellular insulin signaling pathway required for brain insulin to suppress lipolysis. METHODS: We used hyperinsulinemic clamp studies coupled with tracer dilution techniques to assess insulin's ability to suppress lipolysis in two different mouse models with inducible insulin receptor depletion in all tissues (IR(ΔWB)) or restricted to peripheral tissues excluding the brain (IR(ΔPER)). To identify the underlying signaling pathway required for brain insulin to inhibit lipolysis, we continuously infused insulin +/− a PI3K or MAPK inhibitor into the mediobasal hypothalamus of male Sprague Dawley rats and assessed lipolysis during clamps. RESULTS: Genetic insulin receptor deletion induced marked hyperglycemia and insulin resistance in both IR(ΔPER) and IR(ΔWB) mice. However, the ability of insulin to suppress lipolysis was largely preserved in IR(ΔPER), but completely obliterated in IR(ΔWB) mice indicating that insulin is still able to suppress lipolysis as long as brain insulin receptors are present. Blocking the MAPK, but not the PI3K pathway impaired the inhibition of lipolysis by brain insulin signaling. CONCLUSION: Brain insulin is required for insulin to suppress adipose tissue lipolysis and depends on intact hypothalamic MAPK signaling. |
format | Online Article Text |
id | pubmed-10193009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-101930092023-05-19 Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway Metz, Matthäus O'Hare, James Cheng, Bob Puchowicz, Michelle Buettner, Christoph Scherer, Thomas Mol Metab Original Article OBJECTIVES: Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin signaling in regulating lipolysis and defined the intracellular insulin signaling pathway required for brain insulin to suppress lipolysis. METHODS: We used hyperinsulinemic clamp studies coupled with tracer dilution techniques to assess insulin's ability to suppress lipolysis in two different mouse models with inducible insulin receptor depletion in all tissues (IR(ΔWB)) or restricted to peripheral tissues excluding the brain (IR(ΔPER)). To identify the underlying signaling pathway required for brain insulin to inhibit lipolysis, we continuously infused insulin +/− a PI3K or MAPK inhibitor into the mediobasal hypothalamus of male Sprague Dawley rats and assessed lipolysis during clamps. RESULTS: Genetic insulin receptor deletion induced marked hyperglycemia and insulin resistance in both IR(ΔPER) and IR(ΔWB) mice. However, the ability of insulin to suppress lipolysis was largely preserved in IR(ΔPER), but completely obliterated in IR(ΔWB) mice indicating that insulin is still able to suppress lipolysis as long as brain insulin receptors are present. Blocking the MAPK, but not the PI3K pathway impaired the inhibition of lipolysis by brain insulin signaling. CONCLUSION: Brain insulin is required for insulin to suppress adipose tissue lipolysis and depends on intact hypothalamic MAPK signaling. Elsevier 2023-04-24 /pmc/articles/PMC10193009/ /pubmed/37100238 http://dx.doi.org/10.1016/j.molmet.2023.101723 Text en © 2023 The Author(s) 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 | Original Article Metz, Matthäus O'Hare, James Cheng, Bob Puchowicz, Michelle Buettner, Christoph Scherer, Thomas Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway |
title | Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway |
title_full | Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway |
title_fullStr | Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway |
title_full_unstemmed | Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway |
title_short | Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway |
title_sort | brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the mapk pathway |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193009/ https://www.ncbi.nlm.nih.gov/pubmed/37100238 http://dx.doi.org/10.1016/j.molmet.2023.101723 |
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