The Brain: The Key to Our Fight Against Obesity

According to the World Health Organisation (2016), around 650 million adults were considered obese. Meanwhile, the World Obesity Federation estimates that in 2020, around 770 million adults globally were affected by obesity, and that figure is expected to be more than one billion by 2030 – if nothing is done about it.

For adults, WHO, defines obesity as a BMI greater than or equal to 30. This is a complex condition that has only been recently acknowledged globally as a disease. The root causes of obesity have been debated for years, with factors ranging from genetics to lifestyle choices and an evolving food supply laden with carbohydrates and ultra-processed foods. Traditional solutions often focused on self-discipline and a simplistic "eat less, move more" approach, yielding disheartening results.

These traditional solutions are rooted in the fundamental cause of obesity --  an energy imbalance between calories consumed and calories expended. 

Is long-term management of obesity easy?

There are individuals who did manage to shed weight through various means. However, long-term maintenance of weight loss is another matter. Usual obesity interventions result in early rapid weight loss, then followed by a weight plateau – and eventually, progressive weight regain.

A study showed that weight regain is typical. A meta-analysis of long-term weight loss studies indicated that more than 50% of the lost weight was regained within two years. By five years more than 80% of lost weight was regained.

Focusing on the brain

A ray of hope now emerges with medications, including GLP1-RAs, affecting reward and appetite centers and deep brain stimulation targeting neural circuits.

Many experts believe that a crucial organ has been overlooked in the fight against obesity — the brain. Experts believe that obesity is most likely a disorder of the brain, thus the need for interventions that not only focus on willpower. 

Our brain, the “machine”, constantly processes signals from the gut, hormones, and the environment, regulating hunger, satiety, and energy balance. It is the hypothalamus that regulates energy intake and expenditure to maintain weight, but its normal function can be disrupted by biological and environmental factors.

Studies suggest that in individuals with obesity, this intricate machine may malfunctioning. Research posits a deficiency in receptors for dopamine makes these individuals overeat to compensate for pleasure they lack. 

In one study, researchers from Yale infused glucose or fat directly into the stomachs of 28 people which they identified as “lean” (BMI of 25 or less), and into stomachs of 30 people with obesity (BMI of 30 or higher). Their brain activity was then assessed though functional magnetic resonance imaging (fMRI).

After the infusion of glucose and fat, the researchers found evidence of reduced activity across various regions of the brain among lean participants. Yet, there was no change in activity among participants with obesity.

Leptin and Ghrelin: Our hunger hormones

There are also hormones that act on the brain to maintain longer-term weight stability. These are Leptin and Ghrelin, our body’s hunger hormones. Leptin decreases your appetite, while Ghrelin increases it.

Leptin is your body’s "fullness signal”. This hormone is released by our adipose tissue (body fat) and regulates hunger by telling our brain when to stop eating, providing the sensation of feeling full. Leptin regulates your energy balance, so you don’t get a hunger response when your body doesn’t need energy.

Ghrelin, the "hunger hormone", is a hormone produced by the stomach. It acts like a hunger alert system. When your stomach is empty or mostly empty, it releases Ghrelin. Normally, Ghrelin levels are highest right before mealtimes – this causes you to feel hungry and that is when we seek out food. The levels of Ghrelin in your body tend to increase and decrease, depending on how much you eat. So if you are restricting your food intake – as is the case when you are on a calorie-restricted diet – your Ghrelin levels go up. And when your Ghrelin levels go up, you will feel hungrier. 

People with obesity often have low Ghrelin levels. Some researchers believe that this is because people who have obesity are naturally more sensitive to Ghrelin, which is why they feel much hungrier – due to the lower Ghrelin levels.

What ‘breaks’ the brain?

Genes

Genetics play a role in obesity, with certain gene combinations influencing an individual's risk. A study found that there are at least 10 different genes that cause obesity. Most of these genes are involved in the leptin-melanocortin signaling pathway.

For example, mutations in a gene called melanocortin 4 receptor (MC4R) have been linked to obesity. MC4R influences leptin signaling. Leptin is the hormone that stimulates neural circuits that decreases food intake and increases energy expenditure. A study found that humans and rodents with mutations in the leptin gene or the leptin receptor gene are obese.

