The expression of GLP‐1 receptor mRNA and protein allows the effect of GLP‐1 on glucose metabolism in the human hypothalamus and brainstem

In the present work, several experimental approaches were used to determine the presence of the glucagon‐like peptide‐1 receptor (GLP‐1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP‐1 receptor mRNA in several b...

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Veröffentlicht in:	Journal of neurochemistry Jg. 92; H. 4; S. 798 - 806
Hauptverfasser:	Alvarez, Elvira, Martínez, M. Dolores, Roncero, Isabel, Chowen, Julie A., García‐Cuartero, Beatriz, Gispert, Juan D., Sanz, Carmen, Vázquez, Patricia, Maldonado, Antonio, De Cáceres, Javier, Desco, Manuel, Pozo, Miguel Angel, Blázquez, Enrique
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Oxford, UK Blackwell Science Ltd 01.02.2005 Blackwell
Schlagworte:	Adult Aged Aged, 80 and over Biological and medical sciences biological effects Brain Stem - metabolism Cell receptors Cell structures and functions Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Female Fundamental and applied biological sciences. Psychology gene expression Glucagon - metabolism Glucagon - physiology Glucagon-Like Peptide 1 Glucagon-Like Peptide-1 Receptor Glucose - metabolism glucose sensing human brain Humans Hypothalamus - metabolism Male Medical sciences Middle Aged Molecular and cellular biology Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine) Neurology Peptide Fragments - metabolism Peptide Fragments - physiology Protein Binding - physiology Protein Precursors - metabolism Protein Precursors - physiology Receptors, Glucagon - biosynthesis Receptors, Glucagon - genetics RNA, Messenger - biosynthesis Human Phosphates Statistical analysis Enzyme Transferases GLP-1 receptor Central nervous system Glucose Hypothalamus Gene expression Metabolism Statistical study Protein biological effects Encephalon human brain Glucokinase GLUT-1 glucose transporter glucagon-like peptide-1 receptor glucose sensing Positron Emission tomography
ISSN:	0022-3042, 1471-4159
Online-Zugang:	Volltext
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Abstract	In the present work, several experimental approaches were used to determine the presence of the glucagon‐like peptide‐1 receptor (GLP‐1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP‐1 receptor mRNA in several brain areas. In addition, GLP‐1R, glucose transporter isoform (GLUT‐2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP‐1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross‐linking assays. Specific binding of 125I‐GLP‐1(7–36) amide to the GLP‐1R was detected in several brain areas and was inhibited by unlabelled GLP‐1(7–36) amide, exendin‐4 and exendin (9–39). A further aim of this work was to evaluate cerebral‐glucose metabolism in control subjects by positron emission tomography (PET), using 2‐[F‐18] deoxy‐d‐glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP‐1(7–36) amide significantly reduced (p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG‐6‐phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT‐2‐ and GK‐containing cells.
AbstractList	In the present work, several experimental approaches were used to determine the presence of the glucagon‐like peptide‐1 receptor (GLP‐1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP‐1 receptor mRNA in several brain areas. In addition, GLP‐1R, glucose transporter isoform (GLUT‐2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP‐1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross‐linking assays. Specific binding of 125 I‐GLP‐1(7–36) amide to the GLP‐1R was detected in several brain areas and was inhibited by unlabelled GLP‐1(7–36) amide, exendin‐4 and exendin (9–39). A further aim of this work was to evaluate cerebral‐glucose metabolism in control subjects by positron emission tomography (PET), using 2‐[F‐18] deoxy‐ d ‐glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP‐1(7–36) amide significantly reduced ( p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG‐6‐phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT‐2‐ and GK‐containing cells. In the present work, several experimental approaches were used to determine the presence of the glucagon‐like peptide‐1 receptor (GLP‐1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP‐1 receptor mRNA in several brain areas. In addition, GLP‐1R, glucose transporter isoform (GLUT‐2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP‐1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross‐linking assays. Specific binding of 125I‐GLP‐1(7–36) amide to the GLP‐1R was detected in several brain areas and was inhibited by unlabelled GLP‐1(7–36) amide, exendin‐4 and exendin (9–39). A further aim of this work was to evaluate cerebral‐glucose metabolism in control subjects by positron emission tomography (PET), using 2‐[F‐18] deoxy‐d‐glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP‐1(7–36) amide significantly reduced (p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG‐6‐phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT‐2‐ and GK‐containing cells. In the present work, several experimental approaches were used to determine the presence of the glucagon-like peptide-1 receptor (GLP-1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP-1 receptor mRNA in several brain areas. In addition, GLP-1R, glucose