The Journal of clinical investigationSep 15, 2026

A specific brainstem circuit controls the unpleasant and appetite-reducing effects of GLP1R activators

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Updated Sep 16, 2026

Abstract

Silencing Glp1r neurons in specific brain regions revealed distinct roles in body weight regulation, with NTSGlp1r neurons contributing to normal feeding restraint but not to GLP1RA-induced weight loss.

NTSGlp1r neurons are involved in controlling food intake and maintaining body weight under normal conditions.
APGlp1r neurons do not play a role in normal feeding but are linked to the weight-lowering effects of GLP1 receptor agonists.
APGlp1r neurons are also associated with the aversive effects of GLP1 receptor agonists, such as nausea.
The findings suggest a separation in the functions of these neurons, with NTSGlp1r neurons promoting satiation without contributing to the weight loss seen with GLP1 receptor agonists.

Simplified

GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Here, we silenced Glp1r neurons in the nucleus of the solitary tract or area postrema (NTSGlp1r or APGlp1r neurons, respectively) or restored their GLP1R signaling on an otherwise GLP1R-deficient background to determine physiological and pharmacological roles for each neuron population. Although NTSGlp1r neurons contributed to the normal restraint of food intake and body weight, they failed to mediate GLP1RA-dependent weight loss. In contrast, while we detected no role for APGlp1r neurons in physiological feeding, they mediated both the weight-lowering and aversive effects of GLP1RAs. Therefore, while non-aversive NTSGlp1r neurons control physiologic satiation they do not contribute to weight loss during GLP1RA treatment. Rather, APGlp1r neurons mediate both the weight-lowering and aversive effects of GLP1RAs, preventing the separation of their nauseating and weight-loss effects at a circuit level.

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A specific brainstem circuit controls the unpleasant and appetite-reducing effects of GLP1R activators

Abstract

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