Chewing the Fat… on Fat

As the Spanish summer finally makes an appearance after a rather rainy spring, and "Operation Bikini" (the yearly rush to get into shape for bikini season) gets into full swing, it seems fitting that a number of advances in obesity research have been making headlines lately.

From the definitive battle between the weight-loss giants Wegovy and Zepbound, to a metabolic miracle protein called Mitch and a fibre-filled friend that works with bacteria to flip the fat-burning switch, things are looking up for the future of weight loss.

The Battle of the GLP-1 Giants

By now I doubt there’s a person alive that hasn’t heard of Ozempic and Mounjaro, the diabetes treatments rebranded as the wonder-weight loss drugs Wegovy and Zepbound, that have taken the world by storm while making a pretty penny for their investors.

The active ingredients, semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound) are both so-called glucagon-like peptide-1 (GLP-1) receptor agonists. They work by binding to the same receptors in the body as the natural GLP-1 hormone and mimicking its effects, which are basically to lower blood sugar levels, slow stomach emptying and reduce appetite.

Semaglutide was approved for use as the weight-loss drug Wegovy in 2021, giving it a bit of a head-start over tirzepatide, which was only approved as Zepbound in 2023. But since then, the battle for supremacy has been on, a battle which may just have been settled by a recent publication comparing the two directly in a phase 3b clinical trial.

Participants in the trial, 751 adults with obesity but without type 2 diabetes, were injected with the maximum tolerated dose of either tirzepatide or semaglutide once a week for 72 weeks. And at the end of the 72 weeks, the winner was… tirzepatide, with participants achieving an average weight loss of 20.2% compared to an average of 13.7% by the semaglutide crowd.

According to the trial's principal investigator,The better performance of tyrzepatide is probably due to its dual mechanism of action. In addition to acting as a GLP-1 receptor agonist, it also activates a second receptor, the glucose-dependent insulinotropic peptide (GIP) receptor, which is also involved in insulin secretion and the digestive process.

Although it is the first time the two have been compared directly in a controlled clinical setting, the results are not that surprising, as they support the results of prior clinical trials on each drug separately, as well as real-world evidence gathered to date.

Fibre-Fuelled Fat-Burning

Meanwhile, in Japan, a team of researchers have found a different way to increase fat burning without losing muscle mass, one of the major challenges still facing GLP-1 therapies. Rather than focussing on the metabolism or food intake of the patient (like most weight-loss strategies do) they took a novel approach – limiting nutrient availability by regulating the gut microbiota.

The importance of gut bacteria in overall health is by now well-established, particularly in the onset and progression of obesity and obesity-related diseases like Type 2 Diabetes. Gut bacteria work in synergy with the host (that’s us), harvesting nutrients and energy from the food we eat – a delicate balance that is disturbed in people with obesity.

The Japanese team added another ingredient to the formula – acetylated cellulose (AceCel) – to the equation, which when combined with a specific class of gut bacteria called Bacteroides, was shown to remove excess sugars from the gut and trigger the body to burn more fat.

AceCel was inspired by the natural compound acetate, which is produced in the large intestine by the fermentation of dietary fibre and upregulates the host metabolism when released into the bloodstream. With modern diets often lacking in fibre, the team wanted to get acetate to where it was needed without relying on diet, so they combined acetate with cellulose to create the supplement AceCel.

When they tested AceCel on mice, it promoted weight loss without loss of muscle mass, shifting the mice’s metabolism toward burning fat rather than carbohydrates even when the mice were resting. What is interesting, though, is that AceCel only worked in the presence of the Bacteriodes bacteria, demonstrating their synergic action.

Further investigation revealed that the Bacteriodes-AceCel combination was promoting increased carbohydrate fermentation in the gut, reducing the availability of sugar for fuel and forcing the body to turn to fat as an alternative. In effect, AceCel mimics the effects of exercise, a ketogenic diet or long-term fasting on metabolism, without any of the hard work.

Switching off Mitch

Then there is mitochondrial carrier homolog 2 (MTCH2), or Mitch to his friends, a big-boss protein in muscle cells that regulates everything from apoptosis (cell death) to mitochondrial dynamics and metabolism.

Prior research had already shown that deleting the Mitch gene in mice turned them into super-athletes, triggering the development of muscle fibres, improving their endurance and accelerating their metabolisms, making them basically immune to obesity.

Now the same team has taken their research one step further, demonstrating that silencing the expression of Mitch increases the rate of fat and carbohydrate burning in humans too, as well as actually inhibiting the development of new fat cells.

The key to these metabolic changes is the effect of Mitch on the mitochondria in cells. Left to their own devices, mitochondria form extensive fused networks in the cells to improve the efficiency of energy production. What Mitch does is to break down these large networks, so that the mitochondria all have to work as separate and less efficient energy generators.

While this may seem counterintuitive, if your goal is weight loss, reducing energy efficiency is actually a good thing, as it forces your body to increase its fuel consumption and find other ways to increase energy production. Since fat is a more efficient fuel source than glucose, this drive to increase energy production pushes your body into a fat-burning state. Go Mitch!

Looking Closer to Home

All of this is pretty interesting, but while we’re on the subject of promising advances in obesity treatments, let’s not forget the French company EKTAH, who successfully closed a funding round with Capital Cell in December last year, to advance their obesity treatment.

EKTAH’s receptor agonists upregulate and reactivate the tongue fat receptors that become dysregulated in obese people, affecting both appetite and taste. Not only that, but their main drug candidate triggers the release of three natural gut peptides (including GLP-1) at higher levels than existing GLP-1 receptor agonists, and has been shown to reduce food intake by up to 40% in obese mice with no side-effects and while maintaining muscle mass.

Basically, it’s Wegovy and Zepbound on steroids, minus the negative side effects, so if anything has the potential to finally kick obesity to the curb, my money is (quite literally) on EKTAH.