Copper regulates cyclic-AMP-dependent lipolysis.
Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as sodium, potassium, calcium and zinc, but their redox-active transition metal counterparts such as copper and iron have been studied primarily as static enzyme cofactors. Here we report that copper is an endogenous regulator of lipolysis, the breakdown of fat, which is an essential process in maintaining body weight and energy stores. Using a mouse model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we found that copper regulates lipolysis at the level of the second messenger, cyclic AMP (cAMP), by altering the activity of the cAMP-degrading phosphodiesterase PDE3B. Biochemical studies of the copper-PDE3B interaction establish copper-dependent inhibition of enzyme activity and identify a key conserved cysteine residue in a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype.
Department of Chemistry, University of California, Berkeley, California, USA.|Howard Hughes Medical Institute, University of California, Berkeley, California, USA.
Lakshmi
L
Krishnamoorthy
Department of Chemistry, University of California, Berkeley, California, USA.
Joseph A
JA
Cotruvo
Department of Chemistry, University of California, Berkeley, California, USA.
Jefferson
J
Chan
Department of Chemistry, University of California, Berkeley, California, USA.
Harini
H
Kaluarachchi
Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Abigael
A
Muchenditsi
Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Venkata S
VS
Pendyala
Department of Chemistry, University of California, Berkeley, California, USA.
Shang
S
Jia
Department of Chemistry, University of California, Berkeley, California, USA.
Allegra T
AT
Aron
Department of Chemistry, University of California, Berkeley, California, USA.
Cheri M
CM
Ackerman
Department of Chemistry, University of California, Berkeley, California, USA.
Mark N Vander
MN
Wal
Department of Chemistry, University of California, Berkeley, California, USA.
Timothy
T
Guan
Department of Chemistry, University of California, Berkeley, California, USA.
Lukas P
LP
Smaga
Department of Chemistry, University of California, Berkeley, California, USA.
Samouil L
SL
Farhi
Department of Chemistry, University of California, Berkeley, California, USA.
Elizabeth J
EJ
New
Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Svetlana
0000-0001-5275-2587
S
Lutsenko
Department of Chemistry, University of California, Berkeley, California, USA.|Howard Hughes Medical Institute, University of California, Berkeley, California, USA.|Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.|Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
Christopher J
CJ
Chang
D041721:3T3-L1 Cells; D000818:Animals; D003300:Copper / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008066:Lipolysis / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D058987:Phosphodiesterase 3 Inhibitors; D003300:Copper; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517293:Pde3b protein, mouse