Journal Article

Dissociable hindbrain GLP1R circuits for satiety and aversion

Huang, Kuei-Pin, Acosta, Alisha A., Almeida, Milena S., Gbenou, Yenoukoume S. K., Patel, Nisha, Bolding, Kevin A., Adriaenssens, Alice E., Nyema, Nathaniel T., Hanchak, Nicholas D., Alhadeff, Amber L., McKnight, Aaron D., Ghidewon, Misgana Y.

2024

Overview

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting 1 , 2 , effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTS GLP1R neurons triggers satiety in the absence of aversion, whereas activation of AP GLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTS GLP1R and AP GLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTS GLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence. The neural circuits in the hindbrain that link satiety and aversion are shown to be separate, raising the possibility of developing obesity drugs without the common side effects of nausea and vomiting.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14/10 / 631/378/1488/393 / 631/378/87 / 64 / 64/60 / Ablation / Agonists / Animals / Anti-Obesity Agents - adverse effects / Anti-Obesity Agents - pharmacology / Area postrema / Area Postrema - drug effects / Area Postrema - metabolism / Aversion / Avoidance Learning - drug effects / Avoidance Learning - physiology / Brain / Circuits / Drug therapy / Eating - drug effects / Eating - physiology / Effectiveness / FDA approval / Female / Food / Food aversion / Food intake / Food selection / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide 1 - metabolism / Glucagon-Like Peptide-1 Receptor - metabolism / Glucagon-Like Peptide-1 Receptor Agonists / Hindbrain / Humanities and Social Sciences / In vivo methods and tests / Investigations / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Nausea / Neural networks / Neural Pathways - drug effects / Neuroimaging / Neurons / Neurons - drug effects / Neurons - metabolism / Neurons - physiology / Obesity / Obesity - metabolism / Populations / Rhombencephalon - cytology / Rhombencephalon - drug effects / Rhombencephalon - metabolism / Rhombencephalon - physiology / Satiety / Satiety Response - drug effects / Satiety Response - physiology / Science / Science (multidisciplinary) / Side effects / Solitary Nucleus - cytology / Solitary Nucleus - drug effects / Solitary Nucleus - metabolism / Solitary Nucleus - physiology / Solitary tract nucleus / Stimuli / Weight control / Weight loss