Copper regulates cyclic-AMP-dependent lipolysis

Lakshmi Krishnamoorthy, Joseph A. Cotruvo, Jefferson Kar Fai Chan, Harini Kaluarachchi, Abigael Muchenditsi, Venkata S. Pendyala, Shang Jia, Allegra T. Aron, Cheri M. Ackerman, Mark N.Vander Wal, Timothy Guan, Lukas P. Smaga, Samouil L. Farhi, Elizabeth J. New, Svetlana Lutsenko, Christopher J. Chang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)586-592
Number of pages7
JournalNature chemical biology
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Lipolysis
Cyclic AMP
Copper
Oxidation-Reduction
Metals
White Adipocytes
Genetic Models
Coenzymes
Phosphoric Diester Hydrolases
Second Messenger Systems
Cysteine
Zinc
Potassium
Iron
Sodium
Fats
Body Weight
Pharmacology
Ions
Calcium

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Krishnamoorthy, L., Cotruvo, J. A., Chan, J. K. F., Kaluarachchi, H., Muchenditsi, A., Pendyala, V. S., ... Chang, C. J. (2016). Copper regulates cyclic-AMP-dependent lipolysis. Nature chemical biology, 12(8), 586-592. https://doi.org/10.1038/nchembio.2098

Copper regulates cyclic-AMP-dependent lipolysis. / Krishnamoorthy, Lakshmi; Cotruvo, Joseph A.; Chan, Jefferson Kar Fai; Kaluarachchi, Harini; Muchenditsi, Abigael; Pendyala, Venkata S.; Jia, Shang; Aron, Allegra T.; Ackerman, Cheri M.; Wal, Mark N.Vander; Guan, Timothy; Smaga, Lukas P.; Farhi, Samouil L.; New, Elizabeth J.; Lutsenko, Svetlana; Chang, Christopher J.

In: Nature chemical biology, Vol. 12, No. 8, 01.08.2016, p. 586-592.

Research output: Contribution to journalArticle

Krishnamoorthy, L, Cotruvo, JA, Chan, JKF, Kaluarachchi, H, Muchenditsi, A, Pendyala, VS, Jia, S, Aron, AT, Ackerman, CM, Wal, MNV, Guan, T, Smaga, LP, Farhi, SL, New, EJ, Lutsenko, S & Chang, CJ 2016, 'Copper regulates cyclic-AMP-dependent lipolysis', Nature chemical biology, vol. 12, no. 8, pp. 586-592. https://doi.org/10.1038/nchembio.2098
Krishnamoorthy L, Cotruvo JA, Chan JKF, Kaluarachchi H, Muchenditsi A, Pendyala VS et al. Copper regulates cyclic-AMP-dependent lipolysis. Nature chemical biology. 2016 Aug 1;12(8):586-592. https://doi.org/10.1038/nchembio.2098
Krishnamoorthy, Lakshmi ; Cotruvo, Joseph A. ; Chan, Jefferson Kar Fai ; Kaluarachchi, Harini ; Muchenditsi, Abigael ; Pendyala, Venkata S. ; Jia, Shang ; Aron, Allegra T. ; Ackerman, Cheri M. ; Wal, Mark N.Vander ; Guan, Timothy ; Smaga, Lukas P. ; Farhi, Samouil L. ; New, Elizabeth J. ; Lutsenko, Svetlana ; Chang, Christopher J. / Copper regulates cyclic-AMP-dependent lipolysis. In: Nature chemical biology. 2016 ; Vol. 12, No. 8. pp. 586-592.
@article{62b8a8e61473431abefe64b606067264,
title = "Copper regulates cyclic-AMP-dependent lipolysis",
abstract = "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.",
author = "Lakshmi Krishnamoorthy and Cotruvo, {Joseph A.} and Chan, {Jefferson Kar Fai} and Harini Kaluarachchi and Abigael Muchenditsi and Pendyala, {Venkata S.} and Shang Jia and Aron, {Allegra T.} and Ackerman, {Cheri M.} and Wal, {Mark N.Vander} and Timothy Guan and Smaga, {Lukas P.} and Farhi, {Samouil L.} and New, {Elizabeth J.} and Svetlana Lutsenko and Chang, {Christopher J.}",
year = "2016",
month = "8",
day = "1",
doi = "10.1038/nchembio.2098",
language = "English (US)",
volume = "12",
pages = "586--592",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Copper regulates cyclic-AMP-dependent lipolysis

AU - Krishnamoorthy, Lakshmi

AU - Cotruvo, Joseph A.

AU - Chan, Jefferson Kar Fai

AU - Kaluarachchi, Harini

AU - Muchenditsi, Abigael

AU - Pendyala, Venkata S.

AU - Jia, Shang

AU - Aron, Allegra T.

AU - Ackerman, Cheri M.

AU - Wal, Mark N.Vander

AU - Guan, Timothy

AU - Smaga, Lukas P.

AU - Farhi, Samouil L.

AU - New, Elizabeth J.

AU - Lutsenko, Svetlana

AU - Chang, Christopher J.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84976274777&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84976274777&partnerID=8YFLogxK

U2 - 10.1038/nchembio.2098

DO - 10.1038/nchembio.2098

M3 - Article

C2 - 27272565

AN - SCOPUS:84976274777

VL - 12

SP - 586

EP - 592

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 8

ER -