J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M700047-JLR200 on March 30, 2007

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Journal of Lipid Research, Vol. 48, 1273-1279, June 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue

Sandra C. Souza1,*, Marcelo A. Christoffolete1,{dagger}, Miriam O. Ribeiro§, Hideaki Miyoshi*,**, Katherine J. Strissel*, Zlatina S. Stancheva*, Nicole H. Rogers*, Tara M. D'Eon*,{dagger}{dagger}, James W. Perfield, II*, Hitomi Imachi*,§§, Martin S. Obin*, Antonio C. Bianco2,{dagger} and Andrew S. Greenberg2,*

* Jean Mayer United States Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University, Boston, MA
{dagger} Brigham and Women's Hospital and Harvard Medical School, Boston, MA
§ Biological and Health Science Center, Mackenzie Presbyterian University, São Paulo, Brazil
** Hokkaido University Graduate School of Medicine, Sapporo, Japan
{dagger}{dagger} Elixir Pharmaceuticals, Cambridge, MA
§§ Kagawa Medical University, Kagawa, Japan

Published, JLR Papers in Press, March 30, 2007.

1 S. C. Souza and M. A. Christoffolete contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: abianco{at}partners.org (A.C.B.); andrew.greenberg{at}tufts.edu (A.S.G.)

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 (~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 (~3.0°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.

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


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Copyright © 2007 by the American Society for Biochemistry and Molecular Biology.