Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood
Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence...
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2015
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v112_n15_pE1861_Nasif http://hdl.handle.net/20.500.12110/paper_00278424_v112_n15_pE1861_Nasif |
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paper:paper_00278424_v112_n15_pE1861_Nasif |
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dspace |
| institution |
Universidad de Buenos Aires |
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I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Hypothalamus Isl1 Melanocortin Obesity Pomc beta tubulin beta tubulin iii calbindin 1 caspase 3 corticotropin LIM homeodomain protein lim homeodomain transcription factor islet 1 melanocortin monoclonal antibody neurogenin 3 neuropeptide nPE1 protein nPE2 protein proopiomelanocortin protein tamoxifen transcription factor transcription factor Mash1 unclassified drug insulin gene enhancer binding protein Isl-1 LIM homeodomain protein proopiomelanocortin protein binding transcription factor adult adulthood animal experiment animal model Article binding affinity binding site body weight brain region cell differentiation controlled study DNA binding motif embryo embryo development enhancer region food intake gene expression gene mutation human hyperphagia hypothalamus immunocompetent cell in vitro study in vivo study lifespan mediobasal hypothalamus nerve cell nervous system development nonhuman obesity ontogeny pathophysiology priority journal protein binding reporter gene satiety transactivation transgenic zebrafish zebra fish animal cytology eating embryology female fluorescence microscopy gene expression regulation gene silencing genetics hypothalamus knockout mouse male metabolism molecular genetics nerve cell nucleotide sequence obesity physiology reverse transcription polymerase chain reaction sequence homology transgenic mouse Danio rerio Mus Vertebrata Adiposity Animals Base Sequence Cell Differentiation Eating Female Gene Expression Regulation, Developmental Gene Knockdown Techniques Hyperphagia Hypothalamus LIM-Homeodomain Proteins Male Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Molecular Sequence Data Neurons Obesity Pro-Opiomelanocortin Protein Binding Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Transcription Factors Zebrafish |
| spellingShingle |
Hypothalamus Isl1 Melanocortin Obesity Pomc beta tubulin beta tubulin iii calbindin 1 caspase 3 corticotropin LIM homeodomain protein lim homeodomain transcription factor islet 1 melanocortin monoclonal antibody neurogenin 3 neuropeptide nPE1 protein nPE2 protein proopiomelanocortin protein tamoxifen transcription factor transcription factor Mash1 unclassified drug insulin gene enhancer binding protein Isl-1 LIM homeodomain protein proopiomelanocortin protein binding transcription factor adult adulthood animal experiment animal model Article binding affinity binding site body weight brain region cell differentiation controlled study DNA binding motif embryo embryo development enhancer region food intake gene expression gene mutation human hyperphagia hypothalamus immunocompetent cell in vitro study in vivo study lifespan mediobasal hypothalamus nerve cell nervous system development nonhuman obesity ontogeny pathophysiology priority journal protein binding reporter gene satiety transactivation transgenic zebrafish zebra fish animal cytology eating embryology female fluorescence microscopy gene expression regulation gene silencing genetics hypothalamus knockout mouse male metabolism molecular genetics nerve cell nucleotide sequence obesity physiology reverse transcription polymerase chain reaction sequence homology transgenic mouse Danio rerio Mus Vertebrata Adiposity Animals Base Sequence Cell Differentiation Eating Female Gene Expression Regulation, Developmental Gene Knockdown Techniques Hyperphagia Hypothalamus LIM-Homeodomain Proteins Male Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Molecular Sequence Data Neurons Obesity Pro-Opiomelanocortin Protein Binding Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Transcription Factors Zebrafish González, Laura Elisabeth Rubinstein, Marcelo Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| topic_facet |
Hypothalamus Isl1 Melanocortin Obesity Pomc beta tubulin beta tubulin iii calbindin 1 caspase 3 corticotropin LIM homeodomain protein lim homeodomain transcription factor islet 1 melanocortin monoclonal antibody neurogenin 3 neuropeptide nPE1 protein nPE2 protein proopiomelanocortin protein tamoxifen transcription factor transcription factor Mash1 unclassified drug insulin gene enhancer binding protein Isl-1 LIM homeodomain protein proopiomelanocortin protein binding transcription factor adult adulthood animal experiment animal model Article binding affinity binding site body weight brain region cell differentiation controlled study DNA binding motif embryo embryo development enhancer region food intake gene expression gene mutation human hyperphagia hypothalamus immunocompetent cell in vitro study in vivo study lifespan mediobasal hypothalamus nerve cell nervous system development nonhuman obesity ontogeny pathophysiology priority journal protein binding reporter gene satiety transactivation transgenic zebrafish zebra fish animal cytology eating embryology female fluorescence microscopy gene expression regulation gene silencing genetics hypothalamus knockout mouse male metabolism molecular genetics nerve cell nucleotide sequence obesity physiology reverse transcription polymerase chain reaction sequence homology transgenic mouse Danio rerio Mus Vertebrata Adiposity Animals Base Sequence Cell Differentiation Eating Female Gene Expression Regulation, Developmental Gene Knockdown Techniques Hyperphagia Hypothalamus LIM-Homeodomain Proteins Male Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Molecular Sequence Data Neurons Obesity Pro-Opiomelanocortin Protein Binding Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Transcription Factors Zebrafish |
| description |
Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence from mice or humans leads to hyperphagia and severe obesity. Although the pathophysiology of hypothalamic POMC neurons is well understood, the genetic program that establishes the neuronal melanocortinergic phenotype and maintains a fully functional neuronal POMC phenotype throughout adulthood remains unknown. Here, we report that the early expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) in the developing hypothalamus promotes the terminal differentiation of melanocortinergic neurons and is essential for hypothalamic Pomc expression since its initial onset and throughout the entire lifetime. We detected ISL1 in the prospective hypothalamus just before the onset of Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 binds in vitro and in vivo to critical homeodomain binding DNAmotifs present in the neuronal Pomc enhancers nPE1 and nPE2, and mutations of these sites completely disrupt the ability of these enhancers to drive reporter gene expression to hypothalamic POMC neurons in transgenicmice and zebrafish. ISL1 is necessary for hypothalamic Pomc expression during mouse and zebrafish embryogenesis. Furthermore, conditional Isl1 inactivation from POMC neurons impairs Pomc expression, leading to hyperphagia and obesity. Our results demonstrate that ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan. © 2015, National Academy of Sciences. All rights reserved. |
| author |
González, Laura Elisabeth Rubinstein, Marcelo |
| author_facet |
González, Laura Elisabeth Rubinstein, Marcelo |
| author_sort |
González, Laura Elisabeth |
| title |
Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| title_short |
Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| title_full |
Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| title_fullStr |
Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| title_full_unstemmed |
Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| title_sort |
islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood |
| publishDate |
2015 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v112_n15_pE1861_Nasif http://hdl.handle.net/20.500.12110/paper_00278424_v112_n15_pE1861_Nasif |
| work_keys_str_mv |
AT gonzalezlauraelisabeth islet1specifiestheidentityofhypothalamicmelanocortinneuronsandiscriticalfornormalfoodintakeandadiposityinadulthood AT rubinsteinmarcelo islet1specifiestheidentityofhypothalamicmelanocortinneuronsandiscriticalfornormalfoodintakeandadiposityinadulthood |
| _version_ |
1768544767382126592 |
| spelling |
paper:paper_00278424_v112_n15_pE1861_Nasif2023-06-08T14:54:31Z Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood González, Laura Elisabeth Rubinstein, Marcelo Hypothalamus Isl1 Melanocortin Obesity Pomc beta tubulin beta tubulin iii calbindin 1 caspase 3 corticotropin LIM homeodomain protein lim homeodomain transcription factor islet 1 melanocortin monoclonal antibody neurogenin 3 neuropeptide nPE1 protein nPE2 protein proopiomelanocortin protein tamoxifen transcription factor transcription factor Mash1 unclassified drug insulin gene enhancer binding protein Isl-1 LIM homeodomain protein proopiomelanocortin protein binding transcription factor adult adulthood animal experiment animal model Article binding affinity binding site body weight brain region cell differentiation controlled study DNA binding motif embryo embryo development enhancer region food intake gene expression gene mutation human hyperphagia hypothalamus immunocompetent cell in vitro study in vivo study lifespan mediobasal hypothalamus nerve cell nervous system development nonhuman obesity ontogeny pathophysiology priority journal protein binding reporter gene satiety transactivation transgenic zebrafish zebra fish animal cytology eating embryology female fluorescence microscopy gene expression regulation gene silencing genetics hypothalamus knockout mouse male metabolism molecular genetics nerve cell nucleotide sequence obesity physiology reverse transcription polymerase chain reaction sequence homology transgenic mouse Danio rerio Mus Vertebrata Adiposity Animals Base Sequence Cell Differentiation Eating Female Gene Expression Regulation, Developmental Gene Knockdown Techniques Hyperphagia Hypothalamus LIM-Homeodomain Proteins Male Mice, Knockout Mice, Transgenic Microscopy, Fluorescence Molecular Sequence Data Neurons Obesity Pro-Opiomelanocortin Protein Binding Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Transcription Factors Zebrafish Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence from mice or humans leads to hyperphagia and severe obesity. Although the pathophysiology of hypothalamic POMC neurons is well understood, the genetic program that establishes the neuronal melanocortinergic phenotype and maintains a fully functional neuronal POMC phenotype throughout adulthood remains unknown. Here, we report that the early expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) in the developing hypothalamus promotes the terminal differentiation of melanocortinergic neurons and is essential for hypothalamic Pomc expression since its initial onset and throughout the entire lifetime. We detected ISL1 in the prospective hypothalamus just before the onset of Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 binds in vitro and in vivo to critical homeodomain binding DNAmotifs present in the neuronal Pomc enhancers nPE1 and nPE2, and mutations of these sites completely disrupt the ability of these enhancers to drive reporter gene expression to hypothalamic POMC neurons in transgenicmice and zebrafish. ISL1 is necessary for hypothalamic Pomc expression during mouse and zebrafish embryogenesis. Furthermore, conditional Isl1 inactivation from POMC neurons impairs Pomc expression, leading to hyperphagia and obesity. Our results demonstrate that ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan. © 2015, National Academy of Sciences. All rights reserved. Fil:González, L.E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rubinstein, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00278424_v112_n15_pE1861_Nasif http://hdl.handle.net/20.500.12110/paper_00278424_v112_n15_pE1861_Nasif |