Activation of the alpha 7 Nicotinic Acetylcholine Receptor Prevents against Microglial-Induced Inflammation and Insulin Resistance in Hypothalamic Neuronal Cells

Author(s)

do Amaral, Camila Libardi ; Alves Martins, Isis de Cassia ; Costa Veras, Alana Carolina ; Simabuco, Fernando Moreira ; Ross, Michael Glenn ; Desai, Mina ; Ignacio-Souza, Leticia Martins ; Milanski, Marciane ; Torsoni, Adriana Souza ; Torsoni, Marcio Alberto

• Document type: Journal article
• Source: CELLS; v. 11, n. 14, p. 15-pg., 2022-07-01.

Abstract

Neuronal hypothalamic insulin resistance is implicated in energy balance dysregulation and contributes to the pathogenesis of several neurodegenerative diseases. Its development has been intimately associated with a neuroinflammatory process mainly orchestrated by activated microglial cells. In this regard, our study aimed to investigate a target that is highly expressed in the hypothalamus and involved in the regulation of the inflammatory process, but still poorly investigated within the context of neuronal insulin resistance: the alpha 7 nicotinic acetylcholine receptor (alpha 7nAchR). Herein, we show that mHypoA-2/29 neurons exposed to pro-inflammatory microglial conditioned medium (MCM) showed higher expression of the pro-inflammatory cytokines IL-6, IL-1 beta, and TNF-alpha, in addition to developing insulin resistance. Activation of alpha 7nAchR with the selective agonist PNU-282987 prevented microglial-induced inflammation by inhibiting NF-kappa B nuclear translocation and increasing IL-10 and tristetraprolin (TTP) gene expression. The anti-inflammatory role of alpha 7nAchR was also accompanied by an improvement in insulin sensitivity and lower activation of neurodegeneration-related markers, such as GSK3 and tau. In conclusion, we show that activation of alpha 7nAchR anti-inflammatory signaling in hypothalamic neurons exerts neuroprotective effects and prevents the development of insulin resistance induced by pro-inflammatory mediators secreted by microglial cells. (AU)

• FAPESP's process: 16/23833-6 - Role of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in preventing insulin resistance in hypothalamic cells.
• Grantee: Camila Libardi Do Amaral
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/07615-7 - Role of nicotinic acetylcholine receptors alpha7 (±7nAChR) in the hypothalamic control of energy homeostasis and association with central signaling of leptin in mice
• Grantee: Marcio Alberto Torsoni
• Support Opportunities: Regular Research Grants