Isabella Backman

Anti-obesity drugs such as semaglutide (Ozempic, Wegovy) are also promising for the treatment of alcohol use disorder and alcohol-associated liver disease, as growing evidence suggests they reduce the motivation to drink alcohol. Now, surprising new findings reveal that the medications may have direct protective effects on the liver as well.

, Yale School of Medicine (YSM) researchers found that in mice, the drugs, known as GLP-1 receptor agonists, reduced an enzyme that metabolizes alcohol. That, in turn, decreased the production of toxic alcohol metabolites.

“This is the first time that GLP-1 receptor agonists have been shown to regulate alcohol metabolism in the liver,” says principal investigator 

, professor of medicine (digestive diseases) at YSM. “If you’re taking semaglutide, then your body will likely handle alcohol differently.”

However, because these drugs slowed the metabolism of alcohol, the mice also had higher blood alcohol levels, the researchers found.

“GLP-1 receptor agonists seem to have very similar effects in mice and humans,” says Mehal. “If these results are also reproduced in humans, people using GLP-1 receptor agonists might be drinking an amount of alcohol that does not normally put them above the legal blood alcohol level, but because they are taking this drug, it does.”

Further studies in humans are needed to understand these impacts of GLP-1 receptor agonists more fully, he emphasizes.

GLP-1 receptor agonists decrease toxic alcohol metabolites

In the study, researchers gave mice either a GLP-1 receptor agonist or a placebo. They observed that mice receiving the medication had decreased levels of a liver enzyme known as Cyp2e1, which breaks down alcohol into a toxic metabolite called acetaldehyde.

“This is significant because alcohol itself is actually not the most toxic molecule to the liver,” explains Mehal. Rather, acetaldehyde is one of the major drivers of alcohol-related harm to the liver. “These drugs are resulting in less acetaldehyde.”

The findings suggest that not only might GLP-1 receptor agonists help the liver by acting on the brain to reduce alcohol consumption, but also through slowing metabolism of alcohol in the liver, and in turn reducing the levels of toxic metabolites.

Ongoing clinical trials are currently testing the benefits of semaglutide for people living with alcohol-induced liver disease. The study suggests that GLP-1 receptor agonists may offer greater benefits to the liver than previously thought, and that the drug may still help patients who are not abstaining from alcohol.

“Even if some individuals don’t reduce their alcohol intake while they’re on a GLP-1 receptor agonist, they will probably still have hepatic protection, because fewer toxic metabolites will be produced in the liver,” Mehal says.

GLP-1 receptor agonists increase blood alcohol concentration

In another experiment, the researchers measured blood alcohol concentrations of mice 30 minutes after giving them alcohol. They found that mice who had received a GLP-1 receptor agonist had higher blood alcohol concentrations compared to controls, and that these levels took longer to drop.

More research is needed to better understand the consequences of elevated blood alcohol levels on the rest of the body, Mehal says.

“If the liver is not metabolizing alcohol as quickly, the alcohol load could be shifted to other organs,” he poses. “Then, not only might people have a high blood alcohol level, but may also experience more cognitive effects like discoordination.”

The number of people taking these drugs is rapidly increasing—as many as 

 in the U.S. have used or are currently using a GLP-1 receptor agonist. Meanwhile, 

 drink alcohol and 6% report drinking heavily.

As the use of these medications for a range of conditions continues to rise, it is increasingly important to study the interactions between these medications and alcohol, Mehal says.

“There already are large numbers of people who are taking GLP-1 receptor agonists and are drinking either social amounts or excess amounts of alcohol,” says Mehal. “We need to know the effects of these drugs in that setting.

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GLP-1 receptor agonists, such as semaglutide, show promise in treating alcohol use disorder and alcohol-associated liver disease by reducing alcohol consumption motivation and directly protecting the liver. Research indicates these drugs decrease the liver enzyme Cyp2e1, reducing toxic acetaldehyde production. However, they also slow alcohol metabolism, leading to higher blood alcohol levels. This raises concerns about potential cognitive effects and interactions with alcohol. As the use of these medications increases, further human studies are essential to understand their full impact on alcohol metabolism and liver health.

New research reveals GLP-1 receptor agonists may protect the liver from alcohol damage while increasing blood alcohol levels, prompting further human studies.

