Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue

Sandra C. Souza¹^,*, Marcelo A. Christoffolete¹^,, 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. Bianco²^, and Andrew S. Greenberg²^,*

^* 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 tothis 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 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

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