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An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice

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 adi... Full description

Journal Title: Nature medicine 2016-10, Vol.22 (10), p.1120-1130
Main Author: Rohm, Maria
Other Authors: Schäfer, Michaela , Laurent, Victor , Üstünel, Bilgen Ekim , Niopek, Katharina , Algire, Carolyn , Hautzinger, Oksana , Sijmonsma, Tjeerd P , Zota, Annika , Medrikova, Dasa , Pellegata, Natalia S , Ryden, Mikael , Kulyte, Agné , Dahlman, Ingrid , Arner, Peter , Petrovic, Natasa , Cannon, Barbara , Amri, Ez-Zoubir , Kemp, Bruce E , Steinberg, Gregory R , Janovska, Petra , Kopecky, Jan , Wolfrum, Christian , Blüher, Matthias , Berriel Diaz, Mauricio , Herzig, Stephan
Format: Electronic Article Electronic Article
Language: English
Subjects:
AMP
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
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title: An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
format: Article
creator:
  • Rohm, Maria
  • Schäfer, Michaela
  • Laurent, Victor
  • Üstünel, Bilgen Ekim
  • Niopek, Katharina
  • Algire, Carolyn
  • Hautzinger, Oksana
  • Sijmonsma, Tjeerd P
  • Zota, Annika
  • Medrikova, Dasa
  • Pellegata, Natalia S
  • Ryden, Mikael
  • Kulyte, Agné
  • Dahlman, Ingrid
  • Arner, Peter
  • Petrovic, Natasa
  • Cannon, Barbara
  • Amri, Ez-Zoubir
  • Kemp, Bruce E
  • Steinberg, Gregory R
  • Janovska, Petra
  • Kopecky, Jan
  • Wolfrum, Christian
  • Blüher, Matthias
  • Berriel Diaz, Mauricio
  • Herzig, Stephan
subjects:
  • Adipocytes
  • Adipocytes, White - drug effects
  • Adipocytes, White - metabolism
  • Adipose tissue
  • Adipose Tissue, White - drug effects
  • Adipose Tissue, White - metabolism
  • Adipose tissues
  • AMP
  • AMP-activated protein kinase
  • AMP-Activated Protein Kinases - metabolism
  • AMP-Activated Protein Kinases - pharmacology
  • Animals
  • Apoptosis Regulatory Proteins - drug effects
  • Apoptosis Regulatory Proteins - metabolism
  • Basic Medicine
  • Biological Sciences
  • Biologiska vetenskaper
  • Cachexia
  • Cachexia - etiology
  • Cachexia - metabolism
  • Cancer
  • Cell and Molecular Biology
  • Cell- och molekylärbiologi
  • Cells, Cultured
  • Deactivation
  • Energy
  • Genetic aspects
  • Health aspects
  • Homeostasis
  • In Vitro Techniques
  • Inactivation
  • Kinases
  • Lipid Metabolism - drug effects
  • Lipogenesis - drug effects
  • Lipolysis - drug effects
  • Medical and Health Sciences
  • Medical Biotechnology
  • Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
  • Medicin och hälsovetenskap
  • Medicinsk bioteknologi
  • Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
  • Medicinska och farmaceutiska grundvetenskaper
  • Mice
  • Muscles
  • Natural Sciences
  • Naturvetenskap
  • Neoplasms - complications
  • Neoplasms - metabolism
  • Peptide Fragments - pharmacology
  • Peptides
  • Phosphates
  • Preservation
  • Protein kinases
  • Proteins
  • Shielding
  • Skeletal muscle
  • Thermogenesis
  • Thermogenesis - drug effects
  • Tumors
  • Type 2 diabetes
  • Uncoupling protein 1
  • Uncoupling Protein 1 - drug effects
  • Uncoupling Protein 1 - metabolism
ispartof: Nature medicine, 2016-10, Vol.22 (10), p.1120-1130
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
  • 1546-170X
url: Link


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titleAn AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
creatorRohm, Maria ; Schäfer, Michaela ; Laurent, Victor ; Üstünel, Bilgen Ekim ; Niopek, Katharina ; Algire, Carolyn ; Hautzinger, Oksana ; Sijmonsma, Tjeerd P ; Zota, Annika ; Medrikova, Dasa ; Pellegata, Natalia S ; Ryden, Mikael ; Kulyte, Agné ; Dahlman, Ingrid ; Arner, Peter ; Petrovic, Natasa ; Cannon, Barbara ; Amri, Ez-Zoubir ; Kemp, Bruce E ; Steinberg, Gregory R ; Janovska, Petra ; Kopecky, Jan ; Wolfrum, Christian ; Blüher, Matthias ; Berriel Diaz, Mauricio ; Herzig, Stephan
creatorcontribRohm, Maria ; Schäfer, Michaela ; Laurent, Victor ; Üstünel, Bilgen Ekim ; Niopek, Katharina ; Algire, Carolyn ; Hautzinger, Oksana ; Sijmonsma, Tjeerd P ; Zota, Annika ; Medrikova, Dasa ; Pellegata, Natalia S ; Ryden, Mikael ; Kulyte, Agné ; Dahlman, Ingrid ; Arner, Peter ; Petrovic, Natasa ; Cannon, Barbara ; Amri, Ez-Zoubir ; Kemp, Bruce E ; Steinberg, Gregory R ; Janovska, Petra ; Kopecky, Jan ; Wolfrum, Christian ; Blüher, Matthias ; Berriel Diaz, Mauricio ; Herzig, Stephan
descriptionCachexia 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.
