New Delhi, Newer oral weight loss drugs could be doing more than only suppressing appetite — they may also be directly altering brain circuits that control motivation and reward, according to a new study, findings from which may have implications beyond weight loss and impact how one experiences pleasure.
GLP-1 receptor agonists were originally developed to treat type 2 diabetes by improving insulin response, with weight loss emerging as a secondary benefit. The drugs are known to act on cells or neurons in the hindbrain, located at the base of the skull, contributing to feelings of satiety and nausea.
Researchers from the University of Virginia, US, have found in a genetically engineered mouse model that in addition to the known effects, the newer GLP-1 drugs, including recently approved oral medications such as danuglipron and orforglipron, can reach deep brain regions.
The drugs were found to engage a separate circuit linking the hindbrain to the central amygdala (emotions processing centre) and ultimately to dopamine-producing neurons — the pathway is critical to how the brain assigns value to rewarding experiences, including high-calorie foods, the researchers said.
“What we show is that these drugs can reduce not just hunger, but the desire to pursue rewarding food. They’re acting on the system that makes you want the cake, not just the system that makes you feel full,” lead researcher Ali D Guler, a neuroscientist at the University of Virginia, said.
The findings, published in the journal Nature, also help explain differences among drugs in this rapidly growing class, with certain producing more nausea-like effects and others creating a brain state that reduces food motivation without the same level of discomfort, the researchers said.
They added that the discovery comes at a time pharmaceutical companies are racing to develop more accessible alternatives to injectable GLP-1 therapies.
While oral versions of the treatments are easier to produce, more stable and significantly less expensive — potentially expanding access to millions of patients worldwide — the team said that the findings raise broader questions about how the drugs may affect one’s behaviour.
“If these drugs are affecting reward pathways in the brain, that has implications beyond weight loss. It could influence things like addiction, impulse control or even how people experience pleasure,” Guler said.
Early evidence suggests some patients may find it easier to reduce compulsive behaviours, such as smoking, while others could report a diminished sense of enjoyment — Guler said both outcomes underscore the need for deeper study.
He added that as these medications become more widely used, careful oversight will be essential.
“These are powerful compounds. We need to understand them fully as they move into everyday use,” Guler said.
The authors wrote, “Beyond engaging canonical hypothalamic and hindbrain networks that control metabolic homeostasis, GLP1RAs recruit a discrete population of Glp1r-expressing neurons in the central amygdala, which selectively suppress the consumption of palatable foods by reducing dopamine release in the nucleus accumbens.”
“Stimulating these central amygdalar neurons curtails hedonic feeding, whereas (a) targeted deletion of the receptor in this cell population specifically diminishes the anorectic efficacy of GLP1RAs for reward-driven intake,” they said.
“These findings identify a neural circuit through which small-molecule GLP1RAs modulate reward processing, with implications for the treatment of substance-use disorder and binge eating,” the team said. PTI
