title: Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue.
abstract: 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.
authors.affiliation: Jean Mayer United States Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Souza
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Christoffolete
authors.forename: Miriam O
authors.initials: MO
authors.lastname: Ribeiro
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Strissel
authors.forename: Zlatina S
authors.initials: ZS
authors.lastname: Stancheva
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Rogers
authors.forename: Tara M
authors.initials: TM
authors.lastname: D'Eon
authors.forename: James W
authors.initials: JW
authors.lastname: Perfield
authors.forename: Hitomi
authors.initials: H
authors.lastname: Imachi
authors.forename: Martin S
authors.initials: MS
authors.lastname: Obin
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression; D007473:Ion Channels / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D022722:Thermogenesis / Q000187:drug effects*; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000070778:Perilipin-1; D010750:Phosphoproteins; D000071256:Uncoupling Protein 1; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine