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

Author(s)

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]}

Affiliation

^[1] Univ Estadual Campinas, Sch Appl Sci, Limeira - Brazil

^[2] Univ Estadual Campinas, Obes & Comorbid Res Ctr, Limeira - Brazil

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 10, MAR 22 2019.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/23484-1 - Participation of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in the development of insulin resistance prevention
• Grantee: Marcio Alberto Torsoni
• Support Opportunities: Regular Research Grants