However, the rapid increase in obesity over the last 50 years cannot be solely attributed to genetic factors. We’d also need to consider changes in the food supply, marked by the rise of ultra-processed foods. These foods have been linked to overeating and weight gain.

Ultra-processed food

A study established a link between the consumption of ultra-processed food and weight gain.

The study found that individuals consuming ultra-processed foods tended to eat more and gain weight, compared to those who consumed whole foods that were unprocessed. However, the reasons behind the overconsumption remain unclear.

Ultra-processed foods are those that have ingredients predominantly found in industrial food manufacturing, including hydrogenated oils, high-fructose corn syrup, flavoring agents and emulsifiers. 

The consequences of consuming processed foods extend beyond overeating, potentially interfering with leptin’s gut-brain signaling to indicate fullness; and even reprogramming the brain to dislike healthier options. Undoing these neurological changes proves challenging, as the brain is not wired to eat these ultra-processed foods. It adapts negatively to the modern food environment, putting us at risk.

Weight loss medications

Fortunately, there are ways to influence the brain – particularly the hormones – to reduce cravings. 

Weight loss medications

There are weight loss medications that help you lose weight sustainably, helping to regulate hunger and satiety as your weight goes down. 

GLP-1 RAs such as semaglutide work, in part, by mimicking glucagon-like peptide-1 (GLP-1), a key hormone that lets your brain know you are full. They help to control blood sugar and weight in several ways:

• Increases production of the hormone that lowers blood sugar level, especially after taking food.

• Reduces production of the hormone that increases fasting sugar, optimizing fasting sugar levels.

• Slows gastric emptying and decreases appetite, which makes you eat less, feel full longer, lose weight and also slows the release of glucose from your food.

• Overhauls “hunger and craving hormones”, working on the reward centre of the brain, reducing cravings.

These medications have also shown to result in weight loss, which may in turn help to reduce the risk of diabetes complications.

A low-fat, natural, unprocessed diet

Diet high in fats and sugars can interfere with how Leptin works in the brain, making it less effective at signaling when you're full. A more natural, unprocessed diet can help fix this, while also decreasing Ghrelin levels – thereby helping curb hunger. 

Soluble Fibers

Soluble fibers boost the Leptin effect on the brain. A meta-analysis of several studies revealed that those whose meals included dietary fibers reported feeling fuller with lower Leptin levels. Fiber intake also fills the stomach and decreases Ghrelin. In a study with 30 overweight women, a fiber-rich diet increased feelings of fullness.

Protein

Increasing your protein intake can boost Leptin sensitivity and reduce Ghrelin levels making you less hungry and more satiated after meals. In a study where participants increased their protein intake from 15% to 30% while maintaining a steady carbohydrate consumption, participants saw a consistent reduced food intake which was due to heightened Leptin sensitivity. Participants then saw an average weight loss of 5 kg over two weeks.

Fat

Triglycerides, a type of fat found in your blood, can disrupt Leptin effectiveness by blocking its transport to the brain. By switching to a low-fat diet, you can help keep your Leptin levels healthier.

A study showed that when participants switched to a low-fat diet for two weeks, they saw an 18% drop in their free Leptin concentrations. The participants then lost an average of 5.2 kg body weight. More importantly, this enhanced Leptin sensitivity persisted beyond the study duration. This made losing weight easier. 

GLP-1RAs: Real-world results show sustained weight loss and better glucose control

GLP-1 RA treatment has been proven to be effective in improving blood sugar control and weight loss in the long-term.

A real-world data presented at the European Association for the Study of Diabetes (EASD) showed that semaglutide significantly improved the A1c level and body weight for up to 3 years in a large cohort of adults with type 2 diabetes.

This real-world data is significant as people act differently in real life compared to trial settings. In the real-world, some people might adhere to the prescribed treatment, while others don’t. This shows that semaglutide is still effective whether people discontinue the treatment or adhere less.

Treatment with semaglutide was associated with reductions in both A1c (-0.77%; P < .001) and body weight (-4.7 kg; P < .001) at 6 months of treatment. These reductions were maintained for up to 3 years and, in particular, in those patients with higher adherence to the therapy.

A holistic approach to weight loss

GLP-1 RAs such as semaglutide are most effective when it’s used alongside lifestyle changes, such as increased exercise and eating a healthy diet. Medication alone is not the best approach – a healthy lifestyle is also important.