2024-03-29T06:37:07Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1509372022-05-25T10:04:04Zcom_10261_22com_10261_1com_10261_79col_10261_275col_10261_332
2017-06-06T08:51:11Z
urn:hdl:10261/150937
Rapamycin negatively impacts insulin signaling, glucose uptake and uncoupling protein-1 in brown adipocytes
García-Casarrubios, Ester
Arroba, Ana I.
Pescador, Nuria
García, Laura
Cadenas, Susana
Carvalho, Eugenia
Obregón, María Jesús
Valverde, Ángela M.
Comunidad de Madrid
Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España)
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)
Instituto de Salud Carlos III
European Commission
Ministerio de Economía y Competitividad (España)
Generalitat de Catalunya
Fundação para a Ciência e a Tecnologia (Portugal)
European Foundation for the Study of Diabetes
Brown adipocytes
NODAT
Bioenergetics
Thermogenesis
Insulin signaling
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 16 h 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.
2017-06-06T08:51:11Z
2017-06-06T08:51:11Z
2016
2017-06-06T08:51:12Z
artículo
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 1861(12A): 1929-1941 (2016)
http://hdl.handle.net/10261/150937
10.1016/j.bbalip.2016.09.016
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100002809
http://dx.doi.org/10.13039/501100001871
http://dx.doi.org/10.13039/501100001648
http://dx.doi.org/10.13039/100012818
eng
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-52223-C2-1-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013-45887-R
S2010/BMD-2423/MOIR
S2010/BMD-2402/MITOLAB
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-65267-R
closedAccess
Elsevier