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Short-Term High-Fat Diet Consumption Reduces Hypothalamic Expression of the Nicotinic Acetylcholine Receptor alpha 7 Subunit (alpha 7nAChR) and Affects the Anti-inflammatory Response in a Mouse Model of Sepsis

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Parras Souza, Anelise Cristina [1, 2] ; Souza, Camilla Mendes [1, 2] ; Amara, Camila Libardi [1, 2] ; Lemes, Simone Ferreira [1, 2] ; Santucci, Leticia Foglia [1, 2] ; Milanski, Marciane [1, 2] ; Torsoni, Adriana Souza [1, 2] ; Torsoni, Marcio Alberto [1, 2]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Univ Estadual Campinas, Sch Appl Sci, Limeira - Brazil
[2] Univ Estadual Campinas, Obes & Comorbid Res Ctr, Limeira - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: FRONTIERS IN IMMUNOLOGY; v. 10, MAR 22 2019.
Citações Web of Science: 0

Sepsis is one of the leading causes of death in hospitalized patients and the chronic and low-grade inflammation observed in obesity seems to worsen susceptibility and morbidity of infections. However, little is known with respect to a short-term high-fat diet (HFD) and its role in the development of sepsis. Here, we show for the first time, that short-term HFD consumption impairs early nicotinic acetylcholine receptor alpha 7 subunit (alpha 7nAChR)-mediated signaling, one of the major components of the cholinergic anti-inflammatory pathway, with a focus on hypothalamic inflammation and innate immune response. Mice were randomized to a HFD or standard chow (SC) for 3 days, and sepsis was subsequently induced by a lethal intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) or by cecal ligation and puncture (CLP) surgery. In a separate experiment, both groups received LPS (i.p.) or LPS (i.p.) in conjunction with the selective a alpha nAChR agonist, PNU-282987 (i.p. or intracerebroventricular; i.c.v.), and were sacrificed 2 h after the challenge. Short-term HFD consumption significantly reduced the alpha 7nAChR mRNA and protein levels in the hypothalamus and liver (p < 0.05). Immunofluorescence microscopy demonstrated lower cholinergic receptor nicotinic alpha 7 subunit (alpha 7nAChR)+ cells in the arcuate nucleus (ARC) (alpha 7nAChR+ cells in SC = 216 and HFD = 84) and increased F4/80+ cells in the ARC (2.6-fold) and median eminence (ME) (1.6-fold), which can contribute to neuronal damage. Glial fibrillary acidic protein (GFAP)+ cells and neuronal nuclear antigen (NeuN)+ cells were also increased following consumption of HFD. The HFD-fed mice died quickly after a lethal dose of LPS or following CLP surgery (2-fold compared with SC). The LPS challenge raised most cytokine levels in both groups; however, higher levels of TNF-alpha (Spleen and liver), IL-1 beta and IL-6 (in all tissues evaluated) were observed in HFD-fed mice. Moreover, PNU-282987 administration (i.p. or i.c.v.) reduced the levels of inflammatory markers in the hypothalamus following LPS injection. Nevertheless, when the i.c.v. injection of PNU-282987 was performed the anti-inflammatory effect was much smaller in HFD-fed mice than SC-fed mice. Here, we provide evidence that a short-term HFD impairs early alpha 7nAChR expression in central and peripheral tissues, contributing to a higher probability of death in sepsis. (AU)

Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
Beneficiário:Licio Augusto Velloso
Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 16/23484-1 - Participação de receptores colinérgicos do tipo nicotínico alfa7 (alfa7nAChR) na prevenção do desenvolvimento de resistência à insulina
Beneficiário:Marcio Alberto Torsoni
Modalidade de apoio: Auxílio à Pesquisa - Regular