New brain targets for GLP1-based obesity drugs may reduce weight without nausea

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Jul 14 2024

In a recent study published in the journal Nature, a group of researchers identified brain circuits that can be targeted by glucagon-like peptide-1 (GLP1)-based obesity drugs to promote weight loss without causing adverse side effects.

Study: Dissociable hindbrain GLP1R circuits for satiety and aversion. Image Credit: MillaF / Shutterstock

Background 

A long-standing question concerns the relationship between satiety and nausea, as nausea often leads to appetite loss despite occurring independently of physiological satiety. This relationship is particularly relevant given the high prevalence of nausea resulting from various medical conditions. Understanding this relationship is crucial given the prevalence of nausea from various conditions and the urgent need for effective weight-loss treatments. With 2.6 billion people worldwide classified as overweight or obese, the adverse side effects of current weight-loss drugs, especially nausea and vomiting, hinder their efficacy. GLP1 receptor (R) agonists like exenatide, liraglutide, and semaglutide are effective but commonly cause nausea. Further research is needed to develop weight-loss drugs that effectively promote satiety without causing adverse side effects like nausea, thereby improving treatment adherence and efficacy.

About the study 

The present study used various drugs and reagents, including paraformaldehyde, Triton X-100, and semaglutide from suppliers like Millipore Sigma, Bio-Techne, and Cayman. Viral vectors from Addgene and the Neuroscience Center Zurich, as well as herpes simplex virus from the Center for Neuroanatomy with Neurotropic Viruses, were utilized. Mouse models, including Glp1r- internal ribosome entry site-Cre recombinase (ires-Cre) and C57BL/6J (a specific inbred strain of laboratory mice), were housed under controlled conditions from Jackson Labs.

Surgical procedures involved anesthesia and analgesia, with precise viral injections into brain regions like the dorsal vagal complex (DVC), arcuate nucleus of the hypothalamus (ARC), and vagal afferents (nodose ganglion, NG). The study employed advanced techniques such as chemogenetic and optogenetic manipulations, neural ablation, and in vivo imaging. Immunohistochemistry, in situ hybridization, and advanced imaging were used for detailed anatomical and functional analyses.

Experiments assessed GLP1R neuron manipulation on drug-induced anorexia, weight gain prevention, and taste reactivity, using rigorous statistical methods to ensure robust results. Power analyses ensured adequate sample sizes and blinded analyses were conducted to avoid bias. The study's findings were validated through repeated experiments, providing significant insights into GLP1R neurons' roles in obesity treatment, with implications for developing more effective and side-effect-free weight-loss drugs.

Study results 

The study reveals that although GLP1R-expressing cells are distributed throughout the body and brain, GLP1-based obesity drugs specifically target neurons in the hindbrain DVC, ARC, and NG. The necessity of each neural population in the anorexic and weight-loss effects of these drugs had not been systematically tested. Through targeted ablation of each population in Glp1r-ires-Cre mice, researchers discovered that only the DVCGLP1R neurons were essential for the efficacy of GLP1R agonists like exendin-4 and semaglutide in suppressing food intake and preventing weight gain. This identifies the DVC as a crucial site for GLP1R-mediated weight-loss therapeutics.

Activation of DVCGLP1R neurons was shown to suppress food intake in food-deprived mice and reduce body weight through increased satiety without changing energy expenditure. Chronic activation using a Cre-dependent virus encoding NaChBac, a modified bacterial sodium channel, demonstrated this effect in Glp1r-ires-Cre mice. The findings emphasize the importance of DVCGLP1R neurons in reducing food intake and preventing weight gain, underscoring their role as key targets for GLP1-based obesity drugs.

Further investigation into how DVCGLP1R neurons are engaged by obesity drugs and anorexigenic stimuli revealed distinct neural activity patterns in the area postrema (AP) and nucleus of the solitary tract (NTS). Using in vivo two-photon imaging, it was observed that both APGLP1R and NTSGLP1R neurons are activated by semaglutide. However, APGLP1R neurons were more responsive to aversive stimuli, while NTSGLP1R neurons were more responsive to nutritive stimuli, indicating that these neurons have distinct functional roles.

The study also examined the role of these neurons in aversion. Activation of DVCGLP1R neurons induced aversive taste reactivity, suggesting that APGLP1R neurons might drive anorexia through nausea/aversion, while NTSGLP1R neurons inhibit food intake through aversion-independent mechanisms. When testing the necessity of GLP1R in AP or NTS neurons for the effects of GLP1-based obesity drugs, it was found that inhibiting APGLP1R neurons reduced aversion without affecting anorexia. This highlights the potential for developing drugs that target satiety pathways without causing aversion.

Finally, the study mapped the projections of APGLP1R and NTSGLP1R neurons, revealing that they send largely separate projections to the lateral parabrachial nucleus (lPBN) and the paraventricular hypothalamus (PVH), respectively. This anatomical basis supports the functional differences observed, with APGLP1R neurons driving aversion and NTSGLP1R neurons driving satiety. 

Conclusions 

To summarize, this study demonstrates that hindbrain GLP1R neurons are critical for the efficacy of GLP1-based obesity drugs and identifies two distinct GLP1R projections: from the AP driving aversion and from the NTS driving satiety. Functional dissociation of these neurons reveals that activating NTSGLP1R neurons induces satiety without aversion, whereas activating APGLP1R neurons triggers aversion. These findings suggest a promising direction for future drug development, targeting NTSGLP1R neurons to create weight-loss therapies that avoid the adverse side effects seen with current treatments.