Copper regulates cyclic-AMP-dependent lipolysis
Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B. Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as s...
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| Veröffentlicht in: | Nature chemical biology 2016-08, Vol.12 (8), p.586-592 |
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| creator | Krishnamoorthy, Lakshmi Cotruvo, Joseph A Chan, Jefferson 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 |
| description | Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B.
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. |
| doi_str_mv | 10.1038/nchembio.2098 |
| format | Article |
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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.</description><identifier>ISSN: 1552-4450</identifier><identifier>EISSN: 1552-4469</identifier><identifier>DOI: 10.1038/nchembio.2098</identifier><identifier>PMID: 27272565</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13 ; 14 ; 14/34 ; 3T3-L1 Cells ; 631/443/319 ; 631/80/86 ; 631/92/321 ; 631/92/96 ; 64 ; 64/60 ; 82 ; 82/83 ; Animals ; Biochemical Engineering ; Biochemistry ; Bioorganic Chemistry ; Cell Biology ; Chemistry ; Chemistry/Food Science ; Copper - pharmacology ; Cyclic AMP - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 3 - chemistry ; Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism ; Dose-Response Relationship, Drug ; Lipolysis - drug effects ; Mice ; Molecular Structure ; Phosphodiesterase 3 Inhibitors - pharmacology ; Structure-Activity Relationship</subject><ispartof>Nature chemical biology, 2016-08, Vol.12 (8), p.586-592</ispartof><rights>Springer Nature America, Inc. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-e5af2dd3eb1b39028b8c6b5eec7820fcfdb570caa5d49bf922b0db2173fc44173</citedby><cites>FETCH-LOGICAL-c459t-e5af2dd3eb1b39028b8c6b5eec7820fcfdb570caa5d49bf922b0db2173fc44173</cites><orcidid>0000-0001-5275-2587</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nchembio.2098$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nchembio.2098$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27272565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krishnamoorthy, Lakshmi</creatorcontrib><creatorcontrib>Cotruvo, Joseph A</creatorcontrib><creatorcontrib>Chan, Jefferson</creatorcontrib><creatorcontrib>Kaluarachchi, Harini</creatorcontrib><creatorcontrib>Muchenditsi, Abigael</creatorcontrib><creatorcontrib>Pendyala, Venkata S</creatorcontrib><creatorcontrib>Jia, Shang</creatorcontrib><creatorcontrib>Aron, Allegra T</creatorcontrib><creatorcontrib>Ackerman, Cheri M</creatorcontrib><creatorcontrib>Wal, Mark N Vander</creatorcontrib><creatorcontrib>Guan, Timothy</creatorcontrib><creatorcontrib>Smaga, Lukas P</creatorcontrib><creatorcontrib>Farhi, Samouil L</creatorcontrib><creatorcontrib>New, Elizabeth J</creatorcontrib><creatorcontrib>Lutsenko, Svetlana</creatorcontrib><creatorcontrib>Chang, Christopher J</creatorcontrib><title>Copper regulates cyclic-AMP-dependent lipolysis</title><title>Nature chemical biology</title><addtitle>Nat Chem Biol</addtitle><addtitle>Nat Chem Biol</addtitle><description>Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B.
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.</description><subject>13</subject><subject>14</subject><subject>14/34</subject><subject>3T3-L1 Cells</subject><subject>631/443/319</subject><subject>631/80/86</subject><subject>631/92/321</subject><subject>631/92/96</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/83</subject><subject>Animals</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Bioorganic Chemistry</subject><subject>Cell Biology</subject><subject>Chemistry</subject><subject>Chemistry/Food Science</subject><subject>Copper - pharmacology</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 3 - chemistry</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Lipolysis - drug effects</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>Phosphodiesterase 3 Inhibitors - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>1552-4450</issn><issn>1552-4469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtLAzEQh4MoVqtHr9Kjl22T7GY3exFK8QUVPeg55DHbpuxu1qQr9L83pQ_0IHOYgfn4zfAhdEPwmOCUT1q9hEZZN6a45CfogjBGkyzLy9PjzPAAXYawwjjNc8LP0YAWsVjOLtBk5roO_MjDoq_lGsJIb3RtdTJ9fU8MdNAaaNej2nau3gQbrtBZJesA1_s-RJ-PDx-z52T-9vQym84TnbFynQCTFTUmBUVUWmLKFde5YgC64BRXujKKFVhLyUxWqqqkVGGjKCnSSmdZbEN0v8vtetWA0fEJL2vRedtIvxFOWvF309qlWLhvkZWM5UUeA-72Ad599RDWorFBQ13LFlwfBOGEcE6ikIgmO1R7F4KH6niGYLGVLA6SxVZy5G9__3akD1YjMN4BIa7aBXixcr1vo69_En8Ah5aLaA</recordid><startdate>20160801</startdate><enddate>20160801</enddate><creator>Krishnamoorthy, Lakshmi</creator><creator>Cotruvo, Joseph