PMID- 32027543 OWN - NLM STAT- MEDLINE DCOM- 20210623 LR - 20210623 IS - 1522-1601 (Electronic) IS - 0161-7567 (Linking) VI - 128 IP - 4 DP - 2020 Apr 1 TI - Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions. PG - 855-871 LID - 10.1152/japplphysiol.00065.2019 [doi] AB - 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(308), 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. FAU - Przygodda, Franciele AU - Przygodda F AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Lautherbach, Natalia AU - Lautherbach N AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Buzelle, Samyra Lopes AU - Buzelle SL AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Goncalves, Dawit Albieiro AU - Goncalves DA AUID- ORCID: 0000-0003-2621-3330 AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Assis, Ana Paula AU - Assis AP AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Paula-Gomes, Silvia AU - Paula-Gomes S AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Garofalo, Maria Antonieta Rissato AU - Garofalo MAR AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Heck, Lilian Carmo AU - Heck LC AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Matsuo, Flavia Sayuri AU - Matsuo FS AD - Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Mota, Ryerson Fonseca AU - Mota RF AD - Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Osako, Mariana Kiomy AU - Osako MK AD - Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Kettelhut, Isis C AU - Kettelhut IC AD - Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. FAU - Navegantes, Luiz C AU - Navegantes LC AUID- ORCID: 0000-0002-9870-9469 AD - Department of Physiology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200206 PL - United States TA - J Appl Physiol (1985) JT - Journal of applied physiology (Bethesda, Md. : 1985) JID - 8502536 SB - IM MH - *Adipose Tissue, Brown MH - Animals MH - Autophagy MH - Cold Temperature MH - Lysosomes MH - Rats MH - Sympathetic Nervous System MH - *Thermogenesis OTO - NOTNLM OT - autophagy OT - brown adipose tissue OT - protein metabolism OT - sympathetic innervation EDAT- 2020/02/07 06:00 MHDA- 2021/06/24 06:00 CRDT- 2020/02/07 06:00 PHST- 2020/02/07 06:00 [pubmed] PHST- 2021/06/24 06:00 [medline] PHST- 2020/02/07 06:00 [entrez] AID - 10.1152/japplphysiol.00065.2019 [doi] PST - ppublish SO - J Appl Physiol (1985). 2020 Apr 1;128(4):855-871. doi: 10.1152/japplphysiol.00065.2019. Epub 2020 Feb 6.