Effects on hunger neurons in mice

A Yale team reported in PNAS that agouti-related peptide (AgRP) neurons, long viewed as opponents of weight loss, appear to be activated rather than suppressed during semaglutide treatment in mice. In animals genetically engineered to lack AgRP neurons, the researchers said GLP-1 drugs were no longer able to sustain weight loss. The first author said the finding changes how researchers think about the mechanism involved, and the authors note the experiments were conducted in mice, so further research is needed to determine whether the same mechanism operates in humans.

Combination with an experimental metabolic compound

Researchers at UC Berkeley tested an older compound called TOFA alongside GLP-1 drugs including semaglutide in obese mice. They reported that TOFA alone increased energy use by as much as 18% and reduced body fat without significant loss of lean muscle mass, and that combining it with the GLP-1 drugs produced larger improvements in body weight, glucose control, insulin levels and triglycerides than either treatment alone. The senior author described TOFA as complementary rather than a replacement, and the team emphasized that it has so far been studied only in animals.

Redesigning the peptide scaffold

A laboratory study in the Journal of Enzyme Inhibition and Medicinal Chemistry used a short semaglutide-derived segment as the basis for building stabilized peptide scaffolds. The authors designed 108 stapled peptide candidates, synthesized and characterized 35, and reported that most stapled analogues showed improved serum and proteolytic stability relative to semaglutide, with three candidates showing the most favorable stability profiles.

What Isn't Established

None of these three studies involved human participants. The AgRP mechanism has not been shown to operate in people, TOFA's safety and effectiveness in humans remain unknown, and the stapled analogues were assessed for stability and modeled receptor interactions rather than tested for effects in animals or patients. No source here reports how any of this would change clinical use of semaglutide.

The state of the evidence

Semaglutide itself is an approved and widely used drug, but this recent research is at an earlier stage: one mouse mechanism study, one mouse combination study, and one synthetic chemistry paper. Each set of authors separately described further work as necessary.

GLP-1 is a gut hormone that the researchers note is involved in satiety signaling, and it is the same hormone pathway targeted by drugs such as semaglutide (sold as Ozempic and Wegovy). Enteral feeding refers to nutrition delivered through a tube directly into the gut, and the study team defines intolerance as a patient receiving less than 70 percent of their caloric goal.

Study overview

The researchers say they enrolled 109 adults aged 18 to 80 with traumatic brain injury at a tertiary neuro-ICU. According to the report, a standardized feeding strategy targeted 25 kcal per kg per day and was adjusted according to tolerance.

Blood was sampled across four post-injury day windows covering days 1 to 14, the authors write. They report measuring GLP-1, insulin, glucose and glial fibrillary acidic protein, a marker the team associates with brain injury severity.

Key results

The study reports that 50 of the 109 patients met the definition of feeding intolerance and 59 did not. Insulin and glucose did not differ between the two groups, the researchers state, while GLP-1 was higher in the intolerance group.

The authors also report that GLP-1 increased with injury severity and was greatest in patients with a Glasgow Coma Scale score of 3 to 5 compared with 6 to 12. GLP-1 correlated with glial fibrillary acidic protein over the 14 days, the paper says, while intestinal permeability markers did not differ between groups.

In multivariable models, the researchers report that GLP-1 measured on post-injury days 8 to 10, IL-6 over the same window, insulin on days 1 to 3 and admission SOFA score were each independently associated with feeding intolerance. Combining early insulin and SOFA score gave an area under the curve of 0.786, with a reported specificity of 71.4 percent and sensitivity of 75 percent.

What the authors propose

The team proposes that disrupted central GLP-1 signaling may reduce satiety input and produce what they term central GLP-1 resistance, with GLP-1 accumulating in plasma as a secondary effect. On that reading, they suggest higher circulating GLP-1 may indicate that resistance rather than cause the intolerance directly.

Limitations

The authors state plainly that the findings are hypothesis-generating and describe an association, not a demonstrated mechanism. The cohort was a single tertiary neuro-ICU with 109 patients, followed for 14 days, and the paper does not report an external validation of the risk model.

What it means

The researchers conclude that elevated plasma GLP-1 is associated with enteral feeding intolerance after traumatic brain injury and may serve as a pragmatic predictor. Whether altered GLP-1 signaling contributes to that intolerance, the authors say, remains unresolved.

The compound, 5-tetradecyloxy-2-furoic acid, was first discovered in the 1970s and belongs to a class known as ACC inhibitors, which reduce the body's production of lipids such as cholesterol and triglycerides. The study was led by researchers at UC Berkeley and published on August 21.

Study overview

The Berkeley team says its approach differs from GLP-1 medications sold as Ozempic, Wegovy, Mounjaro and Zepbound, which work largely by reducing appetite and food intake. Instead of lowering the calories taken in, the researchers set out to raise the amount of energy the body spends.

"Body weight responds to two levers: taking in fewer calories, or spending more energy," said Anders Naar, a professor of metabolic biology and nutrition at Berkeley and senior author of the study. "GLP-1s work almost entirely on the first, so we went after the second."

Key results

In mice, TOFA increased energy use by as much as 18% without the animals becoming more physically active or raising their body temperature, according to the paper. Treated obese mice lost fat while showing no significant reduction in lean muscle mass.

The researchers also reported improved insulin sensitivity and glucose control, lower triglyceride levels and improvements in signs of fatty liver disease. They say TOFA did not produce the rise in triglycerides seen with some other ACC inhibitors, possibly because of its combined effects on lipid production and energy metabolism.

How the combination works

Alongside acting as an ACC inhibitor, TOFA activates PPAR-alpha and PPAR-delta, cellular receptors that switch on genes involved in taking up fat and burning it for fuel. When the team tried to reproduce the effect using two separate compounds, one suppressing lipid production and one raising energy expenditure, the combination did not improve overall metabolic health as effectively as TOFA alone.

The team also paired TOFA with semaglutide and tirzepatide in mice. That produced larger improvements in body weight, glucose control, insulin levels and triglycerides than either treatment alone, and Naar said the group views TOFA as complementary to GLP-1 drugs rather than a replacement.

Limitations

TOFA has so far been studied only in animals, and the researchers emphasize that its safety and effectiveness in people will need to be evaluated in future studies. Several ACC inhibitors have reached mid-stage clinical trials, but none has been approved to treat metabolic disease.

The research was funded through discretionary UC Berkeley funds, with assistance from the UCSF Liver Center and the University of Michigan Animal Phenotyping Core. The researchers have formed a company, ReRx Therapeutics, to move the work toward possible use in patients.

Outlook

The authors say the results point to a strategy of raising metabolic activity rather than suppressing appetite, and that TOFA appears to engage what first author Justin Y. Lee called a coordinated metabolic response. Whether any of those effects hold in humans is still an open question.