GLP-1 Receptor Agonists Protect the Liver During Alcohol Consumption

Macrophages are the first line of defense of the immune system, helping fight infections and keeping tissues healthy. But in the context of some chronic diseases, these immune cells undergo changes and become pathogenic, helping drive disease and creating inflammation.

Targeting these disease-induced macrophages without also killing off the protective ones has been challenging. But researchers have now discovered markers that are unique to pathogenic macrophages and have developed a molecule that can specifically eliminate them.

While the team conducted these studies specifically in models of the liver disease known as metabolic dysfunction-associated steatohepatitis (MASH), non-small cell lung cancer (NSCLC), and endometriosis, the researchers are optimistic that the small molecule, called Bobcat339, and its future derivatives, could be a one-size-fits-all approach that treats a multitude of chronic diseases associated with inflammation.

“We have found a very potent target associated with multiple chronic diseases, and we have a way to treat this target with Bobcat339,” says 

, professor of obstetrics, gynecology & reproductive sciences at Yale School of Medicine and the study’s principal investigator. “And we are in the process of identifying even more potent molecules to treat these diseases.”

Bobcat339 targets TET3 overexpression and mitigates chronic disease

Across different chronic diseases, the affected part of the body often experiences cellular and molecular changes. Known as the disease microenvironment, this is what triggers healthy macrophages to become pathogenic.

For the study, the researchers exposed healthy human and mouse macrophages to factors that mimicked different disease microenvironments. Doing so turned the macrophages pathogenic. Next, the researchers analyzed gene expression in these macrophages and found that the disease microenvironment upregulated expression of a gene called 

. This in turn induced further changes that fueled inflammation and suppressed the immune system.

These downstream changes, however, also made the macrophages susceptible to Bobcat339. While Bobcat339 is designed to degrade TET3 protein—the product of the 

 alone is not enough to make the macrophages vulnerable to Bobcat339; the additional changes triggered by the disease environment are necessary for Bobcat339 to work.

“Factors in the disease microenvironment not only induce 

 overexpression in the macrophages but also change other genes. That creates a state in which the macrophages—which we call TET3-overexpressing macrophages—become sensitive to TET3 protein degradation,” Huang explains. “It’s a very specific population of macrophages—disease macrophages.”

To the researchers, that suggested Bobcat339 should be able to target macrophages that are driving disease and spare healthy, protective macrophages. And additional experiments showed the molecule was capable of doing exactly that.

The researchers found that Bobcat339 was successfully able to target and kill pathogenic macrophages without harming healthy ones. The team also tested the molecule in mouse models of MASH, NSCLC, and endometriosis. Across these three models, Bobcat339 decreased liver damage and liver fibrosis, reduced tumors and increased survival, and shrunk endometriotic lesions.

Many individuals living with chronic diseases today still have few effective treatment options. In the future, Bobcat339 or its derivatives could be a new tool for helping patients manage their conditions.

To assess the safety of Bobcat339, Huang’s team is conducting rigorous toxicity studies in animal models. So far, the molecule’s safety profile has been promising, she says. “If it continues to not show bad side effects, we can hopefully move onto human trials.”

Researchers have identified markers unique to pathogenic macrophages, which contribute to chronic diseases by driving inflammation. They developed Bobcat339, a molecule that selectively targets and eliminates these harmful macrophages without affecting protective ones. The study, conducted in models of metabolic dysfunction-associated steatohepatitis, non-small cell lung cancer, and endometriosis, demonstrated Bobcat339's efficacy in reducing disease symptoms. The molecule targets TET3 overexpression, a key factor in macrophage pathogenicity. Ongoing toxicity studies show promise for future human trials, potentially offering a novel treatment for chronic inflammatory diseases.

Researchers unveil Bobcat339, a targeted molecule that selectively eliminates pathogenic macrophages.

Molecule Shows Promise for MASH, Endometriosis, and Other Chronic Diseases

Yale researchers have built a 3D-bioprinted synthetic aorta that they have successfully implanted into rats. This technology could advance the treatment of cardiovascular diseases such as coronary artery disease or peripheral arterial disease by allowing scientists to engineer and replace blood vessels in humans. The team recently published their findings in 

Through this new approach, scientists could use an individual’s own cells, or cells from a donor, to rapidly create custom-designed tissues that match the size and shape of the parts of vasculature to be replaced. Current treatments for severe cardiovascular disease include the use of grafts made from a patient’s own tissues (autologous) or synthetic materials. However, autologous grafts require invasive surgery and have a significant failure rate, and synthetic grafts are limited to large blood vessels and prone to leakage and harmful bacterial colonization.

