Drugs like Ozempic and Wegovy mimic a natural hormone called GLP-1 to lower blood sugar and reduce appetite. A newer medicine, Mounjaro (tirzepatide), goes one step further, activating two hormone receptors — GLP-1 and GIP — and delivering greater benefits for both glucose control and weight loss. However, until now, scientists did not fully understand which cells and brain circuits made this possible.
The research team developed fluorescent versions of these dual-target drugs, known as daLUXendins. These probes behave like the real medicines but also light up under a microscope, allowing researchers to track them in fine detail.
In studies on mice, the team discovered that daLUXendins targeted a wider range of pancreatic cells than single-target drugs — not just insulin-producing beta cells, but also alpha and delta cells, which communicate with beta cells to regulate blood sugar. In the brain, the glowing drugs reached regions that control appetite and even lit up metabolite-sensing cells called tanycytes, which send signals about hunger.
'Dual agonists aren't just more powerful because they act on two receptors,' said Professor David Hodson, Radcliffe Department of Medicine, University of Oxford. 'They also reach a broader network of cells, which may be key to their superior effects.'
The study also showed that the drugs' advantage comes from the diversity of cells and neurons they engage — not from deeper penetration into the brain. While the research was carried out in mice and more work is needed to confirm the same effects in humans, the findings could guide the design of even more effective therapies, including triple-target drugs now being tested.
The research, led by Annie de Bray as part of her DPhil at Oxford, took four years from development to publication. During that time, multiple new dual agonists entered clinical trials — but the team's detailed imaging work provides a unique blueprint for understanding how they work at the cellular level.