Obesity and overweight are leading healthcare issues in developed countries and have a significant impact on human health. Despite considerable clinical demand, there are very limited pharmaceutical treatment options currently available. Amongst those recently developed are the serotonin 2C receptor (5-HT2CR) agonist lorcaserin, glucagon-like peptide-1 receptor (GLP-1R) agonists, and melanocortin-4 (MC4R) agonists. These new pharmaceutical treatments function by reducing food intake, however, the brain circuits employed by these medications to produce their therapeutic effect remain unclear. Our work examines the brain circuits required for these medications to function and identifies key pathways involved in regulating food intake.
5-HT2CRs, GLP-1Rs, and MC4Rs are widely distributed throughout the brain including in the key homeostatic region of the nucleus of the solitary tract (NTS) (1,2). The NTS has a major role in the regulation of food intake and several neuropeptides, including GLP-1 produced by preproglucagon (PPGNTS) neurons, are localized here(3). Our results demonstrate that 5-HT2CR agonist lorcaserin requires functional PPGNTS neurons to reduce food intake in mice. Lorcaserin significantly reduced cumulative 1-4 hour food intake in control mice but not PPGNTS ablated mice (treatment x virus F(1,26)= 9.977, p=0.004). Further analysis of the underlying neurocircuitry shows that approximately one-third of PPGNTS neurons express 5-HT2CRs (38.8 ±2.8%) and display the marker of neuronal activity c-FOS following lorcaserin treatment in mice. We next demonstrate, by knocking down expression of the GLP-1R, that GLP-1R NTS neurons are necessary for 5-HT2CR dependent hypophagia. 1-4 hour cumulative food intake was significantly decreased in control mice but not GLP-1R knockdown mice following NTS 5-HT2CR activation (virus x treatment F(2,13)=10.22, p=0.002). However, we identify that NTS GLP-1Rs are not required for GLP-1R agonist induced suppression of food intake. We establish that PPGNTS neurons are also innervated by MC4Rs, and PPGNTS neuron ablation attenuated the prolonged, but not acute, anorectic effect of MC4R agonist melanotan-II (MT-II). MTII reduced cumulative food intake in both PPGNTS neuron ablated and control mice at 1-4 hours (treatment F(1,11)=107.5, p˂0.0001). However, PPGNTS neuron ablated mice were resistant to the anorectic effect of MTII 21 hours (treatment F(1,11)=4.733, p=0.052). These data provide insight into the therapeutic mechanisms of obesity mediations and reveal key brain circuits modulating feeding.

Function of the nucleus of the solitary tract in the therapeutic effect of obesity medication lorcaserin

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