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Ghrelin/Lenomorelin – “Not just a Hunger Hormone”

Anyone who has tried dieting down for long periods knows; that though the calories in calories out law holds true; there is much more to the story when it comes to managing our body’s response; to a calorie deficit over a long period of time. Our body has mechanisms to sense that the level of energy intake is lower than before; and compensate by adjusting the energy expenditure, as well as prompting us to eat more; using hormones and nervous system to heighten our senses and appetite signals. It becomes increasingly difficult to maintain a caloric deficit over several months.

Diet breaks are designed to stabilize various hormones including Ghrelin which is now famous as the “Hunger Hormone”. After long bouts of dieting (calorie deficit), ghrelin is found to increase. Along with its increase, hunger pangs or cravings affect us. Early research in 2000 indicates that ghrelin provides the fuel(food/energy) status to our brain/nervous system; and regulates food intake, fat storage, body weight. Sleep, taste, smell and glucose metabolism are all affected by it! Isn’t it amazing how it links our digestive system with our nervous system?

Functions of Ghrelin

So ghrelin is famous as the “Hunger Hormone” because one of its functions is to increase appetite. However, it has a multifaceted effect in our body. Infact, there are still unanswered questions about its various functions.

Image Reference:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443295/bin/gr1.jpg

Discovery of Ghrelin followed around 30 years of research over peptide derivatives that promote the release of growth hormone[1]. In 1999, this hormone was isolated and named ghrelin – a word originating from ‘ghre’; the Proto-Indo-European root of the word ‘grow’.[2] Over the years since 1999; lot of studies are being made to further understand this hormone and its various functions in the body. Still, most of the mechanisms are not fully understood.

Ghrelin is released in the stomach, pancreas and small intestines as “des-acyl ghrelin”(DAG). In the presence of medium chain fatty acids(mainly from dietary fat/MCT) and a compound called ghrelin O-acyl-transferase (GOAT);  DAG is converted/”acylated” to “acyl ghrelin”(AG). This acyl ghrelin(AG) enters the circulation in our blood; and influences various parts of our brain like the hypothalamus and amygdala. The hypothalamus is the part of our brain responsible for our appetite; while amygdala is the part involved in reward processing. There is a memory/learning aspect of food relationships which are enhanced by ghrelin[3]. Food relationships and response is more complex than the physical sensation of hunger/satiety. For individuals suffering from anorexia nervosa the ghrelin-brain link is found to be absent or inactive. Ghrelin also stimulates the pituitary gland causing the release of the hGH/Human Growth Hormone/Somatotropin; a catabolic hormone which plays an important role for fat oxidation and building muscle. Ghrelin also controls the release for another important and well known hormone Insulin. Ghrelin has receptors in the pancreas and inhibits insulin secretion and consequently increases blood glucose levels.

Over the past decade and a half, a variety of additional functions of ghrelin have been revealed; in areas such as learning and memory, sleep times(circadian clock), stress, anxiety, depression and aging. It also has been found to have a protective role against neurodegenerative diseases such as Parkinson’s disease. Much more research is needed to really unravel the mysteries of this gut hormone.

Dietary Control over Ghrelin

The length of the fatty acid used for ghrelin acylation seems to be of importance for ghrelin’s metabolic effects. So modulation of this aspect could be useful for controlling the effect of this hormone. Interestingly, the GOAT-ghrelin system acts as a nutrient sensor informing the body of the presence of nutrients; rather than the absence. During fasting the total ghrelin levels increase due to increase in DAG; since the conversion to AG is not possible without fatty acids in the gut. A very interesting study[4] conducted on mice show that an increased level of ghrelin (either externally administered or due to a period of calorie deficit) caused a preference to high fat food. The study also found that ghrelin signalling did not seem to have an effect on the hyperphagia(excess eating); that normally follows a period of high calorie deficit in mice.

In a study[5] a group followed moderate calorie restriction(uncontrolled but advisory classes were held) as well as a moderate fat intake(30%) over a period of 6 months and then maintained weight over the next 6 months. The control group maintained weight over the whole 12 months. Ghrelin levels were found to peak for the weight loss group at the end of 6 months; over which they lost around 8.5% of body weight. Over the next 6 months ghrelin levels went back to baseline while maintaining the weight loss. So a rebound weight gain is not required to bring back ghrelin levels after caloric restriction.

Due to the role of fatty acids in the ghrelin acylation which causes a decrease in DAG(and therefore hunger), and because it can be noted that fatty acids in the gastrointestinal tract(where ghrelin is released) is mostly dietary fat, one might wonder whether high fat diets might reduce ghrelin(DAG) responses during a calorie deficit and make hunger management easier.