transporter isoform (GLUT-2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP-1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross-linking assays. Specific binding of 125I-GLP-1(7-36) amide to the GLP-1R was detected in several brain areas and was inhibited by unlabelled GLP-1(7-36) amide, exendin-4 and exendin (9-39). A further aim of this work was to evaluate cerebral-glucose metabolism in control subjects by positron emission tomography (PET), using 2-[F-18] deoxy-D-glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP-1(7-36) amide significantly reduced (p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG-6-phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT-2- and GK-containing cells.In the present work, several experimental approaches were used to determine the presence of the glucagon-like peptide-1 receptor (GLP-1R) and the biological actions of its ligand in the human brain. In situ hybridization histochemistry revealed specific labelling for GLP-1 receptor mRNA in several brain areas. In addition, GLP-1R, glucose transporter isoform (GLUT-2) and glucokinase (GK) mRNAs were identified in the same cells, especially in areas of the hypothalamus involved in feeding behaviour. GLP-1R gene expression in the human brain gave rise to a protein of 56 kDa as determined by affinity cross-linking assays. Specific binding of 125I-GLP-1(7-36) amide to the GLP-1R was detected in several brain areas and was inhibited by unlabelled GLP-1(7-36) amide, exendin-4 and exendin (9-39). A further aim of this work was to evaluate cerebral-glucose metabolism in control subjects by positron emission tomography (PET), using 2-[F-18] deoxy-D-glucose (FDG). Statistical analysis of the PET studies revealed that the administration of GLP-1(7-36) amide significantly reduced (p < 0.001) cerebral glucose metabolism in hypothalamus and brainstem. Because FDG-6-phosphate is not a substrate for subsequent metabolic reactions, the lower activity observed in these areas after peptide administration may be due to reduction of the glucose transport and/or glucose phosphorylation, which should modulate the glucose sensing process in the GLUT-2- and GK-containing cells.
Author	Alvarez, Elvira Chowen, Julie A. Roncero, Isabel Desco, Manuel Maldonado, Antonio De Cáceres, Javier Blázquez, Enrique Gispert, Juan D. Pozo, Miguel Angel Sanz, Carmen Martínez, M. Dolores García‐Cuartero, Beatriz Vázquez, Patricia
Author_xml	– sequence: 1 givenname: Elvira surname: Alvarez fullname: Alvarez, Elvira – sequence: 2 givenname: M. Dolores surname: Martínez fullname: Martínez, M. Dolores – sequence: 3 givenname: Isabel surname: Roncero fullname: Roncero, Isabel – sequence: 4 givenname: Julie A. surname: Chowen fullname: Chowen, Julie A. – sequence: 5 givenname: Beatriz surname: García‐Cuartero fullname: García‐Cuartero, Beatriz – sequence: 6 givenname: Juan D. surname: Gispert fullname: Gispert, Juan D. – sequence: 7 givenname: Carmen surname: Sanz fullname: Sanz, Carmen – sequence: 8 givenname: Patricia surname: Vázquez fullname: Vázquez, Patricia – sequence: 9 givenname: Antonio surname: Maldonado fullname: Maldonado, Antonio – sequence: 10 givenname: Javier surname: De Cáceres fullname: De Cáceres, Javier – sequence: 11 givenname: Manuel surname: Desco fullname: Desco, Manuel – sequence: 12 givenname: Miguel Angel surname: Pozo fullname: Pozo, Miguel Angel – sequence: 13 givenname: Enrique surname: Blázquez fullname: Blázquez, Enrique
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Keywords	Human Phosphates Statistical analysis Enzyme Transferases GLP-1 receptor Central nervous system Glucose Hypothalamus Gene expression Metabolism Statistical study Protein biological effects Encephalon human brain Glucokinase GLUT-1 glucose transporter glucagon-like peptide-1 receptor glucose sensing Positron Emission tomography
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Snippet	In the present work, several experimental approaches were used to determine the presence of the glucagon‐like peptide‐1 receptor (GLP‐1R) and the biological... In the present work, several experimental approaches were used to determine the presence of the glucagon-like peptide-1 receptor (GLP-1R) and the biological...
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SubjectTerms	Adult Aged Aged, 80 and over Biological and medical sciences biological effects Brain Stem - metabolism Cell receptors Cell structures and functions Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Female Fundamental and applied biological sciences. Psychology gene expression Glucagon - metabolism Glucagon - physiology Glucagon-Like Peptide 1 Glucagon-Like Peptide-1 Receptor Glucose - metabolism glucose sensing human brain Humans Hypothalamus - metabolism Male Medical sciences Middle Aged Molecular and cellular biology Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine) Neurology Peptide Fragments - metabolism Peptide Fragments - physiology Protein Binding - physiology Protein Precursors - metabolism Protein Precursors - physiology Receptors, Glucagon - biosynthesis Receptors, Glucagon - genetics RNA, Messenger - biosynthesis
Title	The expression of GLP‐1 receptor mRNA and protein allows the effect of GLP‐1 on glucose metabolism in the human hypothalamus and brainstem
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