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

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°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°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 Thr308, 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.

Urocortin 2 promotes hypertrophy and enhances skeletal muscle function through cAMP and insulin/IGF-1 signaling pathways

“…Recent reports have shown that compounds that act through the cAMP cascade, like catecholamines and β2-agonists, stimulate mTOR signaling in muscles [ 19 , 62 ], hearts [ 63 ] and BAT [ 64 ] from rodents. Consistently, we have shown that the physiological stimulation of sympathetic nervous system in the setting of cold plays a hypertrophic role in BAT by stimulating the cAMP and mTOR signaling [ 65 ]. Our data are in agreement with these previous reports and show that mTOR activity is highly induced by Ucn2 in transfected muscles in parallel to the induction of intracellular cAMP levels.…”

Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats

“…Recently, we demonstrated that sympathetic activation promotes trophic effects on IBAT and suppresses the autophagic‐lysosomal proteolytic process in rats under basal and cold‐stimulated conditions (Przygodda et al, 2020). The cold exposure increases the total and mitochondrial protein content, while IBAT denervation abolishes this effect and increases autophagy (Przygodda et al, 2020). These findings suggest that the sympathetic nervous system is essential for tissue growth and mitochondrial biogenesis, two essential events for non‐shivering thermogenesis.…”

“…We believe that the reduction in mitochondrial protein content induced by DEXA treatment is associated with a reduction in sympathetic activity (Mousovich‐Neto et al, 2019; Przygodda et al, 2020). Recently, we demonstrated that sympathetic activation promotes trophic effects on IBAT and suppresses the autophagic‐lysosomal proteolytic process in rats under basal and cold‐stimulated conditions (Przygodda et al, 2020). The cold exposure increases the total and mitochondrial protein content, while IBAT denervation abolishes this effect and increases autophagy (Przygodda et al, 2020).…”

“…However, the cafeteria diet or the reversion of the high‐protein diet to a normal one induces an increase in insulin levels and sympathetic activity to IBAT (Chaves et al, 2008; Kawashita, Festuccia, et al, 2002), followed by decreased glyceroneogenesis and increased glucose uptake and Gyk activity. The cold exposure induces a decrease in insulin levels but an increase in sympathetic activity to IBAT (Moura et al, 2001; Przygodda et al, 2020). These findings are accompanied by reduced glucose uptake and increased glyceroneogenesis and Gyk activity (Festuccia, Kawashita, et al, 2003; Moura et al, 2001).…”

Non-shivering Thermogenesis Signalling Regulation and Potential Therapeutic Applications of Brown Adipose Tissue

“…Recent studies have found that NP-cGMP signalling can also activate mTORC1 through PKG, thereby inducing adipose browning 63 . Many recent studies have found that certain regulatory factors, including SNS, T3, and Mark4, can affect autophagy by regulating mTOR, ultimately regulating thermogenesis 64 - 66 .…”