Evidence for Possible Period 2 Gene Mediation of the Effects of Alcohol Exposure During the Postnatal Period on Genes Associated with Maintaining Metabolic Signaling in the Mouse Hypothalamus

Abstract

Background Animals exposed to alcohol during the developmental period develop circadian disturbances and metabolic problems that often persist during their adult period. In order to study whether alcohol and the circadian clock interact to alter metabolic signaling in the hypothalamus, we determined whether postnatal alcohol feeding in mice permanently alters metabolic sensing in the hypothalamus. Furthermore, we evaluated whether the effect of circadian disruption via Period2 (Per2) gene mutation prevents alcohol’s effects on metabolic signaling in the hypothalamus. Methods Per2 mutant and wild type male and female mice of the same genetic background were given a milk formula containing ethanol (11.34%; vol/vol) from postnatal day (PD)2–7 and used for gene expression and peptide level determinations in the hypothalamus at PD7 and PD90. Results We report here that postnatal alcohol feeding reduces the expression of proopiomelanocortin (POMC) gene and production of β-endorphin and α-melanocyte stimulating hormone (α-MSH) in the hypothalamus that persists into adulthood. In addition, expressions of metabolic sensing genes in the hypothalamus were also reduced as a consequence of postnatal alcohol exposure. These effects of were not sex-specific and were observed in both males and females. Mice carrying a mutation of the Per2 gene did not show any reductions in hypothalamic levels of POMC and metabolic genes and β-endorphin and α-MSH peptides following alcohol exposure. Conclusions These data suggest that early life exposure to alcohol alters metabolic sensing to the hypothalamus possibly via regulating Per2 gene and/or the cellular circadian clock mechanism.

Alcohol disrupts sleep homeostasis

“…In fact, there is strong and convincing evidence suggesting that alcohol has a profound interaction with circadian rhythms (Agapito, Barreira, Logan, & Sarkar, 2013; Brager, Ruby, Prosser, & Glass, 2011; Chen, Kuhn, Advis, & Sarkar, 2006; Frank et al, 2013; Lindsay, Glass, Amicarelli, & Prosser, 2014; Logan, Williams, & McClung, 2014; Partonen, 2012; Perreau-Lenz & Spanagel, 2008; Prosser, Mangrum, & Glass, 2008; Rosenwasser, 2010; Ruby, Prosser, & Glass, 2006; Seggio, Logan, & Rosenwasser, 2007; Spanagel, Rosenwasser, Schumann, & Sarkar, 2005). We suggest that alcohol may have minimal impact on the circadian regulation of sleep and a more predominant effect on the homeostatic regulation of sleep.…”

MicroRNAs and Ethanol Toxicity

“…Indeed, in the liver, alcohol exposure in a high-fat diet did result in increased nuclear accumulation of Sirt1 (Nascimento, Ip, Luvizotto, Seitz, & Wang, 2013), and Sirt1 mRNA transcripts were also found to be induced in the dorsal hippocampus in peri-pubertal mice following chronic alcohol exposure (Prins et al, 2014). However, in the alcoholic liver model, deacetylase activity was actually reduced (Nascimento et al, 2013) and others have shown that early postnatal alcohol exposure to alcohol results in prolonged suppression of Sirt1 mRNA transcripts in the hypothalamus (Agapito, Barreira, Logan, & Sarkar, 2013). These data collectively show that epigenetic regulators like Sirt1 may be subject to multiple regulatory controls aside from miRNAs and that ethanol regulation of miRNAs may not yield predictable outcomes, even for known direct miRNA targets.…”

Clock genes × stress × reward interactions in alcohol and substance use disorders

“…During the preceding decade, a new family of genes has emerged as a major player in the addiction field: the so-called clock genes (Agapito, Barreira, Logan, & Sarkar, 2013; Agapito, Mian, Boyadjieva, & Sarkar, 2010; Falcón & McClung, 2009; Logan, Williams, & McClung, 2014; McCarthy, Fernandes, Kranzler, Covault, & Welsh, 2013; McClung, 2007; Perreau-Lenz & Spanagel, 2008; Rosenwasser, 2010). Clock genes, such as Period genes ( Per1-Per3 ), Cryptochrome genes ( Cry 1–2 ), Circadian Locomotor Cycle Kaput - ( Clock ), Brain and Muscle ARNT-like protein 1 ( Arntl1 ), Neuronal PAS domain protein 2 (NPAS2 ), or D-box-binding protein (Dbp) genes are molecular components of the circadian clockwork.…”