Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction

Ruggiero-Ruff, Rebecca E.; Villa, Pedro A.; Hijleh, Sarah Abu; Avalos, Bryant; DiPatrizio, Nicholas V.; Haga-Yamanaka, Sachiko; Coss, Djurdjica

doi:10.1038/s41598-023-39643-z

Cited by 4 publications

(1 citation statement)

References 83 publications

(91 reference statements)

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“…The hypothalamus produces hormones involved in the regulation of body temperature, heart rate, blood pressure, appetite, mood, sleep, muscle and bone growth as well as the release of hormones from other glands. Increased body weight in Fmr1 KO mice is associated with hypothalamic dysfunction with higher inhibitory GABAergic synaptic inputs in pro-opiomelanocortin (POMC) neurons [ 82 ]. There is a regulatory nexus involving microtubule-associated protein 1B (MAP1B), FMRP and agouti-related peptide (AgRP) in hypothalamic cells that is linked with food intake and body weight [ 83 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice

Westmark,

Lyon,

Gutierrez

et al. 2024

Nutrients

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Obesity is a pediatric epidemic that is more prevalent in children with developmental disabilities. We hypothesize that soy protein-based diets increase weight gain and alter neurobehavioral outcomes. Our objective herein was to test matched casein- and soy protein-based purified ingredient diets in a mouse model of fragile X syndrome, Fmr1KO mice. The experimental methods included assessment of growth; 24-7 activity levels; motor coordination; learning and memory; blood-based amino acid, phytoestrogen and glucose levels; and organ weights. The primary outcome measure was body weight. We find increased body weight in male Fmr1KO from postnatal day 6 (P6) to P224, male wild type (WT) from P32–P39, female Fmr1KO from P6–P18 and P168–P224, and female Fmr1HET from P9–P18 as a function of soy. Activity at the beginning of the light and dark cycles increased in female Fmr1HET and Fmr1KO mice fed soy. We did not find significant differences in rotarod or passive avoidance behavior as a function of genotype or diet. Several blood-based amino acids and phytoestrogens were significantly altered in response to soy. Liver weight was increased in WT and adipose tissue in Fmr1KO mice fed soy. Activity levels at the beginning of the light cycle and testes weight were greater in Fmr1KO versus WT males irrespective of diet. DEXA analysis at 8-months-old indicated increased fat mass and total body area in Fmr1KO females and lean mass and bone mineral density in Fmr1KO males fed soy. Overall, dietary consumption of soy protein isolate by C57BL/6J mice caused increased growth, which could be attributed to increased lean mass in males and fat mass in females. There were sex-specific differences with more pronounced effects in Fmr1KO versus WT and in males versus females.

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Section: Discussionmentioning

confidence: 99%

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice

Westmark,

Lyon,

Gutierrez

et al. 2024

Nutrients

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From wings to whiskers to stem cells: why every model matters in fragile X syndrome research

Sandoval,

Méndez-Albelo,

et al. 2024

J Neurodevelop Disord

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Fragile X syndrome (FXS) is caused by epigenetic silencing of the X-linked fragile X messenger ribonucleoprotein 1 (FMR1) gene located on chromosome Xq27.3, which leads to the loss of its protein product, fragile X messenger ribonucleoprotein (FMRP). It is the most prevalent inherited form of intellectual disability and the highest single genetic cause of autism. Since the discovery of the genetic basis of FXS, extensive studies using animal models and human pluripotent stem cells have unveiled the functions of FMRP and mechanisms underlying FXS. However, clinical trials have not yielded successful treatment. Here we review what we have learned from commonly used models for FXS, potential limitations of these models, and recommendations for future steps.

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Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice

Villa,

Ruggiero-Ruff,

Jamieson

et al. 2024

J. Neurosci.

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Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, that mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with POMC neurons, which regulate satiety and are affected by obesity, we examined their crosstalk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism.Significance StatementObesity presents a significant health concern, with multiple comorbidities, including impaired reproduction. However, mechanisms are not clear, and studies are confounded by the chronic nature of this condition that leads to synaptic changes and alterations in neuron responsiveness to stimuli. Here, we demonstrate that the interaction between feeding circuitry and reproductive circuitry is altered by chronic obesity. The reason may be that chronically higher activity of POMC neurons in response to higher leptin in obesity, downregulates αMSH receptors on target neurons, including kisspeptin. This may lead to the suppression of kisspeptin neurons, and their inability to regulate pulsatile secretion of GnRH, which then lowers LH pulse frequency, leading to lower LH in the circulation, lower testosterone, and lower sperm count.

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Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction

Cited by 4 publications

References 83 publications

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice

Effects of Soy Protein Isolate on Fragile X Phenotypes in Mice

From wings to whiskers to stem cells: why every model matters in fragile X syndrome research

Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice

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