As a counter to this logic, there is evidence that insulin generation plays an important role in the lowering of ghrelin levels and a diet high in fat might not suppress postprandial ghrelin as much as carbohydrate and protein.

However, some studies[6] [7] show that while ghrelin levels were suppressed while the subjects were in extreme calorie deficit with a ketogenic diet, at the end of a refeeding of a regular diet, ghrelin levels increased above baseline. Some of these studies were not well controlled and lacked a control group and involved unsustainably high caloric deficits. Still, it is interesting that at the end of 8 weeks when the subjects had lost 13% of their weight via chronic calorie deficit, the ghrelin levels were actually lower than baseline. The second study showed that during the initial period of 2-3 weeks, the perceived hunger was high though ghrelin levels were low. This time frame coincides with the adaptation period required to enter ketosis. Post this phase, perceived hunger as well as ghrelin levels were low.

While more well controlled studies with sustainable moderate deficits are required to prove a lower ghrelin levels for a high fat diet vs a moderate/low fat diet with equated deficit; for people who can sustain a high fat calorie deficit diet, it may be worth a shot to help manage ghrelin-induced hunger signals during weight loss.

Another interesting study[8] measured the changes in ghrelin levels during sham feeding(a technique in which nutrients are smelled, chewed, and tasted, but not swallowed) after an overnight fast. It was found to have no significant effect on insulin/glucose levels but ghrelin levels significantly decreased though the response was not as acute as actual feeding.

Genetic factor in Obesity and its link to Ghrelin

A gene (FTO) has been associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods though the actual mechanism of it is unclear. However, a detailed study[9] shows that normal weight subjects with this gene have a different response in the brain to circulating acyl-ghrelin(which denoted the presence of nutrients in the body) than normal weight subjects without this gene. While fasting, the appetite levels were similar in the two groups. After a meal, the subjects were tested again and the subjects with this genotype were found to be more hungry with a reduced postprandial suppression of acyl-ghrelin than the control group. The same study also measured the responses in various parts of the brain as well as ghrelin levels to pictures of high/low calorie foods at fasted and fed states. A significant difference was found between the two groups in the stimulation of the brain at equated levels of ghrelin. Therefore, a genetic predisposition to obesity may also alter the person’s response to ghrelin.

Conclusion

Ghrelin is a gut hormone that affects our appetite, reward triggers, fat oxidation and also controls various other hormone release such as hGH, Insulin. It can sense the presence of nutrients in the gut and signal the brain accordingly. More studies are required to test and prove dietary interventions that can control ghrelin levels during a calorie deficit, but it is possible that a high fat diet can better manage ghrelin levels than a low fat diet during a calorie deficit. Genetic factors influencing obesity are found to be associated with an altered response to ghrelin in the brain.


[1] “Ghrelin – NCBI – NIH.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443295/. Accessed 29 Dec. 2018.

[2] “Ghrelin is a growth-hormone-releasing acylated peptide from … – NCBI.” https://www.ncbi.nlm.nih.gov/pubmed/10604470. Accessed 29 Dec. 2018.

[3] “Ghrelin: A link between memory and ingestive behavior – NCBI – NIH.” 9 Apr. 2016, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899147/. Accessed 31 Dec. 2018.

[4] “Ghrelin increases the rewarding value of high fat diet in … – NCBI – NIH.” 24 Dec. 2009, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854245/. Accessed 31 Dec. 2018.

[5] “Rise of plasma ghrelin with weight loss is not sustained … – NCBI – NIH.” https://www.ncbi.nlm.nih.gov/pubmed/17062800. Accessed 31 Dec. 2018.

[6] “Ketosis and appetite-mediating nutrients and hormones after … – NCBI.” 1 May. 2013, https://www.ncbi.nlm.nih.gov/pubmed/23632752. Accessed 31 Dec. 2018.

[7] “Timeline of changes in appetite during weight loss with a … – NCBI – NIH.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550564/. Accessed 31 Dec. 2018.

[8] “Effects of modified sham feeding on ghrelin levels in healthy … – NCBI.” https://www.ncbi.nlm.nih.gov/pubmed/15472212. Accessed 31 Dec. 2018.

[9] “A link between FTO, ghrelin, and impaired brain food-cue … – NCBI – NIH.” 15 Jul. 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726147/. Accessed 31 Dec. 2018.

Ghrelin/Lenomorelin – “Not just a Hunger Hormone”

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