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GLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice

Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE−/− mice after admin... Full description

Journal Title: Endocrinology (Philadelphia) 2013, Vol.154 (1), p.127-139
Main Author: Panjwani, Naim
Other Authors: Mulvihill, Erin E , Longuet, Christine , Yusta, Bernardo , Campbell, Jonathan E , Brown, Theodore J , Streutker, Catherine , Holland, Dianne , Cao, Xiemin , Baggio, Laurie L , Drucker, Daniel J
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Chevy Chase, MD: Endocrine Society
ID: ISSN: 0013-7227
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title: GLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice
format: Article
creator:
  • Panjwani, Naim
  • Mulvihill, Erin E
  • Longuet, Christine
  • Yusta, Bernardo
  • Campbell, Jonathan E
  • Brown, Theodore J
  • Streutker, Catherine
  • Holland, Dianne
  • Cao, Xiemin
  • Baggio, Laurie L
  • Drucker, Daniel J
subjects:
  • Abridged Index Medicus
  • Animals
  • Apolipoproteins E - deficiency
  • Apolipoproteins E - genetics
  • Atherosclerosis (general aspects, experimental research)
  • Atherosclerosis - metabolism
  • Biological and medical sciences
  • Blood and lymphatic vessels
  • Blotting, Western
  • Body Composition - drug effects
  • Cardiology. Vascular system
  • Diabetes. Impaired glucose tolerance
  • Endocrine pancreas. Apud cells (diseases)
  • Endocrinopathies
  • Etiopathogenesis. Screening. Investigations. Target tissue resistance
  • Fundamental and applied biological sciences. Psychology
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Tolerance Test
  • Hepatocytes - drug effects
  • Hepatocytes - metabolism
  • Interleukin-10 - deficiency
  • Interleukin-10 - genetics
  • Liver - drug effects
  • Liver - metabolism
  • Macrophages - drug effects
  • Macrophages - metabolism
  • Male
  • Medical sciences
  • Mice
  • Mice, Knockout
  • Peptides - pharmacology
  • Receptors, Glucagon - agonists
  • Receptors, Glucagon - genetics
  • Receptors, Glucagon - metabolism
  • Vertebrates: endocrinology
ispartof: Endocrinology (Philadelphia), 2013, Vol.154 (1), p.127-139
description: Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE−/− mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE−/− mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE−/−, C57BL/6, and IL10−/− mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r+/+ and Glp1r−/− mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE−/− mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation.
language: eng
source:
identifier: ISSN: 0013-7227
fulltext: no_fulltext
issn:
  • 0013-7227
  • 1945-7170
url: Link


