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.
Souza
Sandra C
SC
Jean Mayer United States Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
Christoffolete
Marcelo A
MA
Ribeiro
Miriam O
MO
Miyoshi
Hideaki
H
Strissel
Katherine J
KJ
Stancheva
Zlatina S
ZS
Rogers
Nicole H
NH
D'Eon
Tara M
TM
Perfield
James W
JW
Imachi
Hitomi
H
Obin
Martin S
MS
Bianco
Antonio C
AC
Greenberg
Andrew S
AS
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
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