Heart failure is a serious and growing health problem. More than 500,000 people in the Netherlands are estimated to have the condition, and that number is expected to increase in the years ahead. In people with heart failure, the heart cannot pump blood as effectively as it should. This can lead to severe shortness of breath, fatigue, and repeated trips to the hospital.

Digoxin Could Join the ‘Fantastic Four’

Standard heart failure care currently relies on a combination of four medications, commonly known as the ‘Fantastic Four.’ Cardiologists have long investigated whether digoxin could provide additional benefits as a fifth treatment.

Three UMCG studies now provide evidence supporting that possibility. The findings were published in publications including Nature Medicine and the Journal of the American Medical Association (JAMA) and were also presented at the ESC Heart Failure Congress in Barcelona.

Heart Failure Hospitalizations Fell by 25%

One of the studies included 1,000 people with heart failure who were treated at 43 centers across the Netherlands. Half received a low dose of digoxin in addition to their usual treatment for an average of three years, while the other half received a placebo.

Among those taking digoxin, deaths from cardiovascular disease and worsening heart failure were reduced (by 19%). However, that individual result did not reach statistical significance.

The researchers then combined the findings with data from two earlier studies in a meta-analysis, creating a much larger group of patients. With the additional data, they found that digoxin produced a meaningful and statistically significant benefit, even when patients were already taking the four standard heart failure medications.

The clearest benefit was a reduction in hospital admissions for heart failure, which fell by an average of 25%. Low-dose digoxin was also found to be safe and relatively easy to use.

Problems Increased After Digoxin Was Stopped

A third study followed approximately 600 of the original 1,000 participants who had been assigned either digoxin or placebo.

Researchers found that people who had been taking digoxin and then had to stop experienced significantly more problems during the first six weeks compared with people who had never taken the drug. Among 288 patients, 14 were hospitalized or died.

According to the researchers, this finding does not directly prove that digoxin is effective. Still, they considered the size and timing of the effect both impressive and surprising.

A Heart Failure Drug That Costs Less Than Ten Cents a Day

The researchers believe the results of the three studies could eventually lead to changes in heart failure guidelines, potentially allowing many more patients to receive digoxin.

Its low price makes the findings especially notable. Digoxin has been used in medicine for centuries and costs less than ten cents per day. By comparison, many newer heart failure medications cost several euros each day.

Why a Low Dose of Digoxin Matters

Digoxin (digitalis) is the oldest and least expensive medicine used to treat heart failure. At a low dose, the drug primarily works by reducing several harmful compensatory responses that occur when the heart is struggling. For example, digoxin suppresses stress hormones (such as adrenaline) in the blood, which can benefit the heart.

Higher doses of digoxin were commonly prescribed in the past. Those doses caused heart muscle cells to contract more strongly, but that effect ultimately proved less helpful. For a weakened heart muscle, reducing strain is preferable to forcing it to work harder.

During the past 25 to 30 years, several effective new treatments for heart failure have become available. As a result, digoxin use has steadily declined, and only about 15 percent of heart failure patients now receive it.

Earlier research had already suggested that patients given low doses of digoxin did considerably better than those receiving higher doses. Until the new UMCG research, however, randomized, prospective studies had not directly investigated and confirmed this effect.

Funding Made the Digoxin Studies Possible

Research involving older and inexpensive medications can be difficult to fund, even when those drugs have the potential to improve patient care while lowering costs.

Hartstichting therefore provided 3 million euros for this research through its collaboration with ZonMw as part of the Good Use of Medicines program.

The evidence comes from high-energy particle collisions at RHIC, a U.S. Department of Energy (DOE) Office of Science user facility for nuclear physics research that operated at DOE’s Brookhaven National Laboratory from 2000 to early 2026. According to the new study, published in Science, baryon number may be associated with a Y-shaped “junction” of gluons connecting the proton’s three main quarks. If confirmed, that would challenge the long-standing assumption that baryon number belongs exclusively to those quarks.

“Traditionally, scientists have assumed that each of the three main ‘valence’ quarks inside a proton or neutron carries one-third of the baryon number,” said Zhangbu Xu, a professor at Kent State University with a joint appointment at Brookhaven Lab.

A Decades-Old Idea About Gluons

Physicists first proposed the baryon junction, also called a gluon junction, in the 1970s as a way to describe how gluons connect the valence quarks inside a proton. In 1996, four years before RHIC began operating, Dmitri Kharzeev, a theoretical physicist at Stony Brook University and Brookhaven Lab, proposed that this junction might do something even more fundamental. Rather than the valence quarks carrying baryon number, the junction itself could be responsible.

The STAR collaboration has now developed a way to test that possibility using several types of collisions produced at RHIC.

“Using data collected from different types of particle collisions at RHIC, our results suggest that the baryon number is not simply carried by individual quarks,” Xu added. “Our findings strongly support the idea that baryon number is more favorably carried and transported by gluons, the particles that hold quarks together, when arranged in this special configuration.”

Why Baryon Number Matters

Determining what actually carries baryon number matters far beyond the internal structure of a proton. In RHIC collisions, conservation of baryon number means that the total number of baryons, three-quark particles such as protons and neutrons, must remain unchanged before and after the collision. The same conservation principle also applies on the scale of the universe.

“Since the Big Bang, the number of protons and neutrons all together never changes as a function of time,” said Nicole Lewis, a STAR physicist at Rice University who started this project as a postdoc at Brookhaven Lab in 2020. “The reasons for this conservation are not well understood. It’s one of the mysteries of the universe, related to why we have more matter than antimatter,” she said.

Baryon number conservation also has a much more tangible consequence. It helps explain the extraordinary stability of protons, which form a central part of atomic nuclei and do not appear to decay under ordinary circumstances.

“It’s believed that the lifetime of a proton is longer than the lifespan of the universe,” Lewis said. “This allows atomic nuclei to form and be stable — which means matter, as we interact with it in the universe, can exist.”

A More Complicated Proton

The possibility that gluons carry baryon number would overturn the standard simplified description found in many textbooks. In that picture, a proton has a baryon number of plus one, divided equally among its three main valence quarks. Each quark therefore carries plus one third of the baryon number, much as the proton’s electric charge is distributed among its three valence quarks.

But real protons are much more complicated than that simplified model suggests.

“In the naïve quark model, there are three quarks inside a proton, but nothing else,” said Tommy Tsang, formerly a postdoc at Kent State University, now at DOE’s Argonne National Laboratory. “But if we look at details inside, there are not only three quarks but also a lot of gluons interacting, connecting between those quarks, and there are also quarks and antiquarks that pop up from the vacuum, so it’s actually a really complex object.”

Quantum chromodynamics (QCD), the theory used to describe these interactions, has been highly successful in explaining the strong force that acts among quarks and gluons. Even so, models inspired by QCD often need additional assumptions to reproduce some of the particle patterns observed when RHIC smashes nuclei together at nearly the speed of light.

An Unexpected Excess of Baryons

One observation in particular caught the STAR team’s attention. The detector repeatedly records more baryons than antibaryons emerging sideways from the collisions, perpendicular to the direction of the incoming beams.

“In the STAR detector, we consistently see an excess of baryons coming out of the collisions perpendicular to the direction of the colliding beams,” Tsang said. “The fact that we end up with more baryons than antibaryons — or more matter than antimatter — is not surprising since our collisions start with matter,” he said.

These extremely energetic collisions convert tremendous amounts of energy into thousands of newly created particles. What puzzled the researchers was not simply that more baryons than antibaryons were produced. It was where the excess baryons appeared.

If valence quarks alone carried the baryon number, explaining the excess away from the beamline would require all three valence quarks from one colliding proton to stop near the center of the detector. They would then have to undergo a conversion from matter into energy and back into matter, producing new baryons that move outward perpendicular to the beam.

The STAR researchers suspected there might be another explanation.

Electric Charge Provides a Test

The team found a way to investigate the mystery by taking advantage of another property of valence quarks: electric charge. Scientists compared the net baryon number measured in different RHIC nuclear collisions with the way electric charge was redistributed in those same events.

“Measuring the electric charge coming out perpendicular to the collision gives you a definitive way of measuring how many quarks are stopped and transformed into new particles,” said Zebo Tang, a professor at the University of Science and Technology of China who led a group of students performing data analyses and model simulations.

The comparison revealed a striking mismatch. Researchers observed roughly twice as many baryons as should have been produced based on the electric charge associated with stopped quarks.

According to models based on QCD, that means too few quarks were being stopped to account for all the baryons appearing in the detector.

That left an important question: What was carrying the extra baryon number?

The STAR physicists argue that gluons offer a possible answer, specifically the three-pronged gluon junction that connects the proton’s valence quarks.

How the Gluon Junction Could Carry Baryon Number

The proposed mechanism depends on what happens when protons inside colliding nuclei reach enormous energies. According to the STAR team, the “gluon junction” or “baryon junction” that links the quarks may be much easier to stop in a collision than the three quarks themselves.

If the junction is stopped, its energy can be converted into newly produced baryons that travel outward in directions perpendicular to the beams. Meanwhile, the valence quarks that were previously connected by the junction can continue moving forward along the beampipe.

Understanding why requires looking at the changing internal structure of a proton as its energy increases.

“The baryon junction is always there even as protons are accelerated to higher and higher energy,” Prithwish Tribedy, a STAR physicist at Brookhaven Lab. “But at high energy, gluons within the proton split and multiply.”

As the number of gluons increases, the proton’s momentum becomes spread among more of them. Each individual gluon, including those forming the junction, therefore carries a smaller portion of the proton’s total momentum. The valence quarks, however, continue to carry much of the proton’s forward motion.

As a result, when the collision occurs, the comparatively slower three-pronged gluon junction should be easier to stop and convert into new particles than the rapidly moving quarks.

Stopping one connected structure is also simpler than stopping three separate quarks, making such an interaction more likely, according to Tribedy.

“In the collision, the baryon junction gets held behind, and the quarks continue on,” he noted.

Building New Particles After the Collision

Quarks and gluons cannot remain isolated, so after the collision they quickly combine with other particles.

In a simplified example, a quark continuing down the beampipe could join with an antiquark and form a two-quark particle called a meson. At the same time, the three-pronged gluon junction could behave somewhat like a Y-shaped magnet, drawing in three newly created quarks from the vacuum and producing a new baryon.

Actual RHIC collisions are considerably more violent and complex.

“Even though we start with nuclei that contain roughly 100 protons and 100 neutrons, these collisions create thousands of new particles; 99% of the energy is transformed into new particles,” said Rongrong Ma, a Brookhaven Lab physicist.

The STAR team found that collisions producing larger numbers of particles also showed a greater excess of “midrapidity” baryons compared with predictions based on the simpler picture in which quarks alone carry baryon number.

The fact that so many of these baryons emerge perpendicular to the beamline provides strong evidence, according to the researchers, that the baryon junction exists and plays an important role in transporting baryon number.

Rethinking a Fundamental Property of Matter

The results suggest that one of the proton’s defining quantum properties may not reside solely in its three valence quarks. Instead, the gluon structure connecting those quarks could be central to how baryon number is carried through energetic collisions.

“Our research challenges the long-held idea that baryon number is simply divided among and carried by the three quarks,” said Ma. “This new understanding reshapes how we think about the structure of matter and deepens our knowledge of the most fundamental element that is responsible for the universe in its current form.”

The research was supported by the DOE Office of Science, the U.S. National Science Foundation (NSF), and numerous international agencies and organizations listed in the scientific paper. Researchers also used the Open Science Grid, which is supported directly by NSF, along with computing resources at Brookhaven Lab’s Scientific Data and Computing Facilities and the National Energy Research Scientific Computing Center (NERSC), another DOE Office of Science user facility located at DOE’s Lawrence Berkeley National Laboratory.

Led by researchers at Flinders University and the University of Canberra, the study found that aging is associated with a “safety-first” walking strategy. This approach emphasizes stability instead of speed and energy efficiency, helping explain why older adults may fatigue more quickly and also face a greater risk of falling.

Researchers analyzed movement data from 107 healthy adults between the ages of 26 and 86. They found small but meaningful age-related differences in how the ankle and nearby muscles manage each step.

How the Ankle Changes With Age

Lead author and sport and exercise technology expert Dr. Cody Lindsay says the ankle is essential for maintaining balance while also helping propel the body forward.

“As we get older, the body starts to favor stability over efficiency,” says Dr. Lindsay, from the Flinders Caring Futures Institute.

“That helps keep us upright, but it also makes walking more of an effort.”

The researchers found that older adults are more likely to activate opposing muscles around the ankle at the same time. This pattern is known as co-contraction. It makes the ankle joint stiffer and can improve stability when the foot contacts the ground.

However, Dr. Lindsay says this comes at a cost.

“Stiffening the joint makes walking safer, but it also means the muscles are working harder without generating as much forward movement,” he says.

Older participants also generated less push-off power with each step. As a result, their strides were shorter, and their walking speeds were slower.

A Safety First Strategy for Walking

Co-author Associate Professor Maarten Immink says the findings point to a wider change in the way the body manages movement as people grow older.

“The nervous system adopts a safety-first approach, compensating for age-related changes by favoring stability over performance,” says Associate Professor Immink, Lead of the Active Lives Research Program within the Caring Futures Institute at Flinders University.

“These changes can also increase fatigue and make walking longer distances more challenging, while reducing the ability to recover from trips or slips — a key factor in falls among older adults.”

“Even gradual changes can affect confidence and independence, and people may notice they tire more quickly or feel less steady, especially on uneven ground.”

Exercise May Help Preserve Mobility

The findings also suggest possible ways to help people maintain mobility as they age.

Rather than focusing only on building strength, the researchers say exercise programs should also emphasize balance and coordination while paying attention to how different muscles work together during each step.

“For older Australians, simple actions can make a difference, including regular physical activity, balance exercises such as tai chi, lower-leg strengthening and activities that challenge coordination,” says Dr. Lindsay, from Flinders’ College of Health and Enablement.

“Staying active is one of the most important things people can do, and small, consistent exercises can help you stay confident, mobile and independent for longer.”

The researchers hope these findings can contribute to improved prevention and rehabilitation strategies designed to reduce falls and support healthy aging.

The findings may be particularly important for children and teenagers. Because their bodies are still developing, younger generations are expected to experience the greatest lifetime exposure to elevated atmospheric CO₂.

Decades of Blood Data Reveal a Shift

In a study published in Air Quality, Atmosphere and Health, scientists from The Kids Research Institute Australia, Curtin University and The Australian National University (ANU) examined more than 20 years of U.S. population health data. They found persistent changes in several measures of blood chemistry that closely followed the upward trend in atmospheric CO₂.

The researchers used information from the U.S. National Health and Nutrition Examination Survey (NHANES), analyzing blood test results from roughly 7,000 people at two-year intervals between 1999 and 2020.

Since 1999, average serum bicarbonate levels have increased by about 7 percent. Bicarbonate is a blood marker closely associated with carbon dioxide in the body. During the same period, average levels of calcium and phosphorus decreased.

Those biological trends occurred as atmospheric CO₂ climbed from about 369 parts per million (ppm) in 2000 to more than 420 ppm today.

Study author Associate Professor Alexander Larcombe said the results indicate that the body may already be adjusting to changes in the composition of the atmosphere.

“What we’re seeing is a gradual shift in blood chemistry that mirrors the rise in atmospheric carbon dioxide, which is driving climate change,” A/Prof Larcombe said.

How the Body Responds to More CO₂

Bicarbonate is essential for regulating the body’s acid-base balance. As CO₂ increases, the body can retain additional bicarbonate to help keep blood pH stable. Although this response helps preserve that balance, maintaining it over long periods could have physiological effects.

“If current trends continue, modeling indicates average bicarbonate levels could approach the upper limit of today’s accepted healthy range within 50 years,” A/Prof Larcombe said

“Calcium and phosphorus levels could also reach the lower end of their healthy ranges later this century.”

Humans evolved when atmospheric CO₂ concentrations were approximately 280 to 300 ppm. During the past decade, atmospheric levels have risen by an average of about 2.6 ppm each year, while 2024 alone saw an increase of 3.5 ppm.

Fellow Author Dr Phil Bierwirth, a retired environmental geoscientist affiliated with the ANU Emeritus Faculty, emphasized that the study does not establish a direct cause-and-effect relationship. However, he said the consistency of the changes across a large population warrants attention.

“I actually think that what we are seeing is because our bodies are not adapting,” Dr Bierwirth said.

“It appears we are adapted to a range of CO₂ in the air that may now have been surpassed.

“The normal range maintains a delicate balance between how much CO₂ is in the air, our blood pH, our breathing rate and bicarbonate levels in the blood.

“As CO₂ in the air is now higher than humans have ever experienced, it appears to be building up in our bodies. Maybe we can never adapt such that it is vitally important to limit atmospheric levels of CO₂.”

A Potential New Dimension of Climate Risk

The researchers say the results suggest that rising atmospheric CO₂ could represent a form of climate-related risk that is different from more familiar threats such as heatwaves, extreme weather and sea-level rise.

According to A/Prof Larcombe, increasing CO₂ may need to be considered not only as an environmental concern, but also as a long-term public health factor that should be monitored.

“We’re not saying people are suddenly going to become unwell when we cross a certain threshold,” he said.

“But this suggests there may be gradual physiological changes occurring at a population level, and that’s something we should be monitoring as part of future climate change policy.”

The researchers recommend monitoring the composition of the atmosphere together with biological markers across populations. Tracking both alongside established climate indicators could help scientists determine how slow environmental changes affect human biology over periods of decades.

CO₂ Reduction Could Have Health Implications

Cutting CO₂ emissions remains essential for limiting global warming. The findings also raise the possibility that lowering emissions could have an additional role in protecting long-term human health.

The researchers argue that potential physiological effects from rising CO₂ should therefore be considered in future discussions about climate policy, alongside its established environmental consequences.

Associate Professor Larcombe is part of the Wal-yan Respiratory Research Centre, a partnership between The Kids Research Institute Australia, Perth Children’s Hospital and Perth Children’s Hospital Foundation.

Two studies led by Ludwig Princeton’s Jenna AbuSalim and Director Joshua Rabinowitz offer new insight into that process. One appears in the current issue of the Proceedings of the National Academy of Sciences, while the other was published in Nature Metabolism in June. The first study found that plant fiber and certain plant proteins can change microbial metabolism in ways that increase beneficial metabolites while reducing harmful ones. The second showed that several biologically important metabolites usually credited to gut microbes can also be produced in substantial amounts by mammalian metabolism.

“There’s growing interest across medical disciplines in manipulating the human microbiome or using its metabolic products themselves for therapy,” said Rabinowitz. “Diet holds great promise for controlling the microbiome and its outputs. But to devise effective therapeutic interventions, we need to understand what aspects of the diet control which microbial outputs.”

How Plant Foods Shift Gut Metabolites

In the PNAS study, Rabinowitz, AbuSalim and their colleagues examined how plant based foods influence phenol metabolites. Gut bacteria create these compounds when they digest the amino acids tyrosine and phenylalanine, but the resulting metabolites can have very different effects on health.

Phenylpropionate and hippuric acid are produced when bacteria process phenylalanine, and they are associated with gut health and healthy body weight. By contrast, p-cresol sulfate and phenol sulfate come from tyrosine and have been linked to worse outcomes in cancer patients as well as systemic toxicity in people with kidney disease.

“Our studies showed that both the fiber and indigestible proteins from plants — which we call ‘proteins imitating fiber,’ or Prif — shift the balance of phenol metabolites from the harmful kind made from tyrosine to the healthful variety derived from phenylalanine,” said AbuSalim.

Fiber has long been recognized as an important part of a healthy diet, but indigestible plant proteins have received far less attention. AbuSalim, Rabinowitz and their colleagues found that these proteins are processed by gut microbes and can alter both the makeup of the microbiome and the host’s metabolism. Working together with indigestible plant fiber, they can also change the metabolic activity of gut bacteria in ways that favor the production of beneficial phenols.

When Gut Bacteria Turn to the Gut Lining

To trace where these compounds came from, the researchers labeled proteins with stable (non-radioactive) isotopes and followed their digestion in the mouse gut. They found that the “bad” phenols were produced when bacteria consumed proteins from the host, including proteins found in the mucus lining of the gut. The good phenols, in contrast, came almost entirely from indigestible proteins in the diet (Prif).

Fiber reduced the bacterial breakdown of the gut’s mucus lining, which in turn lowered production of the harmful phenols. Prif increased the amount of dietary protein that reached gut microbes, giving them more material to produce the beneficial phenols.

“We think Prifs represent an emerging class of dietary nutrients that shape the composition of the gut microbiome and could have a far-reaching influence on metabolic health,” said AbuSalim.

“Food packaging may eventually list Prif right below fiber,” said Rabinowitz.

Rethinking Where Gut Metabolites Come From

The Nature Metabolism study focused on the origins of phenol metabolites as well as indole metabolites, which are produced from the amino acid tryptophan. Like phenols, indoles are being studied for their possible therapeutic value.

Indole metabolites have been connected to a wide range of diseases, including inflammatory bowel disease, neurodegenerative disorders, and cancer. In cancer research, they have been found to affect processes that include cancer metastasis and anti-tumor immune responses.

Scientists had generally assumed that phenols and indoles were produced only by gut bacteria. AbuSalim, Rabinowitz and their colleagues decided to test that assumption. Researchers have been especially interested in dietary and probiotic approaches that might increase beneficial indole metabolites. But those strategies may need to be reconsidered if mammalian metabolism, rather than microbes, is responsible for much of what circulates in the body.

Using isotope tracing in mice, rats and human cells, the researchers found that mammalian metabolism can produce many indole and phenol metabolites on its own. These included important compounds such as indole-3-lactate and indole-3-acetate.

In mice, circulating levels of these metabolites remained high even after antibiotic treatment disrupted the microbiome. A similar pattern appeared in samples from patients taking antibiotics, including cancer patients. At the same time, metabolites made exclusively by microbes, including indole-3-propionate and p-cresol sulfate, declined after antibiotic treatment.

New Clues for Diet and Microbiome Therapies

Together, the two studies provide a clearer picture of where phenol and indole metabolites come from and how they are produced. The findings could influence the development of therapies designed to raise or lower specific metabolites.

They also add important detail to scientists’ understanding of how diet interacts with the microbiome. Knowing which foods influence particular microbial products could eventually help researchers design more precise dietary, probiotic, or metabolic interventions.

“Beyond that,” said Rabinowitz, “a clearer picture of how different foods interact with the microbiome to modulate the production of bacterial metabolites will help sharpen the guidance nutritionists and doctors can give to people for disease prevention and therapy.”

These studies were funded by the Ludwig Institute for Cancer Research, the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the Princeton Alliance for Collaborative Research and Innovation, Princeton University.

Aside from his post as Director of the Princeton Branch of the Ludwig Institute for Cancer Research, Joshua Rabinowitz is Professor in the Department of Chemistry & Lewis-Sigler Institute for Integrative Genomics and a member of the Rutgers Cancer Institute.

The mouse study, published in Nature Metabolism, found that the outcome depends on which part of the brain is targeted. Activating the receptor in the brainstem reduced appetite, while blocking the same receptor in the hypothalamus produced a similar weight loss effect through a different mechanism.

More than a billion people around the world are living with obesity, a condition that raises the risk of diseases including type 2 diabetes, cardiovascular disease and cancer. Losing weight can reduce some of these risks, but achieving substantial weight loss through diet and exercise alone can be difficult.

How Modern Weight Loss Drugs Target the Brain

A new generation of weight loss medications has emerged in recent years that act on specific receptors involved in appetite. By influencing these receptors, the drugs can reduce food intake, promote weight loss, and help regulate blood sugar.

Several widely used medications, including Wegovy and Ozempic, activate a protein receptor called the glucagon-like peptide 1 receptor (GLP-1R).

Other obesity treatments act on both GLP-1R and another receptor known as the glucose-dependent insulinotropic polypeptide receptor (GIPR). This second target has presented scientists with an unusual puzzle.

Some medications, including Mounjaro and Zepbound, activate GIPR. Others, such as MariTide, block it. Despite producing opposite effects on the same receptor, both approaches can help promote weight loss.

Researchers at the Institute of Metabolic Science, University of Cambridge, set out to understand why. Their experiments in mice revealed that the two types of GIPR drugs work through different regions of the brain. The researchers also found that these approaches can increase weight loss when paired with certain GLP-1-based weight loss medicines.

Tracking GIPR Activity in Different Brain Regions

To identify the brain regions responsible for these effects, the team used genetically engineered mice in which GIPR had been selectively removed from specific areas.

One group lacked GIPR in the brainstem, the region at the base of the brain just above the spinal cord that is involved in appetite and nausea. Another group lacked the receptor in the hypothalamus, an important brain region involved in regulating hunger and body weight. A third group consisted of normal, unmodified mice that served as controls.

The scientists treated the animals with different combinations of a GIPR agonist (which activates the receptor), a GIPR antagonist (which blocks the receptor) and a GLP-1 drug. They then monitored food consumption, body weight, fat mass, blood sugar control and brain activity.

Comparing the different groups allowed the team to pinpoint where each treatment was acting.

The results showed that GIPR agonists primarily work through the brainstem. Activating GIPR in this region reduced appetite and led to lower body weight.

Blocking a Brain Brake on Fullness

GIPR antagonists followed a different route.

Instead of acting primarily through the brainstem, the researchers found that blocking GIPR promoted weight loss through the hypothalamus. In this region, GIPR appears to function as a kind of ‘brake’ that limits how strongly the brainstem responds to signals indicating that the body is full.

Blocking the receptor effectively releases that ‘brake’, allowing fullness signals to have a stronger effect.

The researchers also found evidence that blocking GIPR could enhance the effects of emerging medicines that target the amylin receptor. This suggests that GIPR antagonists might eventually be useful for strengthening several different classes of obesity treatments.

Clues to More Powerful Obesity Drug Combinations

The results help explain why treatments such as MariTide can be effective. MariTide, currently in phase 3 clinical trials, combines GIPR antagonism with GLP-1 receptor agonism.

Understanding how these separate pathways interact could also help researchers design more effective combinations of obesity medicines in the future.

Dr. Jo Lewis, the study’s first author from the Institute of Metabolic Science at the University of Cambridge, said: “Understanding which brain circuits respond to these medications – and how they do so – could help us design better drugs that produce more weight loss with fewer side effects, and which might work in combination with other obesity medicines to even greater effect.

“Our work also strengthens the idea that the brain is central to obesity treatment. Obesity drugs are not acting simply on the gut or pancreas. Instead, they have important effects on specific, identifiable brain circuits that regulate appetite and food intake.”

The research was funded by the Medical Research Council and Wellcome.