Activation of the α7 Nicotinic Acetylcholine Receptor Prevents against Microglial-Induced Inflammation and Insulin Resistance in Hypothalamic Neuronal Cells
Camila Libardi do Amaral,
Ísis de Cássia Alves Martins,
Alana Carolina Costa Veras,
Fernando Moreira Simabuco,
Michael Glenn Ross,
Mina Desai,
Leticia Martins Ignácio-Souza,
Marciane Milanski,
Adriana Souza Torsoni,
Marcio Alberto Torsoni
Affiliations
Camila Libardi do Amaral
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Ísis de Cássia Alves Martins
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Alana Carolina Costa Veras
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Fernando Moreira Simabuco
Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Michael Glenn Ross
The Lundquist Institute, David Geffen School of Medicine, Harbor-UCLA Medical Center, University of California, Los Angeles, CA 90095, USA
Mina Desai
The Lundquist Institute, David Geffen School of Medicine, Harbor-UCLA Medical Center, University of California, Los Angeles, CA 90095, USA
Leticia Martins Ignácio-Souza
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Marciane Milanski
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Adriana Souza Torsoni
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
Marcio Alberto Torsoni
Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira 13484-350, Brazil
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 α7 nicotinic acetylcholine receptor (α7nAchR). 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-1β, and TNF-α, in addition to developing insulin resistance. Activation of α7nAchR with the selective agonist PNU-282987 prevented microglial-induced inflammation by inhibiting NF-κB nuclear translocation and increasing IL-10 and tristetraprolin (TTP) gene expression. The anti-inflammatory role of α7nAchR 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 α7nAchR 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.
