Copper regulates cyclic-AMP-dependent lipolysis

• DOI: 10.1038/nchembio.2098
• Publication Date: 2016-06-06T18:54:55Z
• Authors: Lakshmi Krishnamo...; Joseph A Cotruvo; Jefferson 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
• Keywords: Cyclic Nucleotide Phosphodiesterases; Biochemistry & Molecular Biology; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Lipolysis; Biological Sciences; Phosphodiesterase 3 Inhibitors; Article; Cyclic Nucleotide Phosphodiesterases, Type 3; Dose-Response Relationship; Medicinal and Biomolecular Chemistry; Mice; Structure-Activity Relationship; 03 medical and health sciences; Biochemistry and cell biology; 3T3-L1 Cells; Medicinal and biomolecular chemistry; Cyclic AMP; Animals; Biochemistry and Cell Biology; Drug; Type 3; Copper

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.