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

Preclinical animal study using single nucleus RNA sequencing, histochemistry, viral ablation, and feeding behavior assays in mice.

“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.”

Adult male and female transgenic and wildtype mice (10–32 weeks old), including PpgYFP, PpgCRE, 5-ht2CrCRE, PomcDsRED, Mc4rGFP, and Mc4r null lines.

“Adult male and female PpgYFP [23], PpgCRE [24], 5-ht2CrCRE, 5-ht2CrCRE:YFP [6,25], PomcDsRED [6,26], Mc4rGFP (Jackson Labs, B6.Cg-Tg (Mc4r-MAPT/Sapphire)21Rck/J), loxtb Mc4r null [4] and wildtype (C57BL/6NJ background from transgenic strains) mice (10–32 weeks old) were used (n = 171).”

Total of 171 mice across all experimental groups.

“Adult male and female PpgYFP [23], PpgCRE [24], 5-ht2CrCRE, 5-ht2CrCRE:YFP [6,25], PomcDsRED [6,26], Mc4rGFP (Jackson Labs, B6.Cg-Tg (Mc4r-MAPT/Sapphire)21Rck/J), loxtb Mc4r null [4] and wildtype (C57BL/6NJ background from transgenic strains) mice (10–32 weeks old) were used (n = 171).”

Feeding behavior was measured at 1, 2, 4, and 21 hours post-treatment, with body weight assessed at 24 hours; viral tracing studies involved a 3-week recovery period.

“Mice were administered obesity medications or saline vehicle i.p. at 5 mg/ml dose volume 30 min prior to dark onset, at which point a pre-weighed amount of their standard chow (Teklad 2018, Envigo) was returned, and intake measured 1, 2, 4 and 21 hr later, at which point 24 hr body weight change was also measured.”

5-HT2CRs are widely expressed in PPGNTS neurons, and lorcaserin activates these neurons, which is necessary for its food intake suppressive effect.

“We found that 5-HT2CRs, but not GLP-1Rs or MC4Rs, were widespread in PPGNTS clusters 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.”

PPGNTS neurons are not required for the food intake suppressive effects of the MC4R agonist melanotan-II.

“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.”

Combining lorcaserin with GLP-1R agonists (liraglutide or exendin-4) produced greater food intake reduction than either drug alone.

“Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy.”

The study was conducted in mice, and the authors note that GLP-1R agonists show limited brain penetrance in humans, suggesting potential differences in mechanism between species.

“However, GLP-1R agonists show limited brain penetrance, at least acutely [2,10,11], and liraglutide-induced cFOS in neurons beyond the circumventricular organs is found primarily in cells not expressing GLP-1Rs [12].”