New imaging technique tracks obesity drug tirzepatide in cells

An international research team has developed a new imaging approach to track how popular dual agonist drugs – such as tirzepatide – interact with cells in the pancreas and brain. Published in Nature Metabolism, the findings could support the development of more effective treatments for diabetes and obesity.  

Fluorescent probes illuminate drug pathways

The researchers created fluorescently tagged versions of dual-acting molecules that mimic the effects of tirzepatide – a drug that activates hormone receptors GLP-1R and GIPR to control blood sugar and appetite. These new chemical tools – called daLUXendins – allow researchers to visualise how these drugs move through the body and bind to specific cell types.

Mapping metabolic drug targets

Tirzepatide – often marketed as Mounjaro or Zepbound – belongs to a new generation of therapies known as dual agonists – which stimulate both the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). These receptors are found in the pancreas and the brain, where they influence appetite.

Until now, the exact cellular targets of dual agonist drugs were unclear. Antibodies used for receptor detection can be unreliable or unavailable – limiting researchers’ ability to trace drug pathways in tissue.

“By using our new dual fluorescent probes, we can now track the receptors simultaneously in live tissues and identify which cells respond to treatment,” said study co-author Professor David Hodson from the Radcliffe Department of Medicine at the University of Oxford. “This provides a powerful tool for understanding how dual agonists achieve their metabolic effects.”

Seeing how drugs act on the brain

“We are particularly interested in the dynamics of the peptides,” said study lead Dr Johannes Broichhagen (Leibniz-FMP). Using daLUXendins and super-resolution microscopy, the researchers discovered that these fluorescent probes bind strongly to beta, alpha and delta cells in the pancreas offering insight into the range of metabolic effects triggered by tirzepatide.

In the brain, the researchers were able to visualise the drug reaching regions involved in appetite regulation, including specialist cells known as tanycytes that monitor nutrient signals and relay messages to appetite-control regions.

Towards next-generation treatments

The study also found that the receptors form tiny clusters or ‘nanodomains’ in the pancreas – which may help explain how dual agonists amplify signals.

While the research relied on mouse models and fluorescent surrogates of tirzepatide, the researchers believe the approach can be adapted to human studies and expanded to include other targets – like new triple agonists that also act on glucagon receptors.

The study provides important insights into why dual agonists are so successful. At the same time, it raises two new questions: What would happen if the drugs’ access to the brain were improved? And how do new triple agonists with additional glucagon content work?

“The next step will be to see how these results differ from triple agonists, which are more effective again,” said Hodson.