An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.
Identifieur interne : 001743 ( PubMed/Corpus ); précédent : 001742; suivant : 001744An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.
Auteurs : Maria Rohm ; Michaela Sch Fer ; Victor Laurent ; Bilgen Ekim Üstünel ; Katharina Niopek ; Carolyn Algire ; Oksana Hautzinger ; Tjeerd P. Sijmonsma ; Annika Zota ; Dasa Medrikova ; Natalia S. Pellegata ; Mikael Ryden ; Agné Kulyte ; Ingrid Dahlman ; Peter Arner ; Natasa Petrovic ; Barbara Cannon ; Ez-Zoubir Amri ; Bruce E. Kemp ; Gregory R. Steinberg ; Petra Janovska ; Jan Kopecky ; Christian Wolfrum ; Matthias Blüher ; Mauricio Berriel Diaz ; Stephan HerzigSource :
- Nature medicine [ 1546-170X ] ; 2016.
English descriptors
- KwdEn :
- AMP-Activated Protein Kinases (metabolism), AMP-Activated Protein Kinases (pharmacology), Adipocytes, White (drug effects), Adipocytes, White (metabolism), Adipose Tissue, White (drug effects), Adipose Tissue, White (metabolism), Animals, Apoptosis Regulatory Proteins (drug effects), Apoptosis Regulatory Proteins (metabolism), Cachexia (etiology), Cachexia (metabolism), Cells, Cultured, In Vitro Techniques, Lipid Metabolism (drug effects), Lipogenesis (drug effects), Lipolysis (drug effects), Mice, Neoplasms (complications), Neoplasms (metabolism), Peptide Fragments (pharmacology), Thermogenesis (drug effects), Uncoupling Protein 1 (drug effects), Uncoupling Protein 1 (metabolism).
- MESH :
- chemical , drug effects : Apoptosis Regulatory Proteins, Uncoupling Protein 1.
- chemical , metabolism : AMP-Activated Protein Kinases, Apoptosis Regulatory Proteins, Uncoupling Protein 1.
- chemical , pharmacology : AMP-Activated Protein Kinases, Peptide Fragments.
- complications : Neoplasms.
- drug effects : Adipocytes, White, Adipose Tissue, White, Lipid Metabolism, Lipogenesis, Lipolysis, Thermogenesis.
- etiology : Cachexia.
- metabolism : Adipocytes, White, Adipose Tissue, White, Cachexia, Neoplasms.
- Animals, Cells, Cultured, In Vitro Techniques, Mice.
Abstract
Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.
DOI: 10.1038/nm.4171
PubMed: 27571348
Links to Exploration step
pubmed:27571348Le document en format XML
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Sijmonsma</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Zota, Annika" sort="Zota, Annika" uniqKey="Zota A" first="Annika" last="Zota">Annika Zota</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Medrikova, Dasa" sort="Medrikova, Dasa" uniqKey="Medrikova D" first="Dasa" last="Medrikova">Dasa Medrikova</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Pellegata, Natalia S" sort="Pellegata, Natalia S" uniqKey="Pellegata N" first="Natalia S" last="Pellegata">Natalia S. Pellegata</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ryden, Mikael" sort="Ryden, Mikael" uniqKey="Ryden M" first="Mikael" last="Ryden">Mikael Ryden</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Kulyte, Agne" sort="Kulyte, Agne" uniqKey="Kulyte A" first="Agné" last="Kulyte">Agné Kulyte</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Dahlman, Ingrid" sort="Dahlman, Ingrid" uniqKey="Dahlman I" first="Ingrid" last="Dahlman">Ingrid Dahlman</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Arner, Peter" sort="Arner, Peter" uniqKey="Arner P" first="Peter" last="Arner">Peter Arner</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Petrovic, Natasa" sort="Petrovic, Natasa" uniqKey="Petrovic N" first="Natasa" last="Petrovic">Natasa Petrovic</name><affiliation><nlm:affiliation>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Cannon, Barbara" sort="Cannon, Barbara" uniqKey="Cannon B" first="Barbara" last="Cannon">Barbara Cannon</name><affiliation><nlm:affiliation>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Amri, Ez Zoubir" sort="Amri, Ez Zoubir" uniqKey="Amri E" first="Ez-Zoubir" last="Amri">Ez-Zoubir Amri</name><affiliation><nlm:affiliation>Université Côte d'Azur, Nice, France.</nlm:affiliation></affiliation></author><author><name sortKey="Kemp, Bruce E" sort="Kemp, Bruce E" uniqKey="Kemp B" first="Bruce E" last="Kemp">Bruce E. Kemp</name><affiliation><nlm:affiliation>St Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Steinberg, Gregory R" sort="Steinberg, Gregory R" uniqKey="Steinberg G" first="Gregory R" last="Steinberg">Gregory R. Steinberg</name><affiliation><nlm:affiliation>Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Janovska, Petra" sort="Janovska, Petra" uniqKey="Janovska P" first="Petra" last="Janovska">Petra Janovska</name><affiliation><nlm:affiliation>Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.