The Role of Ghrelin and Ghrelin O-Acyltransferase in Obesity: Targets for Treatment
Bibliographic record
Abstract
Ghrelin is the first identified circulating orexigenic hormone.Following translation of the mRNA to its initial prepropeptide, a variety of posttranslational modifications are performed that allow the peptide to bind to its only known receptor, the growth hormone secretagogue receptor type 1A (GHSR1a).The crucial step in this process is the attachment of an acyl sidechain to the serine-3 residue, which is accomplished through the activity of the enzyme ghrelin O-acyltransferase (GOAT), ultimately leading to the final product named acylated ghrelin.Acylated ghrelin has been shown to signal through various pathways that promote certain phenotypes associated with obesity, including insulin insensitivity, adiposity, and increased feeding.More recently, ghrelin peptides lacking the acyl sidechain have also been found to have influence in various pathways.Due to these effects, the ghrelin system has become a promising target in the goal of combating the current obesity epidemic.Since its discovery, however, ghrelin has been found to be involved in other pathways important for stress, anxiety, depression, and more, making side-effects associated with ghrelin-targeting pharmaceuticals likely.In order for the development of anti-obesity agents to be successful, a detailed knowledge of the ghrelin system and its interrelationships with others is important, not only to develop compounds to target ghrelin and its counterparts but also to help minimize and foresee complications as a result of side-effects.In the current thesis we examine the machinery of the ghrelin system and seek out to identify various ways that metabolic disorders can be approached pharmacologically.We identify two novel ways to inhibit the adipogenic effect of ghrelin using anti-sense strands targeting central GOAT and the development of our own drug, CF801, which reduces circulating acylated ghrelin levels when given peripherally.Both of these approaches contribute to a reduction in weight gain independent of food intake.By inhibiting the enzyme specifically in the brain, we also identify for the first time a role of central GOAT in promoting adiposity, an effect similar to what is found in the periphery.I would like to thank Dr. Alfonso Abizaid, my supervisor at Carleton University, who guided me throughout my graduate degree and acted as an excellent mentor.He provided support and encouragement both in the lab and outside the lab.I would have not been able to finish my degree
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".