Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue

In response to cold, norepinephrine {(NE)-induced} triacylglycerol hydrolysis (lipolysis) in adipocytes of brown adipose tissue {(BAT)} provides fatty acid substrates to mitochondria for heat generation (adaptive thermogenesis). {NE-induced} lipolysis is mediated by protein kinase A {(PKA)-dependent} phosphorylation of perilipin, a lipid droplet-associated protein that is the major regulator of lipolysis. We investigated the role of perilipin {PKA} phosphorylation in {BAT} {NE-stimulated} thermogenesis using a novel mouse model in which a mutant form of perilipin, lacking all six {PKA} phosphorylation sites, is expressed in adipocytes of perilipin knockout {(Peri} {KO)} mice. Here, we show that despite a normal mitochondrial respiratory capacity, {NE-induced} lipolysis is abrogated in the interscapular brown adipose tissue {(IBAT)} of these mice. This lipolytic constraint is accompanied by a dramatic blunting ( approximately 70%) of the in vivo thermal response to {NE.} Thus, in the presence of perilipin, {PKA-mediated} perilipin phosphorylation is essential for {NE-dependent} lipolysis and full adaptive thermogenesis in {BAT.} In {IBAT} of Peri {KO} mice, increased basal lipolysis attributable to the absence of perilipin is sufficient to support a rapid {NE-stimulated} temperature increase ( approximately 3.0 degrees C) comparable to that in wild-type mice. This observation suggests that one or more {NE-dependent} mechanism downstream of perilipin phosphorylation is required to initiate and/or sustain the {IBAT} thermal response.