Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction
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 curren...
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Published in | Scientific reports Vol. 13; no. 1; p. 12666 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Nature Publishing Group
04.08.2023
Nature Publishing Group UK Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | 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
), 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
display lower locomotor activity, especially during their active phase. Moreover, Fmr1
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
mice. POMC neurons express Fmrp, and POMC neurons in Fmr1
have higher inhibitory GABAergic synaptic inputs. Consistent with increased inhibitory innervation, POMC neurons in the Fmr1
mice exhibit lower activity, based on cFOS expression. Notably, Fmr1
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-023-39643-z |