</nlm:affiliation></affiliation></author><author><name sortKey="Kopecky, Jan" sort="Kopecky, Jan" uniqKey="Kopecky J" first="Jan" last="Kopecky">Jan Kopecky</name><affiliation><nlm:affiliation>Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.</nlm:affiliation></affiliation></author><author><name sortKey="Wolfrum, Christian" sort="Wolfrum, Christian" uniqKey="Wolfrum C" first="Christian" last="Wolfrum">Christian Wolfrum</name><affiliation><nlm:affiliation>Swiss Federal Institute of Technology, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland.</nlm:affiliation></affiliation></author><author><name sortKey="Bluher, Matthias" sort="Bluher, Matthias" uniqKey="Bluher M" first="Matthias" last="Blüher">Matthias Blüher</name><affiliation><nlm:affiliation>Department of Medicine, University of Leipzig, Leipzig, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Berriel Diaz, Mauricio" sort="Berriel Diaz, Mauricio" uniqKey="Berriel Diaz M" first="Mauricio" last="Berriel Diaz">Mauricio Berriel Diaz</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Herzig, Stephan" sort="Herzig, Stephan" uniqKey="Herzig S" first="Stephan" last="Herzig">Stephan Herzig</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27571348</idno><idno type="pmid">27571348</idno><idno type="doi">10.1038/nm.4171</idno><idno type="wicri:Area/PubMed/Corpus">001743</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001743</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.</title><author><name sortKey="Rohm, Maria" sort="Rohm, Maria" uniqKey="Rohm M" first="Maria" last="Rohm">Maria Rohm</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sch Fer, Michaela" sort="Sch Fer, Michaela" uniqKey="Sch Fer M" first="Michaela" last="Sch Fer">Michaela Sch Fer</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Laurent, Victor" sort="Laurent, Victor" uniqKey="Laurent V" first="Victor" last="Laurent">Victor Laurent</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ustunel, Bilgen Ekim" sort="Ustunel, Bilgen Ekim" uniqKey="Ustunel B" first="Bilgen Ekim" last="Üstünel">Bilgen Ekim Üstünel</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Niopek, Katharina" sort="Niopek, Katharina" uniqKey="Niopek K" first="Katharina" last="Niopek">Katharina Niopek</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Algire, Carolyn" sort="Algire, Carolyn" uniqKey="Algire C" first="Carolyn" last="Algire">Carolyn Algire</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hautzinger, Oksana" sort="Hautzinger, Oksana" uniqKey="Hautzinger O" first="Oksana" last="Hautzinger">Oksana Hautzinger</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sijmonsma, Tjeerd P" sort="Sijmonsma, Tjeerd P" uniqKey="Sijmonsma T" first="Tjeerd P" last="Sijmonsma">Tjeerd P. Sijmonsma</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Zota, Annika" sort="Zota, Annika" uniqKey="Zota A" first="Annika" last="Zota">Annika Zota</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Medrikova, Dasa" sort="Medrikova, Dasa" uniqKey="Medrikova D" first="Dasa" last="Medrikova">Dasa Medrikova</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Pellegata, Natalia S" sort="Pellegata, Natalia S" uniqKey="Pellegata N" first="Natalia S" last="Pellegata">Natalia S. Pellegata</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ryden, Mikael" sort="Ryden, Mikael" uniqKey="Ryden M" first="Mikael" last="Ryden">Mikael Ryden</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Kulyte, Agne" sort="Kulyte, Agne" uniqKey="Kulyte A" first="Agné" last="Kulyte">Agné Kulyte</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Dahlman, Ingrid" sort="Dahlman, Ingrid" uniqKey="Dahlman I" first="Ingrid" last="Dahlman">Ingrid Dahlman</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Arner, Peter" sort="Arner, Peter" uniqKey="Arner P" first="Peter" last="Arner">Peter Arner</name><affiliation><nlm:affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Petrovic, Natasa" sort="Petrovic, Natasa" uniqKey="Petrovic N" first="Natasa" last="Petrovic">Natasa Petrovic</name><affiliation><nlm:affiliation>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Cannon, Barbara" sort="Cannon, Barbara" uniqKey="Cannon B" first="Barbara" last="Cannon">Barbara Cannon</name><affiliation><nlm:affiliation>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.