Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes
Copyright © 2016 Elsevier B.V. All rights reserved..
New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT. Treatment of brown adipocytes with rapamycin for 16h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Consequently, both insulin-induced glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake were decreased. Early activation of the N-terminal Janus activated kinase (JNK) was also observed, thereby increasing IRS1 Ser 307 phosphorylation. These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Akt phosphorylation in BAT. Rapamycin also inhibited norepinephrine (NE)-induced lipolysis, the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein (UCP)-1 in brown adipocytes. Importantly, basal mitochondrial respiration, proton leak and maximal respiratory capacity were significantly decreased in brown adipocytes treated with rapamycin. In conclusion, we demonstrate, for the first time the important role of brown adipocytes as target cells of rapamycin, suggesting that insulin resistance in BAT might play a major role in NODAT development.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1861 |
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| Enthalten in: |
Biochimica et biophysica acta - 1861(2016), 12 Pt A vom: 29. Dez., Seite 1929-1941 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
García-Casarrubios, Ester [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.10.2017 Date Revised 19.10.2017 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbalip.2016.09.016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes |
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| 500 | |a Date Revised 19.10.2017 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2016 Elsevier B.V. All rights reserved. | ||
| 520 | |a New onset diabetes after transplantation (NODAT) is a metabolic disorder that affects 40% of patients on immunosuppressive agent (IA) treatment, such as rapamycin (also known as sirolimus). IAs negatively modulate insulin action in peripheral tissues including skeletal muscle, liver and white fat. However, the effects of IAs on insulin sensitivity and thermogenesis in brown adipose tissue (BAT) have not been investigated. We have analyzed the impact of rapamycin on insulin signaling, thermogenic gene-expression and mitochondrial respiration in BAT. Treatment of brown adipocytes with rapamycin for 16h significantly decreased insulin receptor substrate 1 (IRS1) protein expression and insulin-mediated protein kinase B (Akt) phosphorylation. Consequently, both insulin-induced glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake were decreased. Early activation of the N-terminal Janus activated kinase (JNK) was also observed, thereby increasing IRS1 Ser 307 phosphorylation. These effects of rapamycin on insulin signaling in brown adipocytes were partly prevented by a JNK inhibitor. In vivo treatment of rats with rapamycin for three weeks abolished insulin-mediated Akt phosphorylation in BAT. Rapamycin also inhibited norepinephrine (NE)-induced lipolysis, the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and uncoupling protein (UCP)-1 in brown adipocytes. Importantly, basal mitochondrial respiration, proton leak and maximal respiratory capacity were significantly decreased in brown adipocytes treated with rapamycin. In conclusion, we demonstrate, for the first time the important role of brown adipocytes as target cells of rapamycin, suggesting that insulin resistance in BAT might play a major role in NODAT development | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bioenergetics | |
| 650 | 4 | |a Brown adipocytes | |
| 650 | 4 | |a Insulin signaling | |
| 650 | 4 | |a NODAT | |
| 650 | 4 | |a Thermogenesis | |
| 650 | 7 | |a Glucose Transporter Type 4 |2 NLM | |
| 650 | 7 | |a Insulin |2 NLM | |
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| 650 | 7 | |a Uncoupling Protein 1 |2 NLM | |
| 650 | 7 | |a Glucose |2 NLM | |
| 650 | 7 | |a IY9XDZ35W2 |2 NLM | |
| 650 | 7 | |a Sirolimus |2 NLM | |
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| 700 | 1 | |a de Moura, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Arroba, Ana I |e verfasserin |4 aut | |
| 700 | 1 | |a Pescador, Nuria |e verfasserin |4 aut | |
| 700 | 1 | |a Calderon-Dominguez, María |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Herrero, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Serra, Dolors |e verfasserin |4 aut | |
| 700 | 1 | |a Cadenas, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Reis, Flavio |e verfasserin |4 aut | |
| 700 | 1 | |a Carvalho, Eugenia |e verfasserin |4 aut | |
| 700 | 1 | |a Obregon, Maria Jesus |e verfasserin |4 aut | |
| 700 | 1 | |a Valverde, Ángela M |e verfasserin |4 aut | |
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