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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. Souza^1,*, Marcelo A. Christoffolete^1,, Miriam O. Ribeiro, Hideaki Miyoshi^*,**, Katherine J. Strissel^*, Zlatina S. Stancheva^*, Nicole H. Rogers^*, Tara M. D'Eon^*,, James W. Perfield, II^*, Hitomi Imachi^*,, Martin S. Obin^*, Antonio C. Bianco^2, and Andrew S. Greenberg^2,*

^* Jean Mayer United States Department of Agriculture-Human Nutrition Research Center on Aging at Tufts University, Boston, MA
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
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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