Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction
Abstract Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene are linked to Fragile X Syndrome, the most common monogenic cause of intellectual disability and autism. People affected with mutations in FMR1 have higher incidence of obesity, but the mechanisms are largely unknown. In t...
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| Format: | Article |
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Nature Portfolio
2023-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-39643-z |
| _version_ | 1797452832080658432 |
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| author | Rebecca E. Ruggiero-Ruff Pedro A. Villa Sarah Abu Hijleh Bryant Avalos Nicholas V. DiPatrizio Sachiko Haga-Yamanaka Djurdjica Coss |
| author_facet | Rebecca E. Ruggiero-Ruff Pedro A. Villa Sarah Abu Hijleh Bryant Avalos Nicholas V. DiPatrizio Sachiko Haga-Yamanaka Djurdjica Coss |
| author_sort | Rebecca E. Ruggiero-Ruff |
| collection | DOAJ |
| description | Abstract Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene are linked to Fragile X Syndrome, the most common monogenic cause of intellectual disability and autism. People affected with mutations in FMR1 have higher incidence of obesity, but the mechanisms are largely unknown. In the current study, we determined that male Fmr1 knockout mice (KO, Fmr1 −/y ), but not female Fmr1 −/−, exhibit increased weight when compared to wild-type controls, similarly to humans with FMR1 mutations. No differences in food or water intake were found between groups; however, male Fmr1 −/y display lower locomotor activity, especially during their active phase. Moreover, Fmr1 −/y have olfactory dysfunction determined by buried food test, although they exhibit increased compulsive behavior, determined by marble burying test. Since olfactory brain regions communicate with hypothalamic regions that regulate food intake, including POMC neurons that also regulate locomotion, we examined POMC neuron innervation and numbers in Fmr1 −/y mice. POMC neurons express Fmrp, and POMC neurons in Fmr1 −/y have higher inhibitory GABAergic synaptic inputs. Consistent with increased inhibitory innervation, POMC neurons in the Fmr1 −/y mice exhibit lower activity, based on cFOS expression. Notably, Fmr1 −/y mice have fewer POMC neurons than controls, specifically in the rostral arcuate nucleus, which could contribute to decreased locomotion and increased body weight. These results suggest a role for Fmr1 in the regulation of POMC neuron function and the etiology of Fmr1-linked obesity. |
| first_indexed | 2024-03-09T15:14:22Z |
| format | Article |
| id | doaj.art-249cd518923b4245bcbd2d5cdee90de4 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:14:22Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-249cd518923b4245bcbd2d5cdee90de42023-11-26T13:10:01ZengNature PortfolioScientific Reports2045-23222023-08-0113111310.1038/s41598-023-39643-zIncreased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunctionRebecca E. Ruggiero-Ruff0Pedro A. Villa1Sarah Abu Hijleh2Bryant Avalos3Nicholas V. DiPatrizio4Sachiko Haga-Yamanaka5Djurdjica Coss6Division of Biomedical Sciences, School of Medicine, University of California, RiversideDivision of Biomedical Sciences, School of Medicine, University of California, RiversideDivision of Biomedical Sciences, School of Medicine, University of California, RiversideDivision of Biomedical Sciences, School of Medicine, University of California, RiversideDivision of Biomedical Sciences, School of Medicine, University of California, RiversideDepartment of Molecular, Cell, and Systems Biology, College of Natural and Agricultural Sciences, University of California, RiversideDivision of Biomedical Sciences, School of Medicine, University of California, RiversideAbstract Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene are linked to Fragile X Syndrome, the most common monogenic cause of intellectual disability and autism. People affected with mutations in FMR1 have higher incidence of obesity, but the mechanisms are largely unknown. In the current study, we determined that male Fmr1 knockout mice (KO, Fmr1 −/y ), but not female Fmr1 −/−, exhibit increased weight when compared to wild-type controls, similarly to humans with FMR1 mutations. No differences in food or water intake were found between groups; however, male Fmr1 −/y display lower locomotor activity, especially during their active phase. Moreover, Fmr1 −/y have olfactory dysfunction determined by buried food test, although they exhibit increased compulsive behavior, determined by marble burying test. Since olfactory brain regions communicate with hypothalamic regions that regulate food intake, including POMC neurons that also regulate locomotion, we examined POMC neuron innervation and numbers in Fmr1 −/y mice. POMC neurons express Fmrp, and POMC neurons in Fmr1 −/y have higher inhibitory GABAergic synaptic inputs. Consistent with increased inhibitory innervation, POMC neurons in the Fmr1 −/y mice exhibit lower activity, based on cFOS expression. Notably, Fmr1 −/y mice have fewer POMC neurons than controls, specifically in the rostral arcuate nucleus, which could contribute to decreased locomotion and increased body weight. These results suggest a role for Fmr1 in the regulation of POMC neuron function and the etiology of Fmr1-linked obesity.https://doi.org/10.1038/s41598-023-39643-z |
| spellingShingle | Rebecca E. Ruggiero-Ruff Pedro A. Villa Sarah Abu Hijleh Bryant Avalos Nicholas V. DiPatrizio Sachiko Haga-Yamanaka Djurdjica Coss Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction Scientific Reports |
| title | Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction |
| title_full | Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction |
| title_fullStr | Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction |
| title_full_unstemmed | Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction |
| title_short | Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction |
| title_sort | increased body weight in mice with fragile x messenger ribonucleoprotein 1 fmr1 gene mutation is associated with hypothalamic dysfunction |
| url | https://doi.org/10.1038/s41598-023-39643-z |
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