Hypothalamic mechanisms of appetite regulation involve stress response and epigenetic modification
| dc.contributor.author | Cao, Chang | en |
| dc.contributor.committeechair | Cline, Mark A. | en |
| dc.contributor.committeemember | Jarome, Timothy J. | en |
| dc.contributor.committeemember | Siegel, Paul B. | en |
| dc.contributor.committeemember | Olsen, Michelle Lynne | en |
| dc.contributor.committeemember | Gilbert, Elizabeth R. | en |
| dc.contributor.department | Animal and Poultry Sciences | en |
| dc.date.accessioned | 2022-11-26T07:00:12Z | en |
| dc.date.available | 2022-11-26T07:00:12Z | en |
| dc.date.issued | 2021-06-03 | en |
| dc.description.abstract | Appetite regulation is primarily mediated by the hypothalamus, within which many neurotransmitters that regulate feeding are shared by the stress response circuitry. Stressors, especially those occur during critical periods of life, influence epigenetic programming and gene expression in the long-term. Therefore, the aim of this dissertation was to elucidate how hypothalamic mechanisms of appetite regulation correlate with the stress response and epigenetic modifications, using avian models and intracerebroventricular administration of various appetite-regulating factors. We first administered two methylation modifiers, S-adenosylmethionine (SAM), a methyl donor, and 5-azacytidine (AZA), a methylation inhibitor, to determine their effects on appetite. When measuring food intake immediately post-injection, SAM didn't affect fed or fasted chickens from a line selected for low bodyweight (LWS, individuals with anorexia), but suppressed feeding in fed and fasted broilers. In Japanese quail, SAM transiently induced satiety in fed but not fasted chicks. Intriguingly, AZA increased feeding in fasted LWS but decreased it in fed chicks. While it didn't affect either fed or fasted broilers, AZA induced satiety in both fed and fasted quail. These results suggests that SAM/AZA can directly affect appetite depending on genetics and nutritional state. The LWS chickens, when injected with SAM or AZA on day of hatch, didn't show increased feeding to the orexigenic stimulation of neuropeptide Y central injection on day 5 post-hatch. This suggests that epigenetic modifications occurred following SAM/AZA injection and affect appetite regulation that persisted. In other studies, we injected broilers with prostaglandin E2 (PGE2) or β-melanocyte-stimulating hormone (β-MSH) since their effects on appetite are unknown in meat-type chicks. We found that they both potently induced satiety, but the effective duration was longer in β-MSH-injected birds (up to 9 hours) than in PGE2-injected chicks (lasted for 1.5 hours). They both activated the paraventricular nucleus of the hypothalamus. The satiety induced by β-MSH mainly involved corticotropin-releasing factor and mesotocin, while the effect of PGE2 included ghrelin and brain-derived neurotropic factor. Nevertheless, all affected appetite-related factors have connections with the stress response. Thus, our results demonstrate that the hypothalamic mechanisms underlying anorexia induced by different neuroactive molecules involve the stress response and epigenetic modifications. | en |
| dc.description.abstractgeneral | Eating disorders (EDs) all involve abnormal eating behaviors and altered body weight. These aberrant conditions are associated with a change in metabolism and pose great risk to human health and animal production, and are generally characterized by two opposite outcomes, anorexia and obesity. Although affected by multiple systems within the body, appetite regulation is mainly controlled by the brain, especially the hypothalamus. Thus, it is important to understand the hypothalamic mechanisms underlying the regulation of eating behavior. In the hypothalamus, many neurotransmitters affect multiple pathways, including the stress response and those that regulate appetite. Additionally, stress, especially when occurring during early life, can influence behaviors later in life through inducing epigenetic modifications (changes to the packaging of the DNA nucleotide sequence) that alter gene expression. Therefore, the aim of this dissertation was to elucidate how hypothalamic mechanisms of appetite regulation correlate with the stress response and epigenetic modifications, using avian models. To focus on the effects within the brain, we directly injected various appetite regulating factors into the brain in each of the experiments. Previously, our group demonstrated that early-life cold exposure and delayed food supply changed DNA methylation and affected expression of appetite-related genes and food intake in a chicken line predisposed to anorexia. We herein injected chicks with one of two methylation modifiers, S-adenosylmethionine (SAM), a methyl donor, and 5-azacytidine (AZA), a methylation inhibitor, to evaluate their effects on feeding behavior. When food intake was measured immediately after injection, SAM did not affect food intake in either fed or fasted line chickens from a genetic line selected for low body weight (LWS, individuals with anorexia), but suppressed food intake in both fed and fasted broiler (meat-type chickens) chicks. In Japanese quail, however, SAM only transiently induced satiety in fed chicks but not in fasted ones. Intriguingly, AZA increased food intake in fasted LWS chicks but decreased it in fed chicks, but AZA had no effects on food consumption in either fed or fasted broilers. Additionally, AZA suppressed food intake in both fed and fasted quail. These results suggest that SAM and AZA affect appetite differently depending on genetic background and nutritional states. LWS chickens, when injected with SAM or AZA on day of hatch, did not eat more after being injected with the potent hunger factor, neuropeptide Y, at 5 days of age. This indicates that epigenetic modifications occurred following SAM/AZA injection and had persisting effects on appetite regulation. In the other two studies, we injected broiler chicks with prostaglandin E2 (PGE2), a fatty acid-based molecule, or β-melanocyte-stimulating hormone (β-MSH), a peptide. These two molecules have been reported to regulate feeding behavior in rodents and layer-type chickens, but effects are unknown in broilers. They both potently decreased food intake in broilers, but the effective duration was much longer in β-MSH-injected birds (up to 9 hours) than in PGE2-injected chicks (lasted for 1.5 hours). They both activated the paraventricular nucleus of the hypothalamus, while β-MSH also activated the arcuate nucleus and ventromedial nucleus. We further found that the anorexia induced by β-MSH involved corticotropin-releasing factor, mesotocin, and their receptors, while the effect of PGE2 was associated with a change in ghrelin and brain-derived neurotropic factor gene expression. Nevertheless, all of these affected factors have connections with the stress response. Thus, results indicate that the hypothalamic mechanisms underlying anorexia induced by different neuroactive molecules involve the stress response and epigenetic modifications. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:31347 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/112697 | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | Appetite | en |
| dc.subject | Hypothalamus | en |
| dc.subject | Stress | en |
| dc.subject | DNA methylation | en |
| dc.subject | birds | en |
| dc.title | Hypothalamic mechanisms of appetite regulation involve stress response and epigenetic modification | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Animal and Poultry Sciences | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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