Ghrelin and Your Guilty Pleasure Food

Happiness is crossing off the last thing written in your planner; happiness is seeing a text notification from your crush; happiness is opening your In-n-Out bag, sinking your teeth into that juicy Double-Double, animal style.

Hungry yet? Winding this back down to the nitty-gritty science of your guilty pleasure food and that connection to your body’s ability to regulate food intake, we introduce ghrelin as a primary stimulant of appetite and hunger thus, feeding. By following this logic, we can assume then that there exists a communicative pathway of “reward” associated with food intake.

This is what the hormone looks like, with its initial pre-mRNA processing and splicing form in blue and ghrelin itself in green. Ghrelin is a octanoylated peptide hormone secreted predominantly from a stomach endocrine cell and is called P/D1-type cells in humans. Its unique receptor, GHSR-1A is a growth hormone secretagogue receptor type (G-Protein coupled receptor) which is catalyzed or activated by the enzyme ghrelin O-acyl transferase.

Figure: http://www.pdb.org/pdb/files/1p7x.pdb

A striking feature of understanding ghrelin’s fluctuation levels in our bodies is how the rise in plasma levels occurs just before a meal and is lowered after a meal is had, assuming a healthy body and consistent meal cycle. A metabolic/ hormonal explanation for this preprandial (pre-meal) ghrelin release can be attributed to low D-glucose concentrations (stimulating) or high D-glucose concentrations (suppressing).

Another way in which ghrelin is released is via coordination of a descending pathway from the vagus nerve that signals for food anticipation (like seeing your waiter bring your food) or the brain crying for food (like realizing that you haven’t eaten yet and NEED to eat).

Figure: https://playwithfireimprov.com/blog/

In association with the mesolimbic (reward) system in our bodies, ghrelin’s regulation of food-as-reward has indirectly been controlled by the cholinergic neruones on the laterodorsal tegmental area of the hypothalamus, that also expresses the GHSR-1A. Ghrelin presence in the hippocampus appears important in regulating our motivations and learned (cycles) of feeding behavior.

While the neuronal circuitry involved in the food reward system is a bit sophisticated and novel in fields of research, here is a simplified version: Reward processing is initiated when the VTA (ventral tegmental area) of the midbrain’s dopaminergic cell group is activated. The activations come from response to or the anticipation of natural rewards, like food or sex, or artificial rewards, like alcohol or drugs.

This is why upon consumption of food reward triggers dopamine release in the nucleus accubens (NAc) in the hypothalamus and induces feelings of satiety after a meal. The NAc shell engages projections with LHA (lateral hypothalamic area) neurons that control food intake; LHA neurons have also been proposed as important players in food intake regulation. Orexin, a neuropeptide that regulates arousal, wakefulness, and appetite, induces signals that also appear to mediate actions of ghrelin on food reward.

In connection to what we talked about last week concerning leptin, this picture in particular is a good sum-up review of how both leptin and ghrelin regulate food intake and energy homeostasis in the body via signaling to the hypothalamus.

Figure: http://www.precisionnutrition.com/leptin-ghrelin-weight-loss

What is incredibly interesting about ghrelin is though, that while studies link ghrelin signaling as crucial for food intake homeostasis, it has been found that its unique receptor, GHSR-1A is able to signal in a ghrelin-independent way! GHSR-1A is able to activate and dimerise without ghrelin binding itself, revealing its incredibly plastic nature and how adaptable this receptor is.

Now that you know more about ghrelin and its role in regulating your appetite, hopefully you have become more aware of how remarkable the GHSR-1A is! I mean, it doesn’t even need ghrelin binding to activate, what could that mean for the future, in regards to medical application?