出版社：American Society for Biochemistry and Molecular Biology
摘要：In response to cold, norepinephrine (NE)-induced triacylglycerolhydrolysis (lipolysis) in adipocytes of brown adipose tissue(BAT) provides fatty acid substrates to mitochondria for heatgeneration (adaptive thermogenesis). NE-induced lipolysis ismediated by protein kinase A (PKA)-dependent phosphorylationof perilipin, a lipid droplet-associated protein that is themajor regulator of lipolysis. We investigated the role of perilipinPKA phosphorylation in BAT NE-stimulated thermogenesis usinga novel mouse model in which a mutant form of perilipin, lackingall six PKA phosphorylation sites, is expressed in adipocytesof perilipin knockout (Peri KO) mice. Here, we show that despitea normal mitochondrial respiratory capacity, NE-induced lipolysisis abrogated in the interscapular brown adipose tissue (IBAT)of these mice. This lipolytic constraint is accompanied by adramatic blunting (70%) of the in vivo thermal response to NE.Thus, in the presence of perilipin, PKA-mediated perilipin phosphorylationis essential for NE-dependent lipolysis and full adaptive thermogenesisin BAT. In IBAT of Peri KO mice, increased basal lipolysis attributableto the absence of perilipin is sufficient to support a rapidNE-stimulated temperature increase (3.0°C) comparable tothat in wild-type mice. This observation suggests that one ormore NE-dependent mechanism downstream of perilipin phosphorylationis required to initiate and/or sustain the IBAT thermal response.Supplementary key words norepinephrine-induced thermal response • protein kinase A-stimulated lipolysis • brown adipocytes
Abbreviations: ATGL, adipose tissue triacylglycerol lipase; BAT, brown adipose tissue; HSL, hormone-sensitive lipase; IBAT, interscapular brown adipose tissue; NE, norepinephrine; Peri A, perilipin isoform A; Peri KO, perilipin knockout; PKA, protein kinase A; TAG, triacylglycerol; UCP1, uncoupling protein-1; WAT, white adipose tissue; WT, wild-type
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 (