A</creator><creator>Chan, Jefferson</creator><creator>Kaluarachchi, Harini</creator><creator>Muchenditsi, Abigael</creator><creator>Pendyala, Venkata S</creator><creator>Jia, Shang</creator><creator>Aron, Allegra T</creator><creator>Ackerman, Cheri M</creator><creator>Wal, Mark N Vander</creator><creator>Guan, Timothy</creator><creator>Smaga, Lukas P</creator><creator>Farhi, Samouil L</creator><creator>New, Elizabeth J</creator><creator>Lutsenko, Svetlana</creator><creator>Chang, Christopher J</creator><general>Nature Publishing Group US</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5275-2587</orcidid></search><sort><creationdate>20160801</creationdate><title>Copper regulates cyclic-AMP-dependent lipolysis</title><author>Krishnamoorthy, Lakshmi ; Cotruvo, Joseph A ; Chan, Jefferson ; 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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-e5af2dd3eb1b39028b8c6b5eec7820fcfdb570caa5d49bf922b0db2173fc44173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13</topic><topic>14</topic><topic>14/34</topic><topic>3T3-L1 Cells</topic><topic>631/443/319</topic><topic>631/80/86</topic><topic>631/92/321</topic><topic>631/92/96</topic><topic>64</topic><topic>64/60</topic><topic>82</topic><topic>82/83</topic><topic>Animals</topic><topic>Biochemical Engineering</topic><topic>Biochemistry</topic><topic>Bioorganic Chemistry</topic><topic>Cell Biology</topic><topic>Chemistry</topic><topic>Chemistry/Food Science</topic><topic>Copper - pharmacology</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 3 - chemistry</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Lipolysis - drug effects</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>Phosphodiesterase 3 Inhibitors - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krishnamoorthy, Lakshmi</creatorcontrib><creatorcontrib>Cotruvo, Joseph A</creatorcontrib><creatorcontrib>Chan, Jefferson</creatorcontrib><creatorcontrib>Kaluarachchi, Harini</creatorcontrib><creatorcontrib>Muchenditsi, Abigael</creatorcontrib><creatorcontrib>Pendyala, Venkata S</creatorcontrib><creatorcontrib>Jia, Shang</creatorcontrib><creatorcontrib>Aron, Allegra T</creatorcontrib><creatorcontrib>Ackerman, Cheri M</creatorcontrib><creatorcontrib>Wal, Mark N Vander</creatorcontrib><creatorcontrib>Guan, Timothy</creatorcontrib><creatorcontrib>Smaga, Lukas P</creatorcontrib><creatorcontrib>Farhi, Samouil L</creatorcontrib><creatorcontrib>New, Elizabeth J</creatorcontrib><creatorcontrib>Lutsenko, Svetlana</creatorcontrib><creatorcontrib>Chang, Christopher J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krishnamoorthy, Lakshmi</au><au>Cotruvo, Joseph A</au><au>Chan, Jefferson</au><au>Kaluarachchi, Harini</au><au>Muchenditsi, Abigael</au><au>Pendyala, Venkata S</au><au>Jia, Shang</au><au>Aron, Allegra T</au><au>Ackerman, Cheri M</au><au>Wal, Mark N Vander</au><au>Guan, Timothy</au><au>Smaga, Lukas P</au><au>Farhi, Samouil L</au><au>New, Elizabeth J</au><au>Lutsenko, Svetlana</au><au>Chang, Christopher J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Copper regulates cyclic-AMP-dependent lipolysis</atitle><jtitle>Nature chemical biology</jtitle><stitle>Nat Chem Biol</stitle><addtitle>Nat Chem Biol</addtitle><date>2016-08-01</date><risdate>2016</risdate><volume>12</volume><issue>8</issue><spage>586</spage><epage>592</epage><pages>586-592</pages><issn>1552-4450</issn><eissn>1552-4469</eissn><abstract>Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B.
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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>27272565</pmid><doi>10.1038/nchembio.2098</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-5275-2587</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13 14 14/34 3T3-L1 Cells 631/443/319 631/80/86 631/92/321 631/92/96 64 64/60 82 82/83 Animals Biochemical Engineering Biochemistry Bioorganic Chemistry Cell Biology Chemistry Chemistry/Food Science Copper - pharmacology Cyclic AMP - metabolism Cyclic Nucleotide Phosphodiesterases, Type 3 - chemistry Cyclic Nucleotide Phosphodiesterases, Type 3 - metabolism Dose-Response Relationship, Drug Lipolysis - drug effects Mice Molecular Structure Phosphodiesterase 3 Inhibitors - pharmacology Structure-Activity Relationship |
| title | Copper regulates cyclic-AMP-dependent lipolysis |
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