The hungry gene.
New Year, New Insights (2025 Update)
Since this article was written, the landscape of weight management and appetite regulation has seen significant advancements. Medications like Mounjaro (tirzepatide) and Ozempic (semaglutide) have emerged as groundbreaking tools for managing appetite and weight, especially for individuals with genetic predispositions like the MC4R gene variant. These medications are dual- or single-action GLP-1 receptor agonists that target appetite suppression and enhance satiety, offering hope for those struggling with weight management due to genetic and hormonal challenges.
While liraglutide was mentioned as a treatment option, the newer medications provide enhanced efficacy with once-weekly dosing and additional metabolic benefits. For more on how these treatments compare and the role of genetics in personalizing weight management, keep reading.
Ever felt hungry after you've had a full meal?
Well, it might be because your brain just hasn’t got the message. Literally. When we eat food a signal is sent back to the brain to relay this message. Our brain then tells us that we are full or satisfied and the drive to eat is reduced.
However, imagine if this didn't happen. What if you still felt hungry after you had eaten?
That's what happens to people with genetic mutations in the appetite gene. Receptors in the hypothalamus of the brain, called the melanocortin 4 receptors (MC4R), don’t get the message. They continue to feel hungry and there is a tendency to over- eat if you are not conscious of what is happening. Just knowing which variation you have allows you to overrule your basic instincts.
This gene variation means that:
- You have an increased drive to eat
- You feel less full after a meal
- Weight loss can be difficult because your response to diet and exercise is less effective.
If you are struggling with weight loss and have this gene variation, a drug called liraglutide has been shown to have good results because it helps with appetite suppression. Liraglutide can sometimes be prescribed on the NHS.
It is, however, a difficult gene to manage because there are no easy fixes and the sensation of hunger is a strong natural driver.
That said, there are plenty of things you can do to help:
1. Be mindful when eating. Don’t be distracted when eating as this tends to cause you to eat more. That means stay off your device and think about the food you are eating. Savour each mouthful!
2. Try plating. Studies have shown that neater and better balanced presentation of food is perceived to taste better and reduce the feeling of hunger after eating.
3. Pause and wait for 5 minutes. When you have finished eating, pause and give your body time to get the message through to your brain that you have eaten.
4. Note the drive to snack. Be conscious that you will be more likely to snack between meals, so try avoidance measures. Grab some fresh air, chat to a friend or colleague, crack Wordle....
5. Eat lots of protein. Eat high satiety foods, non starchy vegetables, soups and foods with a high protein content. Over 20% should be protein. It doesn't have to be animal protein - plant protein powders can help to improve the feeling of fullness. Lentils, chickpeas, quinoa and tofu are all good sources.
6. Eat high amounts of soluble fibre. It is excellent for gut health - this helps to reduce firmicutes (and so reduces fermentation and the amount of energy absorbed) and improves feeling of fullness. Examples include oats, peas, beans, carrots, and psyllium husk powder.
7. Drink water. Drink lots of water pre-meal.
The MC4R gene
The MC4R gene is one of the genes recognised as having a key genetic impact on obesity and increased BMI. It can be tough if you have this gene, but understanding is the first step.
MC4R is an important receptor in the brain where it sneakily controls the amount of food we eat. It does this by directly regulating how much we eat: controlling our satiety levels by signalling when we’re full, or controlling our appetite levels when we’re hungry.
2025 Update on Treatments
Recent advances in appetite regulation have brought newer, more effective options to the forefront. Medications like tirzepatide (Mounjaro) and semaglutide (Ozempic) have shown significant success in reducing appetite and improving satiety, particularly for individuals with genetic predispositions like the MC4R TC or CC variants.
Both medications are GLP-1 receptor agonists, with tirzepatide also targeting the GIP receptor, offering a dual mechanism of action. These treatments not only reduce the drive to overeat but also improve insulin sensitivity and metabolic health. Studies have highlighted their efficacy in addressing monogenic obesity and improving outcomes for individuals with challenging genetic profiles.
Add After the Explanation of MC4R Function
The discovery of dual-action GLP-1 and GIP receptor agonists like tirzepatide represents a significant leap forward. These medications work by enhancing the brain’s satiety signals and regulating glucose metabolism, offering a promising intervention for individuals with defective appetite signalling due to MC4R or other genetic variants.
While these medications are not cures, they provide powerful tools for managing the strong hunger drive associated with genetic predispositions, allowing for more effective weight management strategies when combined with dietary and behavioural interventions.
With our DNA test you can test to see if you have the MC4R gene as well as much more!
Appetite regulation in the brain
Appetite regulation occurs in the hypothalamus of the brain. The MC4R is the receptor that acts as the molecular ear in the brain. When it is stimulated it sends a message to shut down eating. However, if it is partially or fully defective then this message is not sent and over-eating occurs. That's why it is commonly referred to as the “death by buffet" gene.
It is also found in our nervous system where it influences energy balance i.e. how well you burn calories.
There are several MC4R variants:
- TT: normal
- TC: 22% of the population linked to increased weight, waist circumference.
- CC: 6-8% of the population linked to childhood obesity
The MC4R CC variant is found in 6-8% of the general population, so it is relatively rare, and is an example where monogenic obesity occurs and severe inheritable obese traits are seen. This is when there is complete loss of MC4R function - it is associated with early-onset severe obesity and increased appetite being triggered in childhood.
However, the MC4R TC variant is more common and occurs on average in about 22% of the general population. The variants result in the individual having both increased appetite and reduced feeling of fullness/satiety. This results in eating behaviours such as eating larger amount of foods, snacking more often, and tending to like eating fatty foods. This variant is associated with increased risk of obesity. Each copy of the variant leads to increased BMI, increased waist circumference and hyperinsulinemia (increased insulin release). Higher levels of insulin drives the body to store more energy in fat cells.
In children who have the CC variant it can cause health problems and dealing with these are complex. Working with a health professional is often required to help to deal with these challenging issues.
MC4R is not the only gene that has been identified that affects appetite. The FTO gene also plays a part and was one of the first well-studied genes in relation to weight.
Other important genes in managing weight include:
- Perilipin gene: increases or decreases the ability to add lipids to fat cells
- ADRB2 gene: increases or decreases the ability to remove lipids from fat cells
- PPARG gene: the survival gene that constantly checks for calorie excess and helps the body to store fat. Great in times of low food, but an issue when calories are in excess.
- FABP2: the hibernation / "fat absorption" gene increases fat absorption from the diet and slows down metabolism.
Summary
Although the MC4R gene may seem like an unhelpful gene, like many genes it depends on the environment. When food is scarce the drive to build up stores is higher and the motivation to find food and build those stores is also higher. When food was scarce this gene may well have helped survival.
Many of the genes that are dominant in a particular ethnicity / society and that may be problematic today can be traced back to a time in that society when they would have been beneficial. However, in the Western world with the prevalence of high calorie foods it is less helpful and the strong drive to eat can lead to being overweight. Yesterdays survival gene becomes today's obesity gene.
With regards to the MC4R gene it is challenging to manage.
Understanding hunger is the first step to controlling the urge to eat. Hacks like high protein diets and drinking water before a meal can then also help to maintain a healthy weight.
References:
1. The Melanocortin System behind the Dysfunctional Eating Behaviors
2. Neural melanocortin receptors in obesity and related metabolic disorders
3. Biased signaling at neural melanocortin receptors in regulation of energy homeostasis
Written by Rochez O’ Grady with contributions from Dr Geoff Mullan
