Effects of ethanol on plasma ghrelin levels in the rat during early and late adolescence.

Ghrelin is an appetite-regulating peptide that is primarily secreted by endocrine cells in the stomach and is implicated in regulation of alcohol consumption and alcohol-reinforced behaviors. In the present study, adolescent Sprague-Dawley rats received intermittent ethanol (AIE) exposure by intragastric intubation (5 g/kg) or vapor inhalation, manipulations conducted between postnatal days (PD) 28-43. On the first and last day of AIE exposure, the level of intoxication was examined 1 h after ethanol gavage or upon removal from the vapor chamber. This was immediately followed by a blood draw for determination of the blood ethanol concentration (BEC) and plasma levels of acylated ghrelin (acyl-ghrelin; active). On PD29, plasma levels of acyl-ghrelin were significantly elevated in male (but not female) rats in response to acute ethanol exposure by both gastric gavage and vapor inhalation. Importantly, assessment of plasma acyl-ghrelin in response to repeated ethanol exposure revealed a complex interaction of both sex and method of AIE exposure. On PD43, vapor inhalation increased plasma acyl-ghrelin in both males and females compared to their air-control counterparts, whereas there was no change in plasma levels of acyl-ghrelin in either male or female rats in response to exposure by intragastric gavage. Assessment of plasma acyl-ghrelin following a 30-day ethanol-free period revealed AIE exposure did not produce a change in basal levels. In addition, an acute ethanol challenge in adult rats of 5 g/kg via gastric gavage had no effect on plasma ghrelin levels when assessed 1 h after initiation of exposure. Collectively, these observations suggest that acyl-ghrelin, a primary gut-brain signaling hormone, is elevated by ethanol during early adolescence independent of administration route, and in gender-dependent fashion.

Recent Advances in the Neurobiology of Altered Motivation Following Bariatric Surgery.

PURPOSE OF REVIEW: There is compelling evidence in the clinical population that long-term weight loss secondary to bariatric surgery is mitigated by the reemergence of maladaptive feeding behaviors and in some cases new onset substance abuse. RECENT FINDINGS: A review of the current literature suggests that physical restructuring of the GI tract during WLS alters secretion of feeding peptides and nutrient-sensing mechanisms that directly target the brain's endogenous reward system, the mesolimbic dopamine system. Post-surgical changes in GI physiology augment activation of the mesolimbic system. In some patients, this process may contribute to a reduced appetite for palatable food whereas in others it may support maladaptive motivated behavior for food and chemical drugs. It is concluded that future studies are required to detail the timing and duration of surgical-induced changes in GI-mesolimbic communication to more fully understand this phenomenon.

Vapor Cannabis Exposure Promotes Genetic Plasticity in the Rat Hypothalamus.

It is well established that cannabis use promotes appetite. However, how cannabis interacts with the brain's appetite center, the hypothalamus, to stimulate feeding behavior is unknown. A growing body of evidence indicates that the hypothalamic transcriptome programs energy balance. Here, we tested the hypothesis that cannabis targets alternative polyadenylation (APA) sites within hypothalamic transcripts to regulate transcriptomic function. To do this, we used a novel cannabis vapor exposure model to characterize feeding in adult male Long Evans rats and aligned this behavioral response with APA events using a Whole Transcriptome Termini Sequencing (WTTS-Seq) approach as well as functional RNA abundance measurements with real-time quantitative polymerase chain reactions. We found that vapor cannabis exposure promoted food intake in free-feeding and behaviorally sated rats, validating the appetite stimulating properties of cannabis. Our WTTS-Seq analysis mapped 59 unique cannabis-induced hypothalamic APAs that occurred primarily within exons on transcripts that regulate synaptic function, excitatory synaptic transmission, and dopamine signaling. Importantly, APA insertions regulated RNA abundance of Slc6a3, the dopamine transporter, suggesting a novel genetic link for cannabis regulation of brain monoamine function. Collectively, these novel data indicate that a single cannabis exposure rapidly targets a key RNA processing mechanism linked to brain transcriptome function.

Examining the Impact of Estrogen on Binge Feeding, Food-Motivated Behavior, and Body Weight in Female Rats.

OBJECTIVE: Binge-eating disorder is associated with diminished self-control, emotional distress, and obesity. In this context, women are nearly twice as likely to develop binge-eating disorder and depression relative to men. Here, the physiological, psychological, and endocrine parameters were characterized in female rats subjected to a binge-eating protocol. METHODS: Nonrestricted female Long Evans rats (n = 8/group) received 2-hour restricted access to a high-fat diet (HFD) (4.54 kcal/g) every day or every third day. The progression of estrous cycling, the functional relevance of estrogen signaling for binge feeding, and binge-induced changes in food motivation were measured. RESULTS: Female rats developed a binge pattern of feeding that included alternation between caloric overconsumption and compensatory voluntary restriction without impacting estrous cycling. Notably, rats that received daily HFD exposure progressively decreased binge meals. Estrogen replacement in normal cycling or ovariectomized rats mimicked the reduction in body weight in female rats that received daily HFD access. Operant responding was unaffected by binge feeding; however, estrogen augmented operant performance in HFD-exposed rats. CONCLUSIONS: Collectively, these data suggest that estrogen protects against binge-induced increases in body weight gain without affecting food motivation in female rats.

Mapping diet-induced alternative polyadenylation of hypothalamic transcripts in the obese rat.

RNA biogenesis has emerged as a powerful biological event that regulates energy homeostasis. In this context insertion of alternative polyadenylation sites (APSs) dictate the fate of newly synthesized RNA molecules and direct alternative splicing of nascent transcripts. Thus APSs serve a mechanistic function by regulating transcriptome expression and function. In this study we employed a novel RNA-Seq Next Generation Sequencing (NGS) approach that utilized the power of Whole Transcriptome Termini Site Sequencing (WTTS-Seq) to simultaneously measure APS events on multiple RNA biotypes. We used this technique to measure APS events in the hypothalamus of adult male Long Evans rats exposed to a palatable high fat diet (HFD) or chow. Rats maintained on HFD displayed typical hyperphagic feeding and ensuing body weight gain over the one-month manipulation period. Our WTTS-Seq analysis mapped approximately 89,000 unique hypothalamic APSs induced by HFD relative to chow fed controls. HFD exposure produced APSs on multiple RNA biotypes in the hypothalamus. The majority of detected APSs occur on mRNA transcripts that encode functional proteins. Notably we find APSs on micro (miRNA) and long non-coding RNAs (lncRNA), newly recognized transcription factors that regulate body weight in rodents. In addition we detect APSs on protein encoding mRNAs that control neuron projection development and synapse organization and glutamate signaling, key events hypothesized to maintain excess food intake. Importantly, quantitative real time PCR indicated that APS insertion led to increased hypothalamic expression of multiple RNA biotypes. Collectively these data highlight APS events as a novel genetic mechanism that directs hypothalamic RNA biogenesis stimulated by diet-induced obesity.