THU125 Altered Pro-opiomelanocortin (POMC) Neuron Function Characterizes Energy Expenditure Dysfunction And Increased Body Weight Linked To Fragile X Gene Mutation

Disclosure: R.E. Ruggiero-Ruff: None. P. Villa: None. S. Abu Hijleh: None. B. Avalos: None. N. DiPatrizio: None. D. Coss: None. Obesity is a world-wide epidemic that has become a major public health concern. Obesity increases the risk of cardiovascular disease, type 2 diabetes, stroke, and dementia. Children and adolescents with Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, have higher rates of obesity compared to peers. FXS is caused by a mutation of the Fragile X messenger ribonucleoprotein gene (FMR1), which leads to the loss of FMRP, a ubiquitously expressed mRNA binding protein. Food intake and energy expenditure are regulated by orexigenic neuropeptide Y (NPY)/agouti-related protein (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neurons from the hypothalamus. While our understanding of mechanisms of intellectual disability in FXS patients is beginning to emerge, the role of FMR1 gene in the hypothalamus is unknown. In this study, we used a knock-out (KO) mouse model to analyze if obesity in FXS patients stems from dysregulation of the hypothalamic circuitry regulating food intake and energy expenditure. Consistent with what is seen in the human population, KO males weigh more than their WT littermates. There were no differences in growth hormone or basal or fasting glucose levels. There was no difference in food intake, however KO males exhibited lower locomotor activity in the dark cycle, during their active phase. Since POMC neurons regulate energy expenditure in addition to food intake, we analyzed POMC neuron number, using immunohistochemistry. We determined fewer POMC neurons in KO male mice compared to WT. AgRP/NPY neurons modulate POMC neurons through GABAergic neuronal transmission. We determined that KO males have increased obligatory GABAa receptor subunit on POMC neurons. We also analyzed GABAa receptor and vesicular GABA transporter (VGAT) apposition on POMC neurons to identify synaptic receptors and indeed, KO males had significantly higher levels of GABAa-VGAT appositions, indicating increased synaptic input. In summary, our results suggest a role for FMR1 in the regulation of POMC neuronal activity in the regulation of locomotor activity and point to a role in modulating motor activity and energy expenditure in obese Fragile X patients. Presentation: Thursday, June 15, 2023