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languageeng
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subjectAdipocytes ; Adipocytes, White - drug effects ; Adipocytes, White - metabolism ; Adipose tissue ; Adipose Tissue, White - drug effects ; Adipose Tissue, White - metabolism ; Adipose tissues ; AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; AMP-Activated Protein Kinases - pharmacology ; Animals ; Apoptosis Regulatory Proteins - drug effects ; Apoptosis Regulatory Proteins - metabolism ; Basic Medicine ; Biological Sciences ; Biologiska vetenskaper ; Cachexia ; Cachexia - etiology ; Cachexia - metabolism ; Cancer ; Cell and Molecular Biology ; Cell- och molekylärbiologi ; Cells, Cultured ; Deactivation ; Energy ; Genetic aspects ; Health aspects ; Homeostasis ; In Vitro Techniques ; Inactivation ; Kinases ; Lipid Metabolism - drug effects ; Lipogenesis - drug effects ; Lipolysis - drug effects ; Medical and Health Sciences ; Medical Biotechnology ; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ; Medicin och hälsovetenskap ; Medicinsk bioteknologi ; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ; Medicinska och farmaceutiska grundvetenskaper ; Mice ; Muscles ; Natural Sciences ; Naturvetenskap ; Neoplasms - complications ; Neoplasms - metabolism ; Peptide Fragments - pharmacology ; Peptides ; Phosphates ; Preservation ; Protein kinases ; Proteins ; Shielding ; Skeletal muscle ; Thermogenesis ; Thermogenesis - drug effects ; Tumors ; Type 2 diabetes ; Uncoupling protein 1 ; Uncoupling Protein 1 - drug effects ; Uncoupling Protein 1 - metabolism
ispartofNature medicine, 2016-10, Vol.22 (10), p.1120-1130
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0Rohm, Maria
1Schäfer, Michaela
2Laurent, Victor
3Üstünel, Bilgen Ekim
4Niopek, Katharina
5Algire, Carolyn
6Hautzinger, Oksana
7Sijmonsma, Tjeerd P
8Zota, Annika
9Medrikova, Dasa
10Pellegata, Natalia S
11Ryden, Mikael
12Kulyte, Agné
13Dahlman, Ingrid
14Arner, Peter
15Petrovic, Natasa
16Cannon, Barbara
17Amri, Ez-Zoubir
18Kemp, Bruce E
19Steinberg, Gregory R
20Janovska, Petra
21Kopecky, Jan
22Wolfrum, Christian
23Blüher, Matthias
24Berriel Diaz, Mauricio
25Herzig, Stephan
title
0An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
1Nature medicine
addtitleNat Med
descriptionCachexia 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.
