Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions

Autor(es):Mostrar menos -

Przygodda, Franciele ^[1] ; Lautherbach, Natalia ^[2] ; Buzelle, Samyra Lopes ^[2] ; Goncalves, Dawit Albieiro ^{[1, 2]} ; Assis, Ana Paula ^[2] ; Paula-Gomes, Silvia ^[2] ; Rissato Garofalo, Maria Antonieta ^[1] ; Heck, Lilian Carmo ^[1] ; Matsuo, Flavia Sayuri ^[3] ; Mota, Ryerson Fonseca ^[3] ; Osako, Mariana Kiomy ^[3] ; Kettelhut, Isis C. ^[2] ; Navegantes, Luiz C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell & Mol Biol & Pathogen Bioagents, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Applied Physiology; v. 128, n. 4, p. 855-871, APR 2020.
• Citações Web of Science: 0

Resumo

The sympathetic nervous system (SNS) activates cAMP signaling and promotes trophic effects on brown adipose tissue (BAT) through poorly understood mechanisms. Because norepinephrine has been found to induce antiproteolytic effects on muscle and heart, we hypothesized that the SNS could inhibit autophagy in interscapular BAT (IBAT). Here, we describe that selective sympathetic denervation of rat IBAT kept at 25 degrees C induced atrophy, and in parallel dephosphorylated forkhead box class O (FoxO), and increased cathepsin activity, autophagic flux, autophagosome formation, and expression of autophagy-related genes. Conversely, cold stimulus (4 degrees C) for up to 72 h induced thermogenesis and IBAT hypertrophy, an anabolic effect that was associated with inhibition of cathepsin activity, autophagic flux, and autophagosome formation. These effects were abrogated by sympathetic denervation, which also upregulated Gabarapl1 mRNA. In addition, the cold-driven sympathetic activation stimulated the mechanistic target of rapamycin (mTOR) pathway, leading to the enhancement of protein synthesis. evaluated in vivo by puromycin incorporation, and to the inhibitory phosphorylation of Unc51-like kinase-1, a key protein in the initiation of autophagy. This coincided with a higher content of exchange protein-1 directly activated by cAMP (Epac1), a cAMP effector, and phosphorylation of Akt at Thr(3)(08), all these effects being abolished by denervation. Systemic treatment with norepinephrine for 72 h mimicked most of the cold effects on IBAT. These data suggest that the noradrenergic sympathetic inputs to IBAT restrain basal autophagy via suppression of FoxO and, in the setting of cold, stimulate protein synthesis via the Epac/Akt/mTOR-dependent pathway and suppress the autophagosome formation, probably through posttranscriptional mechanisms. NEW \& NOTEWORTHY The underlying mechanisms related to the anabolic role of sympathetic innervation on brown adipose tissue (BAT) are unclear. We show that sympathetic denervation activates autophagic-lysosomal degradation, leading to a loss of mitochondrial proteins and BAT atrophy. Conversely, cold-driven sympathetic activation suppresses autophagy and stimulates protein synthesis, leading to BAT hypertrophy. Given its high-potential capacity for heat production, understanding the mechanisms that contribute to BAT mass is important to optimize chances of survival for endotherms in cold ambients. (AU)

• Processo FAPESP: 12/24524-6 - Controle da massa muscular pela via de sinalização do AMPc
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/10089-2 - Controle neural, hormonal e nutricional da autofagia
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Temático
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• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
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• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/17111-0 - Papel do sistema nervoso simpático no controle do metabolismo de proteínas no tecido adiposo marrom
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• Modalidade de apoio: Bolsas no Brasil - Doutorado
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• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado