GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is approved for the treatment of obesity; however, there is still much to be learned regarding the neuronal sites of action that underlie its suppressive effects on food intake and body weight. Peripherally administered liraglutide in rats acts in part through central GLP-1Rs in both the hypothalamus and the hindbrain. Here, we extend findings supporting a role for hindbrain GLP-1Rs in mediating the anorectic effects of liraglutide in male rats. To dissociate the contribution of GLP-1Rs in the area postrema (AP) and the nucleus tractus solitarius (NTS), we examined the effects of liraglutide in both NTS AAV-shRNA–driven Glp1r knockdown and AP-lesioned animals. Knockdown of NTS GLP-1Rs, but not surgical lesioning of the AP, attenuated the anorectic and body weight–reducing effects of acutely delivered liraglutide. In addition, NTS c-Fos responses were maintained in AP-lesioned animals. Moreover, NTS Glp1r knockdown was sufficient to attenuate the intake- and body weight–reducing effects of chronic daily administered liraglutide over 3 weeks. Development of improved obesity pharmacotherapies requires an understanding of the cellular phenotypes targeted by GLP-1R agonists. Fluorescence in situ hybridization identified Glp1r transcripts in NTS GABAergic neurons, which when inhibited using chemogenetics, attenuated the food intake– and body weight–reducing effects of liraglutide. This work demonstrates the contribution of NTS GLP-1Rs to the anorectic potential of liraglutide and highlights a phenotypically distinct (GABAergic) population of neurons within the NTS that express the GLP-1R and are involved in the mediation of liraglutide signaling.

Acute changes in systemic glycaemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis

“…In that sense, our work suggests that hypothalamic access is important for long-term fat mobilization induced by GLP-1R agonists, in good agreement with the work of Secher et al who identified the ARC as an important site for the long-term, weight-reducing action of liraglutide (Secher et al, 2014). However, our results do not preclude the possibility that GLP-1R agonists also act on other neural substrate in the NTS (Fortin et al, 2020). Indeed, our study together suggest that glycemic change can modulate the passage of GLP-1R agonist in hindbrain and hypothalamic structure through tanycyte-dependent and independent mechanisms, and throughout different timeframe.…”

“…Hence, the microenvironment determined by the structure of the local capillaries and tanycytes-mediated signaling might confer to each CVO an idiosyncratic and distinct ability to integrate changes in nutrients availability and adapt blood-to-brain passage of metabolic signals. This hypothesis is in line with a recent study by Fortin and colleagues which demonstrates that AP is not required for food intake and body weight-reducing effects of acutely delivered liraglutide, while GLP-1R signaling onto NTS neurons mediates part of the acute anorectic effects of liraglutide (Fortin et al, 2020).…”

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

“…Recent studies have highlighted the importance of NTS GLP-1Rs in mediating the effects of GLP-1 analogs. Selective knockdown of NTS GLP-1Rs attenuates liraglutide-induced decreases in food intake and body weight ( Fortin et al, 2020 ). Moreover, local activation of NTS GLP-1Rs decreases EtOH intake and prevents EtOH-induced accumbal dopamine release ( Vallöf et al, 2019a ).…”

“…In the central nervous system (CNS), GLP-1Rs are expressed in several brain regions involved in regulating metabolism and energy balance, with preferential localization in inhibitory GABAergic neurons over excitatory glutamatergic neurons ( Hayes et al, 2010 ; Cork et al, 2015 ; Fortin et al, 2020 ; Graham et al, 2020 ). In the hypothalamus, activation of GLP-1Rs has been shown to regulate food intake, glycemia, and stress responses ( Kinzig et al, 2003 ; Sandoval et al, 2008 ; Hayes et al, 2010 ; Ghosal et al, 2017 ).…”

Central and peripheral GLP-1 systems independently and additively suppress eating

“…However, one or both of these Glp1r populations may be polysynaptically connected to PPG NTS neurons, in which case vagal and/or endocrine peripheral GLP-1 could still provide substantial input to the central GLP-1 system. PPG NTS neurons may alternatively (or additionally) receive input from other Glp1r-expressing neuronal populations which are accessible to peripheral GLP-1/GLP-1RAs and are reportedly necessary for their hypophagic effects, such as glutamatergic neurons 45 or GABAergic NTS neurons 46 . We therefore investigated whether PPG NTS neurons are a necessary component of any neurocircuits recruited by peripheral GLP-1RAs to suppress eating, by testing whether PPG NTS neuronal ablation attenuates the anorexigenic effects of two long-acting anti-obesity GLP-1RAs, liraglutide and semaglutide ( Fig.…”