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The pancreas is a mixed gland primarily composed of exocrine tissue, which secretes digestive enzymes into the digestive tract, and an endocrine component organized into small clusters known as islets of Langerhans, constituting approximately 1% of the pancreatic mass. Each adult islet contains an average of 1,500 cells, including beta-, alpha- and delta-cells, which produce and secrete insulin (INS), glucagon (GCG), and somatostatin (SST) respectively. The destruction of insulin-producing beta-cells or the defective insulin secretion give rise to type 1 and type 2 diabetes mellitus, respectively. These chronic metabolic disorders are characterized by the dysregulation of glucose homeostasis. The pathophysiology of diabetes has been extensively studied and beta-cell biology is now described in great details. Glucose is taken up by beta-cells, metabolized and generates an increase in the intracellular ATP:ADP ratio that drives the closure of ATP-sensitive potassium (KATP) channels. This causes membrane depolarization, leading to the activation of voltage-gated calcium channels, which increases intracellular calcium level and initiates insulin secretion. This secretory process is enhanced by signals mediated by insulinotropic Gαs coupled G Protein Coupled Receptors (GPCRs) that increase cAMP levels. For example, this occurs through GCG-, Glucagon-like Peptide 1- (GLP1) and Glucose-dependent insulinotropic polypeptide (GIP)-Receptors, all of which are expressed at the beta-cell surface. In parallel, SST secreted by delta-cells, by acting through its receptors expressed on beta-cells, decreases cAMP levels and insulin secretion. Drugs targeting beta-cell secretion are used to treat patients suffering of type 2 diabetes. They increase insulin secretion by closing the KATP channels (sulfonylureas) or by increasing intracellular cAMP (GLP1R agonists). However, many aspects of pancreatic islet function remain to be further understood. Specifically, more needs to be learned about the role of signals from alpha- and delta-cells on beta-cells within the islets.

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Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression

Stefan Wagner, Daniel I. Brierley, Alasdair Leeson-Payne, Wanqing Jiang, ... Lora K. Heisler

Objective

Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT2CR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here.

Methods

We profiled PPG neurons in the nucleus of the solitary tract (PPGNTS) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGNTS neurons for obesity medication effects on food intake by virally ablating PPGNTS neurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin.

Results

We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTSclusters and that lorcaserin significantly activated PPGNTS neurons. Accordingly, ablation of PPGNTS neurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPGNTS 5-HT2CR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy.

Conclusions

These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGNTS neurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HT2CR agonists.