TY - JOUR TI - The role of Period 2 gene in mediating alcohol effects on metabolic signals in proopiomelanocortin producing neurons DO - https://doi.org/doi:10.7282/T3JW8CGW PY - 2013 AB - An increasing body of knowledge suggests that fetal alcohol exposure disrupts circadian homeostasis and metabolic functions. In order to determine the mechanism by which fetal alcohol exposure alters the metabolic functions, we determined the postnatal ethanol-induced changes in the function of Proopiomelanocortin (Pomc) neurons known to regulate metabolic homeostasis. Additionally, we evaluated the role of a clock regulatory gene, Period 2 (Per2), in mediation of alcohol effects on Pomc neurons. To determine the interaction between alcohol and Per2 on β-endorphin neuronal activity, we first measured the secretion of this peptide from mediobasal hypothalamic (MBH) cells of postnatal mice in primary cultures following treatment with ethanol for various time periods. We found that ethanol acutely stimulated but chronically inhibited β-endorphin secretion in vitro and these effects of ethanol on β-endorphin secretion were absent following Per2 mutation. We also evaluated the effect of the clock gene mutation on postnatal alcohol programming of Pomc and metabolic genes expression in the hypothalamus. For this, We measured the levels of Pomc and various metabolic genes (Stat3, Sirt1, Asb4 and Pgc1α) and Pomc gene products β-endorphin and α-melanocyte stimulating (α-MSH) hormone in the MBH of alcohol-treated Per2 mutant and wild type mice at postnatal day 7 and 90. Postnatal ethanol exposures suppressed Pomc and metabolic genes and Pomc-derived products β-endorphin and α-MSH in the MBH for a prolonged period of time. Per2 mutation prevented these effects of postnatal ethanol on Pomc and metabolic genes. Furthermore, in order to determine the effect of Per2 gene deletion on postnatal alcohol programming of the circadian expression of metabolic genes in Pomc neurons, we created an Egfp- Pomc -Per2 mutant mice and employed these mice to determine gene expression in Laser captured isolated Pomc expressing neurons. We found that postnatal ethanol exposures permanently altered circadian expression of Pomc and metabolic genes in Pomc neurons. Per2 mutation prevented the postnatal ethanol-induced alteration of metabolic genes in Pomc neurons. Together, these data suggest that early life exposure to ethanol alters metabolic sensing in Pomc expressing neurons possibly via regulation of Per2 gene. KW - Neuroscience KW - Proopiomelanocortin KW - Fetus--Metabolism KW - Fetal alcohol syndrome LA - eng ER -