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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: Journal of Applied Physiology; v. 128, n. 4, p. 855-871, APR 2020.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 12/24524-6 - Control of muscle mass by cAMP signaling pathway
• Grantee: Isis Do Carmo Kettelhut
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/10089-2 - Neural, hormonal and nutritional control of autophagy
• Grantee: Isis Do Carmo Kettelhut
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/00508-2 - RANKL system in TLR4 signaling pathway
• Grantee: Ryerson Fonseca Mota
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/26088-7 - Study of RANKL/RANK/OPG signaling pathway in beige adipose tissue differentiation
• Grantee: Flávia Sayuri Matsuo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/11092-6 - RANKL system in phenotypic switch of macrophages in adipose tissue inflammation
• Grantee: Mariana Kiomy Osako
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 13/17111-0 - Role of the sympathetic nervous system in the control of the protein metabolism in brown adipose tissue
• Grantee: Franciele Przygodda
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/18861-0 - FOXO HYPERACETYLATION AS A MECHANISM OF SUPPRESSION OF ATROPHY GENE PROGRAM INDUCED BY BETA2-ADRENERGIC SIGNALING IN RODENT SKELETAL MUSCLE
• Grantee: Dawit Albieiro Pinheiro Gonçalves
• Support Opportunities: Scholarships in Brazil - Post-Doctoral