LAUSR

The Sympathetic Nervous System (SNS) activates cAMP signaling and promotes trophic effects on brown adipose tissue through poorly understood mechanisms. Because norepinephrine has been found to induce anti-proteolytic effects on muscle and heart, we hypothesized that SNS could inhibit autophagy in interscapular brown adipose tissue (IBAT). Here we describe that selective sympathetic denervation of rat IBAT kept at 25oC induced atrophy, and in parallel dephosphorylated FoxO, and increased cathepsins activity, autophagic flux, autophagosome formation, and expression of autophagy-related genes. Conversely, cold stimulus (4oC) for up to 72 h induced thermogenesis and IBAT hypertrophy, an anabolic effect that was associated with inhibition of cathepsins 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 (ULK1), a key protein in the initiation of autophagy. This coincided with a higher content of Epac1, a cAMP effector, and phosphorylation of Akt at Thr308, being all these effects abolished by denervation. The 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 Epac/Akt/mTOR-dependent pathway and suppress the autophagosome formation probably through posttranscriptional mechanisms.