Bioprinted vasculature could offer a better solution.

“This would be another alternative for people who are suffering from cardiovascular disease that allows them to maintain a higher quality of life,” says 

, professor emeritus of surgery (gastrointestinal) and of cellular and molecular physiology, and the study’s principal investigator.

A new proof-of-concept of bioprinted vasculature

Previously, scientists have tried to bioengineer tissues using a bioreactor, a chamber with a porous tube at its core into which they would inject the cells. The major downside of this method is that it is time-consuming—it can take weeks to create viable tissues.

In the new study, the researchers investigated the feasibility of bioprinting aortas. They cultured the main cells that make up the aorta—aortic cells, smooth muscle cells, and fibroblasts—from rats. Then, they loaded syringes into the bioprinter, which ejected these cells onto a rolling stainless-steel tube. After letting the cells incubate for a couple of days, the bioprinted aortas were ready for implantation.

The researchers tested their synthetic vascular structures in 20 rats. Twenty additional rats underwent the same surgical procedure without the implantation of the aorta. Rats in both groups resumed normal behavior following surgery and remained in good health. Notably, the procedure was also successful in rats who received aortas built from the cells of a different animal.

This is proof-of-concept of using bioprinted vasculature to treat cardiovascular diseases, the team says. “You might think it’s a far stretch from a rat to a human, but it isn’t,” says Geibel. “It’s just a matter of sizing—humans will require a lot more cells.”

The potential to use cells from a donor could help further reduce the time a patient waits to receive a bioprinted vessel. “Theoretically, we wouldn’t need to collect the cells from the patient with a cardiovascular disease,” Geibel says. “We could collect them from another individual and begin culturing them so that we have enough cells ready to go.”

The ability to bioprint human vasculature within days could have lifechanging implications, Geibel says. People with diabetes-related foot conditions, for instance, often have poor circulation that reduces blood flow to the feet. If left untreated, an amputation can be necessary. Custom-made blood vessels could be a new treatment for the condition that can help save the foot.

“You know the old adage—'one small step for a man, one giant leap for mankind,’” Geibel says. “This is the first step to get us toward technology in the future that will allow us to change how we help patients in a way that is dramatic.”

Yale researchers have developed a 3D-bioprinted synthetic aorta, successfully implanted in rats, potentially revolutionizing cardiovascular disease treatment. This technology enables the engineering and replacement of blood vessels using an individual's or donor's cells, offering a promising alternative to current grafts, which have limitations and risks. The bioprinting process is faster than traditional methods, producing viable tissues in days. This advancement could significantly improve patient outcomes, particularly for those with conditions like diabetes-related foot issues, by providing custom-made blood vessels to enhance circulation and prevent amputations.

Yale researchers unveil a groundbreaking 3D-bioprinted synthetic aorta, promising revolutionary advancements in cardiovascular disease treatment and patient care.

Bioprinted Aorta Shows Promise for Cardiovascular Disease Treatment

Researchers have identified a mechanism underlying insulin resistance in adolescents with obesity. The findings, published in 

, present a targetable pathway that could one day allow clinicians to intervene and prevent the onset of type 2 diabetes.

The number of youths with obesity has skyrocketed over the past several decades, and in turn, so have diseases previously associated with older age groups, such as heart disease and type 2 diabetes.

Adolescence is an especially vulnerable time in life to develop type 2 diabetes.
Nicola Santoro, MD, PhD

In a new study, Yale researchers observed how adolescents with obesity responded to insulin. Typically, insulin halts fat breakdown in adipose tissue—the connective tissue commonly known as “body fat.” But the researchers found that in adolescents who were insulin-resistant, insulin’s ability to block fat breakdown was impaired compared with those without insulin resistance.

“If fat cells don’t respond to insulin by stopping this breakdown process, the fat gets secreted into other tissues and causes a whole host of diseases,” explains Aaron Slusher, PhD, former associate research scientist at Yale School of Medicine (YSM) and the study’s first author.

Future medications that target this pathway and block the fat secretion from the liver could potentially prevent insulin-resistant adolescents from developing type 2 diabetes, the authors say.

