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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...

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Autores principales: Metz, Matthäus, O'Hare, James, Cheng, Bob, Puchowicz, Michelle, Buettner, Christoph, Scherer, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
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.
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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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