Effects of obesity induced by high-calorie diet and its treatment with exenatide on muscarinic acetylcholine receptors in rat hippocampus

Author(s)

Passos Silva, Marcelo Florencio ^[1] ; Alves, Patricia Lucio ^[1] ; Alponti, Rafaela Fadoni ^{[1, 2]} ; Silveira, Paulo Flavio ^[1] ; Francis Abdalla, Fernando Mauricio ^[1]

Affiliation

^[1] Inst Butantan, Pharmacol Lab, Ave Vital Brasil 1500, BR-05503900 Sao Paulo, SP - Brazil

^[2] Univ Oeste Paulista, Fac Med, Jau, SP - Brazil

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 169, NOV 2019.
• Web of Science Citations: 0

Abstract

Here, we described the effects of obesity induced by high-calorie diet and its treatment with exenatide, an anti-diabetogenic and potential anti-obesogenic drug derived from the venom of the Gila monster Heloderma suspectum, on the affinity, density, subtypes and intracellular signaling pathways linked to activation of muscarinic acetylcholine receptors (mAChRs) in rat hippocampus. Male Wistar rats were divided into three groups: control (CT), obese induced by high-calorie diet (DIO) and DIO treated with exenatide (DIO + E). {[}H-3]Quinuclidinyl benzilate specific binding analysis showed that the equilibrium dissociation constant (K-D) did not differ among CT, DIO and DIO+ E, indicating that affinity is not affected by high-calorie diet or its treatment with exenatide. On the other hand, the density of mAChRs obtained in DIO animals was lower than that obtained from CT rats, and that DIO+ E restored the density of mAChRs. Immunoprecipitation assays reveal a decrease in the expression of M-1 and M-3 subtypes of DIO animals when compared with CT. Treatment with exenatide (DIO+ E) restored the expression of the two subtypes similar to obtained from CT. On the other hand, the M-2, M-4 and M-5 mAChR subtypes expression did not differ among CT, DIO and DIO+ E. Carbacol caused a concentration-dependent increase in the accumulation of total {[}H-3] inositol phosphate in CT, DIO and DIO+ E. However, the magnitude of the maximal response to carbachol was lower in DIO when compared with those obtained from CT and DIO+ E animals, which did not differ from each other. Our results indicate that obesity induced by high-calorie diet strongly influences the expression and intracellular signaling coupled to M-1-M-3 mAChR subtypes. The exenatide ameliorated these effects, suggesting an important role on hippocampal muscarinic cholinergic system. This action of obesity induced by high-calorie diet and its treatment with exenatide might be a key step mediating cellular events important for learning and memory. (AU)

• FAPESP's process: 16/24258-5 - Effects of diet-induced obesity and its treatment with exenatide on expression of muscarinic acethylcholine receptor subtypes in rat hippocampus
• Grantee: Fernando Maurício Francis Abdalla
• Support Opportunities: Regular Research Grants