“Adolescence is an especially vulnerable time in life to develop type 2 diabetes,” says 

, associate professor of pediatrics at YSM and the study’s second author. “Our study is a big step forward in understanding how insulin works—and how when it is not working correctly in fat tissue, it can lead eventually to type 2 diabetes.”

The findings follow previously made discoveries from preclinical animal research conducted by 

, George R. Cowgill Professor of Medicine (Endocrinology) at YSM and co-author of the study.

“Stopping the flux of fat from adipose tissue to other tissues would be key to reduce the rates of the cardiometabolic complications of obesity,” Santoro says.

Lipolysis is not suppressed in youth with obesity

For the study, the researchers took biopsies of the layer of adipose tissue beneath the skin from 30 adolescents with obesity—17 of whom were insulin-resistant—before and during infusions of insulin. They excluded potential participants if they had previously been diagnosed with type 2 diabetes.

Sonia Caprio, MD (left); Nicola Santoro, MD, PhD (center); and Gerald Shulman, MD, PhD (right)

To determine insulin resistance, they used an oral glucose tolerance test—a clinical test that is typically used to diagnose prediabetes and diabetes and involves measuring blood sugar levels before and after drinking a glucose solution. Subjects whose blood glucose levels took longer to return to normal were classified as insulin-resistant.

The team took the biopsies both before and after two insulin infusions—the first at a low concentration of insulin for two hours, followed by a second, higher concentration for an additional two hours. Meanwhile, the researchers looked for proteins associated with lipolysis—the process through which the body breaks down fat.

“When the participants initially came into the lab, they had done an overnight fast,” says Slusher. “When you’re in a fasted state, your fat cells are undergoing a process in which they allow fat to be excreted so that it can travel around and provide energy to other parts of the body. Insulin infusion mimics a signal to the body that it has been fed, which typically stops lipolysis and facilitates the storage of fat.”

In adolescents who were insulin-resistant, insulin was unable to inhibit the breakdown of fat, largely because insulin failed to activate the main enzyme regulating fat breakdown in adipose tissue. As a result, excess fatty acids continued to flow into other tissues, which may help explain why some adolescents with obesity develop type 2 diabetes.

“We are seeing a well-characterized mechanism respond differently in two distinct populations of children with obesity,” Slusher says.

Future research focuses on type 2 diabetes prevention

, professor of pediatrics (endocrinology) at YSM and senior author of the study, began treating children in the early ’90s, childhood obesity was not common. “But little by little, we saw an increase in the prevalence of obesity—and it became very concerning to us,” she says. “By the beginning of the 2000s, we realized kids were being diagnosed with type 2 diabetes, which was—at least in our clinic—previously unheard of.”

The team hopes their identification of this altered mechanism can help researchers better understand how to therapeutically intervene.

I want to stop the onset of type 2 diabetes—that’s our goal.
Sonia Caprio, MD

“We can see if interventions—such as dietary changes or physical activity interventions, or perhaps a new pharmacologic agent—impact this target favorably,” says Slusher. “Then, we can hopefully design a strategy to make these youth more sensitive to insulin signaling and mitigate negative downstream consequences.”

Caprio’s laboratory is currently studying how drugs such as semaglutide—currently used for weight loss and treating type 2 diabetes—improve insulin sensitivity and prevent type 2 diabetes in youth. “I want to stop the onset of type 2 diabetes—that’s our goal,” she says.

The research reported in this news article was supported by the National Institutes of Health (awards R01HD02801625A1, T32DK007058, R01DK124272, RO1DK119968, R01MD015974, RO1DK113984, P3DK045735, RO1DK133143, and RC2DK120534) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.

Researchers have identified a mechanism contributing to insulin resistance in adolescents with obesity, offering a potential target for preventing type 2 diabetes. The study observed impaired insulin function in halting fat breakdown in insulin-resistant adolescents, leading to excess fatty acids entering other tissues. This discovery could guide future interventions, including medications, dietary changes, or physical activity, to enhance insulin sensitivity. The research, supported by the National Institutes of Health and Yale University, aims to mitigate the rising incidence of type 2 diabetes in youth.

Researchers uncover a mechanism of insulin resistance in obese adolescents, paving the way for potential interventions to prevent type 2 diabetes.