Hypophagia induced by hindbrain serotonin is mediated through central GLP-1 signaling and involves 5-HT2C and 5-HT3 receptor activation

Abstract

The overlap in neurobiological circuitry mediating the physiological and behavioral response to satiation and noxious/stressful stimuli are not well understood. The interaction between serotonin (5-HT) and glucagon-like peptide-1 (GLP-1) could play a role as upstream effectors involved in mediating associations between anorectic and noxious/stressful stimuli. We hypothesize that 5-HT acts as an endogenous modulator of the central GLP-1 system to mediate satiation and malaise in rats. Here, we investigate whether interactions between central 5-HT and GLP-1 signaling are behaviorally and physiologically relevant for the control of food intake and pica (i.e., behavioral measure of malaise). Results show that the anorexia and body weight changes induced by administration of exogenous hindbrain 5-HT are dependent on central GLP-1 receptor signaling. Furthermore, anatomical evidence shows mRNA expression of 5-HT2C and 5-HT3 receptors on GLP-1-producing preproglucagon (PPG) neurons in the medial nucleus tractus solitarius by fluorescent in situ hybridization, suggesting that PPG neurons are likely to express both of these receptors. Behaviorally, the hypophagia induced by the pharmacological activation of both of these receptors is also dependent on GLP-1 signaling. Finally, 5-HT3, but not 5-HT2C receptors, are required for the anorectic effects of the interoceptive stressor LiCl, suggesting the hypophagia induced by these 5-HT receptors may be driven by different mechanisms. Our findings highlight 5-HT as a novel endogenous modulator of the central GLP-1 system and suggest that the central interaction between 5-HT and GLP-1 is involved in the control of food intake in rats.

GDF15 Induces Anorexia through Nausea and Emesis

“…We then tested the ability of Ond to attenuate pica, anorexia, and the consequent body weight loss induced by GDF15. Systemic Ond pre-treatment by itself did not affect food intake nor body weight and did not stimulate kaolin intake compared to their relative controls ( Figures 4A-4C), corroborating previous reports (Hayes and Covasa, 2006;Leon et al, 2019). Post hoc analysis revealed that systemic Ond pre-treatment was effective in attenuating GDF15-induced anorexia, leading to greater food intake compared to GDF15treated animals at 24 h and 48 h, respectively.…”

“…103639-04-9)was either dissolved in artificial cerebrospinal fluid (aCSF; Harvard Apparatus, Cat. 59-7316) for icv delivery (25 µg) or dissolved in 0.9% saline and injected at 1 mg/kg ip as previously described (Hayes and Covasa, 2006;Leon et al, 2019). LiCl (0.15 M in 0.9% saline, 20 mL/kg, Sigma Aldrich, Cat.…”

“…Indeed, while serotonin (5-HT) is classically known to play a key role in emesis (Endo et al, 2000), with 5-HT receptor 3 (5-HT3R) antagonists (e.g., ondansetron; Ond) being among the most widely used antiemetics (Aapro, 2005;Herrstedt, 2018), many patients under-going emetogenic chemotherapy receiving 5-HT3R antagonists, alone or in combination with other antiemetics (e.g., aprepitant and olanzapine), still report feeling ill and have reduced appetite following treatment (Feyer and Jordan, 2011;Grunberg et al, 2004;Hesketh, 2008;Keeley, 2009;Sutherland et al, 2018). Given that both hindbrain terminal vagal afferent fibers and AP/ NTS neurons express 5-HT3Rs, which are collectively thought to contribute to the intake suppressive effects and nausea/ emesis of chemotherapy (Browning, 2015;Leon et al, 2019), testing whether antagonizing vagal or brainstem 5-HT3R signaling influences AP/NTS GDF15-GFRAL signaling could be of relevance to anorexia and nausea/emesis. As many ongoing trials are underway examining the GDF15 system, an open question is whether or not, in addition to long-term changes in anorexia and body weight loss, exogenous GDF15 administration can produce behaviors indictive of nausea and/or emesis (specifically in species that can vomit).…”

Exenatide, a GLP‐1 analog, has healing effects on LPS‐induced autism model: Inflammation, oxidative stress, gliosis, cerebral GABA, and serotonin interactions

“…In a growing number of studies, Exenatide, a long‐acting glucagon‐like peptide 1 (GLP‐1) analog, has been reported to stimulate neurogenesis, suppress inflammation, and have healing effects on behavior by showing antioxidant properties in the central nervous system (CNS) (Perry et al, 2003; Solmaz et al, 2015). In addition, GLP has also been shown to have modulatory effects on serotonin and GABA in CNS (Leon et al, 2019; Rebosio, Balbi, Passalacqua, Ricciarelli, & Fedele, 2018).…”

Perinatal Protein Malnutrition Modulates the Immunoreactivity of 5-Ht1b and Density of 5-Ht in the Nucleus of the Solitary Tract (Nts) of Young Rats in Response to a Feeding Stimulus / Desnutrição Protéica Perinatal Modula a Imunorreatividade De 5-Ht1b E a Densidade De 5-Ht No Núcleo Do Trato Solitário (Nts) De Ratos Jovens Em Resposta À Estimulo Alimentar

“…In this context, the family of receptors 5-HT2, and the receptors 5-HT1A and 5-HT3 have been implicated in satiety signalization specifically in the NTS, through activation of GLP-1 producing neurons (20,30,31). Despite we know this, much remains to be elucidated, especially with regard to its responses to environmental stimuli.…”