</nlm:affiliation></affiliation></author><author><name sortKey="Amri, Ez Zoubir" sort="Amri, Ez Zoubir" uniqKey="Amri E" first="Ez-Zoubir" last="Amri">Ez-Zoubir Amri</name><affiliation><nlm:affiliation>Université Côte d'Azur, Nice, France.</nlm:affiliation></affiliation></author><author><name sortKey="Kemp, Bruce E" sort="Kemp, Bruce E" uniqKey="Kemp B" first="Bruce E" last="Kemp">Bruce E. Kemp</name><affiliation><nlm:affiliation>St Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Steinberg, Gregory R" sort="Steinberg, Gregory R" uniqKey="Steinberg G" first="Gregory R" last="Steinberg">Gregory R. Steinberg</name><affiliation><nlm:affiliation>Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada.</nlm:affiliation></affiliation></author><author><name sortKey="Janovska, Petra" sort="Janovska, Petra" uniqKey="Janovska P" first="Petra" last="Janovska">Petra Janovska</name><affiliation><nlm:affiliation>Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.</nlm:affiliation></affiliation></author><author><name sortKey="Kopecky, Jan" sort="Kopecky, Jan" uniqKey="Kopecky J" first="Jan" last="Kopecky">Jan Kopecky</name><affiliation><nlm:affiliation>Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.</nlm:affiliation></affiliation></author><author><name sortKey="Wolfrum, Christian" sort="Wolfrum, Christian" uniqKey="Wolfrum C" first="Christian" last="Wolfrum">Christian Wolfrum</name><affiliation><nlm:affiliation>Swiss Federal Institute of Technology, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland.</nlm:affiliation></affiliation></author><author><name sortKey="Bluher, Matthias" sort="Bluher, Matthias" uniqKey="Bluher M" first="Matthias" last="Blüher">Matthias Blüher</name><affiliation><nlm:affiliation>Department of Medicine, University of Leipzig, Leipzig, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Berriel Diaz, Mauricio" sort="Berriel Diaz, Mauricio" uniqKey="Berriel Diaz M" first="Mauricio" last="Berriel Diaz">Mauricio Berriel Diaz</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Herzig, Stephan" sort="Herzig, Stephan" uniqKey="Herzig S" first="Stephan" last="Herzig">Stephan Herzig</name><affiliation><nlm:affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Nature medicine</title><idno type="eISSN">1546-170X</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AMP-Activated Protein Kinases (metabolism)</term><term>AMP-Activated Protein Kinases (pharmacology)</term><term>Adipocytes, White (drug effects)</term><term>Adipocytes, White (metabolism)</term><term>Adipose Tissue, White (drug effects)</term><term>Adipose Tissue, White (metabolism)</term><term>Animals</term><term>Apoptosis Regulatory Proteins (drug effects)</term><term>Apoptosis Regulatory Proteins (metabolism)</term><term>Cachexia (etiology)</term><term>Cachexia (metabolism)</term><term>Cells, Cultured</term><term>In Vitro Techniques</term><term>Lipid Metabolism (drug effects)</term><term>Lipogenesis (drug effects)</term><term>Lipolysis (drug effects)</term><term>Mice</term><term>Neoplasms (complications)</term><term>Neoplasms (metabolism)</term><term>Peptide Fragments (pharmacology)</term><term>Thermogenesis (drug effects)</term><term>Uncoupling Protein 1 (drug effects)</term><term>Uncoupling Protein 1 (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Apoptosis Regulatory Proteins</term><term>Uncoupling Protein 1</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>AMP-Activated Protein Kinases</term><term>Apoptosis Regulatory Proteins</term><term>Uncoupling Protein 1</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>AMP-Activated Protein Kinases</term><term>Peptide Fragments</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Neoplasms</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Adipocytes, White</term><term>Adipose Tissue, White</term><term>Lipid Metabolism</term><term>Lipogenesis</term><term>Lipolysis</term><term>Thermogenesis</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Cachexia</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Adipocytes, White</term><term>Adipose Tissue, White</term><term>Cachexia</term><term>Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>In Vitro Techniques</term><term>Mice</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27571348</PMID><DateCreated><Year>2016</Year><Month>09</Month><Day>26</Day></DateCreated><DateCompleted><Year>2017</Year><Month>08</Month><Day>08</Day></DateCompleted><DateRevised><Year>2017</Year><Month>11</Month><Day>16</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1546-170X</ISSN><JournalIssue CitedMedium="Internet"><Volume>22</Volume><Issue>10</Issue><PubDate><Year>2016</Year><Month>Oct</Month></PubDate></JournalIssue><Title>Nature medicine</Title><ISOAbbreviation>Nat. Med.