New study unveils brain targets for improved GLP1-based obesity drugs

A recent study published in the journal Nature revealed researchers have identified specific brain circuits that can be targeted by glucagon-like peptide-1 (GLP1)-based obesity drugs to promote weight loss without the common side effect of nausea.

The relationship between satiety and nausea has long puzzled scientists. While nausea often leads to appetite loss, it operates independently of physiological satiety. This distinction is crucial because nausea is a prevalent side effect of many weight-loss drugs, complicating their use.

 The study utilised a comprehensive array of drugs, reagents, surgical procedures and advanced techniques. The researchers conducted experiments on mouse models housed under controlled conditions.

 The study revealed that GLP1-based obesity drugs target neurons in the hindbrain, specifically in the DVC, ARC, and nodose ganglion (NG). By systematically ablating each neural population in mice, researchers found that only the DVC GLP1R neurons were crucial for the drugs' efficacy in suppressing food intake and preventing weight gain.

Activation of DVC GLP1R neurons suppressed food intake and reduced body weight by increasing satiety without altering energy expenditure. Chronic activation of these neurons in mice confirmed their role in reducing food intake and preventing weight gain, highlighting their potential as targets for obesity drugs.

The study also explored the role of these neurons in aversion. Activation of DVC GLP1R neurons induced aversive taste reactivity, suggesting that AP GLP1R neurons might drive anorexia through nausea, while NTS GLP1R neurons inhibit food intake through non-aversive mechanisms. Inhibiting AP GLP1R neurons reduced aversion without affecting anorexia, highlighting a potential pathway for developing drugs that promote satiety without causing nausea.

 Mapping the projections of AP GLP1R and NTS GLP1R neurons showed that they send separate projections to the lateral parabrachial nucleus (lPBN) and the paraventricular hypothalamus (PVH), respectively. This anatomical basis supports the observed functional differences, with AP GLP1R neurons driving aversion and NTS GLP1R neurons driving satiety.

This research demonstrates that hindbrain GLP1R neurons are critical for the efficacy of GLP1-based obesity drugs and identifies two distinct projections: AP GLP1R neurons driving aversion and NTS GLP1R neurons driving satiety. By targeting NTS GLP1R neurons, future weight-loss therapies could potentially avoid the adverse side effects of nausea, offering a more effective and tolerable treatment for obesity.