Short-Term High-Fat Diet Consumption Reduces Hypothalamic Expression of the Nicotinic Acetylcholine Receptor Œ±7 Subunit (Œ±7nAChR) and Affects the Anti-inflammatory Response in a Mouse Model of Sepsis
Authors: Marciane Milanski
Marcio Alberto Torsoni
Simone Ferreira Lemes
Leticia Foglia Santucci
Adriana Souza Torsoni
Camilla Mendes Souza
Camila Libardi Amaral
Anelise Cristina Parras Souza
Journal: Frontiers in Immunology (2019)
Discipline: IMMUNOLOGY
Keywords: LPS; high-fat diet; inflammation; sepsis; short-term
Affiliations: School of Applied Sciences, University of Campinas, Limeira, Brazil., Obesity and Comorbidities Research Center, State University of Campinas, Limeira, Brazil.

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 Œ±7 subunit (Œ±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 Œ±7nAChR 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 Œ±7nAChR mRNA and protein levels in the hypothalamus and liver (p &lt; 0.05). Immunofluorescence microscopy demonstrated lower cholinergic receptor nicotinic Œ±7 subunit (Œ±7nAChR)+ cells in the arcuate nucleus (ARC) (Œ±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-Œ± (Spleen and liver), IL-1Œ≤ 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 Œ±7nAChR expression in central and peripheral tissues, contributing to a higher probability of death in sepsis. 

Retracted: No

PubPeer comments:
 There are no specific antibodies against a7-nicotinic receptors. Please see: Herber DL, Severance EG, Cuevas J, Morgan D, Gordon MN. Biochemical and histochemical evidence of nonspecific binding of alpha7nAChR antibodies to mouse brain tissue. J Histochem Cytochem. 2004;52(10):1367-76. Allen Brain Atlas shows no expression in hypothalamus: https: mouse.brain-map.org experiment show 74511738 Transcriptomics data also show absence of a7-nicotinic receptors in arcuate nucleus: PMID: 26329458 ,