</ISOAbbreviation></Journal><ArticleTitle>An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.</ArticleTitle><Pagination><MedlinePgn>1120-1130</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/nm.4171</ELocationID><Abstract><AbstractText>Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rohm</LastName><ForeName>Maria</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schäfer</LastName><ForeName>Michaela</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Laurent</LastName><ForeName>Victor</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Üstünel</LastName><ForeName>Bilgen Ekim</ForeName><Initials>BE</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Niopek</LastName><ForeName>Katharina</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Algire</LastName><ForeName>Carolyn</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hautzinger</LastName><ForeName>Oksana</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sijmonsma</LastName><ForeName>Tjeerd P</ForeName><Initials>TP</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zota</LastName><ForeName>Annika</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Medrikova</LastName><ForeName>Dasa</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pellegata</LastName><ForeName>Natalia S</ForeName><Initials>NS</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ryden</LastName><ForeName>Mikael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kulyte</LastName><ForeName>Agné</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dahlman</LastName><ForeName>Ingrid</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arner</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Petrovic</LastName><ForeName>Natasa</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cannon</LastName><ForeName>Barbara</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Amri</LastName><ForeName>Ez-Zoubir</ForeName><Initials>EZ</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-8426-5396</Identifier><AffiliationInfo><Affiliation>Université Côte d'Azur, Nice, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Centre National de la Recherche Scientifique (CNRS), Nice, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kemp</LastName><ForeName>Bruce E</ForeName><Initials>BE</Initials><AffiliationInfo><Affiliation>St Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Mary MacKillop Institute for Health, Research Australian Catholic University, Melbourne, Victoria, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steinberg</LastName><ForeName>Gregory R</ForeName><Initials>GR</Initials><AffiliationInfo><Affiliation>Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Janovska</LastName><ForeName>Petra</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kopecky</LastName><ForeName>Jan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wolfrum</LastName><ForeName>Christian</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Swiss Federal Institute of Technology, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blüher</LastName><ForeName>Matthias</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Leipzig, Leipzig, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Berriel Diaz</LastName><ForeName>Mauricio</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Herzig</LastName><ForeName>Stephan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>08</Month><Day>29</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Nat Med</MedlineTA><NlmUniqueID>9502015</NlmUniqueID><ISSNLinking>1078-8956</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051017">Apoptosis Regulatory Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C112510">Cidea protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010446">Peptide Fragments</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C000604372">Ucp1 protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000071256">Uncoupling Protein 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D055372">AMP-Activated Protein Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="C554549">Prkab1 protein, mouse</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Curr Opin Clin Nutr Metab Care. 2014 Nov;17(6):509-14</RefSource><PMID Version="1">25111867</PMID></CommentsCorrections><CommentsCorrections 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