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0Adipocytes
1Adipocytes, White - drug effects
2Adipocytes, White - metabolism
3Adipose tissue
4Adipose Tissue, White - drug effects
5Adipose Tissue, White - metabolism
6Adipose tissues
7AMP
8AMP-activated protein kinase
9AMP-Activated Protein Kinases - metabolism
10AMP-Activated Protein Kinases - pharmacology
11Animals
12Apoptosis Regulatory Proteins - drug effects
13Apoptosis Regulatory Proteins - metabolism
14Basic Medicine
15Biological Sciences
16Biologiska vetenskaper
17Cachexia
18Cachexia - etiology
19Cachexia - metabolism
20Cancer
21Cell and Molecular Biology
22Cell- och molekylärbiologi
23Cells, Cultured
24Deactivation
25Energy
26Genetic aspects
27Health aspects
28Homeostasis
29In Vitro Techniques
30Inactivation
31Kinases
32Lipid Metabolism - drug effects
33Lipogenesis - drug effects
34Lipolysis - drug effects
35Medical and Health Sciences
36Medical Biotechnology
37Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
38Medicin och hälsovetenskap
39Medicinsk bioteknologi
40Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
41Medicinska och farmaceutiska grundvetenskaper
42Mice
43Muscles
44Natural Sciences
45Naturvetenskap
46Neoplasms - complications
47Neoplasms - metabolism
48Peptide Fragments - pharmacology
49Peptides
50Phosphates
51Preservation
52Protein kinases
53Proteins
54Shielding
55Skeletal muscle
56Thermogenesis
57Thermogenesis - drug effects
58Tumors
59Type 2 diabetes
60Uncoupling protein 1
61Uncoupling Protein 1 - drug effects
62Uncoupling Protein 1 - metabolism
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1Schäfer, Michaela
2Laurent, Victor
3Üstünel, Bilgen Ekim
4Niopek, Katharina
5Algire, Carolyn
6Hautzinger, Oksana
7Sijmonsma, Tjeerd P
8Zota, Annika
9Medrikova, Dasa
10Pellegata, Natalia S
11Ryden, Mikael
12Kulyte, Agné
13Dahlman, Ingrid
14Arner, Peter
15Petrovic, Natasa
16Cannon, Barbara
17Amri, Ez-Zoubir
18Kemp, Bruce E
19Steinberg, Gregory R
20Janovska, Petra
21Kopecky, Jan
22Wolfrum, Christian
23Blüher, Matthias
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titleAn AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice
authorRohm, Maria ; Schäfer, Michaela ; Laurent, Victor ; Üstünel, Bilgen Ekim ; Niopek, Katharina ; Algire, Carolyn ; Hautzinger, Oksana ; Sijmonsma, Tjeerd P ; Zota, Annika ; Medrikova, Dasa ; Pellegata, Natalia S ; Ryden, Mikael ; Kulyte, Agné ; Dahlman, Ingrid ; Arner, Peter ; Petrovic, Natasa ; Cannon, Barbara ; Amri, Ez-Zoubir ; Kemp, Bruce E ; Steinberg, Gregory R ; Janovska, Petra ; Kopecky, Jan ; Wolfrum, Christian ; Blüher, Matthias ; Berriel Diaz, Mauricio ; Herzig, Stephan
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0Adipocytes
1Adipocytes, White - drug effects
2Adipocytes, White - metabolism
3Adipose tissue
4Adipose Tissue, White - drug effects
5Adipose Tissue, White - metabolism
6Adipose tissues
7AMP
8AMP-activated protein kinase
9AMP-Activated Protein Kinases - metabolism
10AMP-Activated Protein Kinases - pharmacology
11Animals
12Apoptosis Regulatory Proteins - drug effects
13Apoptosis Regulatory Proteins - metabolism
14Basic Medicine
15Biological Sciences
16Biologiska vetenskaper
17Cachexia
18Cachexia - etiology
19Cachexia - metabolism
20Cancer
21Cell and Molecular Biology
22Cell- och molekylärbiologi
23Cells, Cultured
24Deactivation
25Energy
26Genetic aspects
27Health aspects
28Homeostasis
29In Vitro Techniques
30Inactivation
31Kinases
32Lipid Metabolism - drug effects
33Lipogenesis - drug effects
34Lipolysis - drug effects
35Medical and Health Sciences
36Medical Biotechnology
37Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
38Medicin och hälsovetenskap
39Medicinsk bioteknologi
40Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
41Medicinska och farmaceutiska grundvetenskaper
42Mice
43Muscles
44Natural Sciences
45Naturvetenskap
46Neoplasms - complications
47Neoplasms - metabolism
48Peptide Fragments - pharmacology
49Peptides
50Phosphates
51Preservation
52Protein kinases
53Proteins
54Shielding
55Skeletal muscle
56Thermogenesis
57Thermogenesis - drug effects
58Tumors
59Type 2 diabetes
60Uncoupling protein 1
61Uncoupling Protein 1 - drug effects
62Uncoupling Protein 1 - metabolism
toplevelpeer_reviewed
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0Rohm, Maria
1Schäfer, Michaela
2Laurent, Victor
3Üstünel, Bilgen Ekim
4Niopek, Katharina
5Algire, Carolyn
6Hautzinger, Oksana
7Sijmonsma, Tjeerd P
8Zota, Annika
9Medrikova, Dasa
10Pellegata, Natalia S
11Ryden, Mikael
12Kulyte, Agné
13Dahlman, Ingrid
14Arner, Peter
15Petrovic, Natasa
16Cannon, Barbara
17Amri, Ez-Zoubir
18Kemp, Bruce E
19Steinberg, Gregory R
20Janovska, Petra
21Kopecky, Jan
22Wolfrum, Christian
23Blüher, Matthias
24Berriel Diaz, Mauricio
25Herzig, Stephan
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addtitleNat Med
date2016-10
risdate2016
volume22
issue10
spage1120
epage1130
pages1120-1130
issn
01078-8956
11546-170X
eissn1546-170X
abstractCachexia 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.
copUnited States
pubNature Publishing Group
pmid27571348
doi10.1038/nm.4171
tpages11
orcididhttps://orcid.org/0000-0001-8426-5396