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titleGLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice
creatorPanjwani, Naim ; Mulvihill, Erin E ; Longuet, Christine ; Yusta, Bernardo ; Campbell, Jonathan E ; Brown, Theodore J ; Streutker, Catherine ; Holland, Dianne ; Cao, Xiemin ; Baggio, Laurie L ; Drucker, Daniel J
creatorcontribPanjwani, Naim ; Mulvihill, Erin E ; Longuet, Christine ; Yusta, Bernardo ; Campbell, Jonathan E ; Brown, Theodore J ; Streutker, Catherine ; Holland, Dianne ; Cao, Xiemin ; Baggio, Laurie L ; Drucker, Daniel J
descriptionGlucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE−/− mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE−/− mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE−/−, C57BL/6, and IL10−/− mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r+/+ and Glp1r−/− mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE−/− mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation.
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subjectAbridged Index Medicus ; Animals ; Apolipoproteins E - deficiency ; Apolipoproteins E - genetics ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - metabolism ; Biological and medical sciences ; Blood and lymphatic vessels ; Blotting, Western ; Body Composition - drug effects ; Cardiology. Vascular system ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fundamental and applied biological sciences. Psychology ; Glucagon-Like Peptide-1 Receptor ; Glucose Tolerance Test ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Interleukin-10 - deficiency ; Interleukin-10 - genetics ; Liver - drug effects ; Liver - metabolism ; Macrophages - drug effects ; Macrophages - metabolism ; Male ; Medical sciences ; Mice ; Mice, Knockout ; Peptides - pharmacology ; Receptors, Glucagon - agonists ; Receptors, Glucagon - genetics ; Receptors, Glucagon - metabolism ; Vertebrates: endocrinology
ispartofEndocrinology (Philadelphia), 2013, Vol.154 (1), p.127-139
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1Mulvihill, Erin E
2Longuet, Christine
3Yusta, Bernardo
4Campbell, Jonathan E
5Brown, Theodore J
6Streutker, Catherine
7Holland, Dianne
8Cao, Xiemin
9Baggio, Laurie L
10Drucker, Daniel J
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0GLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice
1Endocrinology (Philadelphia)
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descriptionGlucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE−/− mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE−/− mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE−/−, C57BL/6, and IL10−/− mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r+/+ and Glp1r−/− mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE−/− mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation.
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0Abridged Index Medicus
1Animals
2Apolipoproteins E - deficiency
3Apolipoproteins E - genetics
4Atherosclerosis (general aspects, experimental research)
5Atherosclerosis - metabolism
6Biological and medical sciences
7Blood and lymphatic vessels
8Blotting, Western
9Body Composition - drug effects
10Cardiology. Vascular system
11Diabetes. Impaired glucose tolerance
12Endocrine pancreas. Apud cells (diseases)
13Endocrinopathies
14Etiopathogenesis. Screening. Investigations. Target tissue resistance
15Fundamental and applied biological sciences. Psychology
16Glucagon-Like Peptide-1 Receptor
17Glucose Tolerance Test
18Hepatocytes - drug effects
19Hepatocytes - metabolism
20Interleukin-10 - deficiency
21Interleukin-10 - genetics
22Liver - drug effects
23Liver - metabolism
24Macrophages - drug effects
25Macrophages - metabolism
26Male
27Medical sciences
28Mice
29Mice, Knockout
30Peptides - pharmacology
31Receptors, Glucagon - agonists
32Receptors, Glucagon - genetics
33Receptors, Glucagon - metabolism
34Vertebrates: endocrinology
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1Mulvihill, Erin E
2Longuet, Christine
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4Campbell, Jonathan E
5Brown, Theodore J
6Streutker, Catherine
7Holland, Dianne
8Cao, Xiemin
9Baggio, Laurie L
10Drucker, Daniel J
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titleGLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE−/− Mice
authorPanjwani, Naim ; Mulvihill, Erin E ; Longuet, Christine ; Yusta, Bernardo ; Campbell, Jonathan E ; Brown, Theodore J ; Streutker, Catherine ; Holland, Dianne ; Cao, Xiemin ; Baggio, Laurie L ; Drucker, Daniel J
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0Abridged Index Medicus
1Animals
2Apolipoproteins E - deficiency
3Apolipoproteins E - genetics
4Atherosclerosis (general aspects, experimental research)
5Atherosclerosis - metabolism
6Biological and medical sciences
7Blood and lymphatic vessels
8Blotting, Western
9Body Composition - drug effects
10Cardiology. Vascular system
11Diabetes. Impaired glucose tolerance
12Endocrine pancreas. Apud cells (diseases)
13Endocrinopathies
14Etiopathogenesis. Screening. Investigations. Target tissue resistance
15Fundamental and applied biological sciences. Psychology
16Glucagon-Like Peptide-1 Receptor
17Glucose Tolerance Test
18Hepatocytes - drug effects
19Hepatocytes - metabolism
20Interleukin-10 - deficiency
21Interleukin-10 - genetics
22Liver - drug effects
23Liver - metabolism
24Macrophages - drug effects
25Macrophages - metabolism
26Male
27Medical sciences
28Mice
29Mice, Knockout
30Peptides - pharmacology
31Receptors, Glucagon - agonists
32Receptors, Glucagon - genetics
33Receptors, Glucagon - metabolism
34Vertebrates: endocrinology
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1Mulvihill, Erin E
2Longuet, Christine
3Yusta, Bernardo
4Campbell, Jonathan E
5Brown, Theodore J
6Streutker, Catherine
7Holland, Dianne
8Cao, Xiemin
9Baggio, Laurie L
10Drucker, Daniel J
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8Cao, Xiemin
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abstractGlucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE−/− mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE−/− mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE−/−, C57BL/6, and IL10−/− mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r+/+ and Glp1r−/− mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE−/− mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation.
copChevy Chase, MD
pubEndocrine Society
pmid23183176
doi10.1210/en.2012-1937
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