Subchronic exposure to 1,2-naphthoquinone induces adipose tissue inflammation and changes the energy homeostasis of mice, partially due to TNFR1 and TLR4

Clílton Kraüss de Oliveira Ferreira; Clara Machado Campolim; Olívia Pizetta Zordão; Fernando Moreira Simabuco; Chadi Pellegrini Anaruma; Rodrigo Martins Pereira; Vitor Ferreira Boico; Luiz Guilherme Salvino; Maíra Maftoum Costa; Nathalia Quintero Ruiz; Leandro Pereira de Moura; Mario Jose Abdalla Saad; Soraia Katia Pereira Costa; Young-Bum Kim; Patricia Oliveira Prada

doi:10.1016/j.toxrep.2023.06.002

Subchronic exposure to 1,2-naphthoquinone induces adipose tissue inflammation and changes the energy homeostasis of mice, partially due to TNFR1 and TLR4

Toxicol Rep. 2023 Jun 15:11:10-22. doi: 10.1016/j.toxrep.2023.06.002. eCollection 2023 Dec.

Authors

Clílton Kraüss de Oliveira Ferreira¹, Clara Machado Campolim², Olívia Pizetta Zordão², Fernando Moreira Simabuco¹, Chadi Pellegrini Anaruma³, Rodrigo Martins Pereira¹, Vitor Ferreira Boico¹, Luiz Guilherme Salvino¹, Maíra Maftoum Costa¹, Nathalia Quintero Ruiz¹, Leandro Pereira de Moura^{1

3}, Mario Jose Abdalla Saad², Soraia Katia Pereira Costa⁴, Young-Bum Kim⁵, Patricia Oliveira Prada^{1

2

6}

Affiliations

¹ Faculty of Applied Sciences, State University of Campinas, Limeira, SP, Brazil.
² Department of Internal Medicine, Faculty of Medical Science, State University of Campinas, Campinas, SP, Brazil.
³ Department of Physical Education, Institute of Biosciences - São Paulo State University, Rio Claro, SP, Brazil.
⁴ Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
⁵ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁶ Max-Planck Institute for Metabolism Research, Köln, Germany.

Abstract

Air pollution affects energy homeostasis detrimentally. Yet, knowledge of how each isolated pollutant can impact energy metabolism remains incomplete. The present study was designed to investigate the distinct effects of 1,2-naphthoquinone (1,2-NQ) on energy metabolism since this pollutant increases at the same rate as diesel combustion. In particular, we aimed to determine in vivo effects of subchronic exposure to 1,2-NQ on metabolic and inflammatory parameters of wild-type mice (WT) and to explore the involvement of tumor necrosis factor receptor 1 (TNFR1) and toll-like receptor 4 (TLR4) in this process. Males WT, TNFR1KO, and TLR4KO mice at eight weeks of age received 1,2-NQ or vehicle via nebulization five days a week for 17 weeks. In WT mice, 1,2-NQ slightly decreased the body mass compared to vehicle-WT. This effect was likely due to a mild food intake reduction and increased energy expenditure (EE) observed after six weeks of exposure. After nine weeks of exposure, we observed higher fasting blood glucose and impaired glucose tolerance, whereas insulin sensitivity was slightly improved compared to vehicle-WT. After 17 weeks of 1,2-NQ exposure, WT mice displayed an increased percentage of M1 and a decreased (p = 0.057) percentage of M2 macrophages in adipose tissue. The deletion of TNFR1 and TLR4 abolished most of the metabolic impacts caused by 1,2-NQ exposure, except for the EE and insulin sensitivity, which remained high in these mice under 1,2-NQ exposure. Our study demonstrates for the first time that subchronic exposure to 1,2-NQ affects energy metabolism in vivo. Although 1,2-NQ increased EE and slightly reduced feeding and body mass, the WT mice displayed higher inflammation in adipose tissue and impaired fasting blood glucose and glucose tolerance. Thus, in vivo subchronic exposure to 1,2-NQ is harmful, and TNFR1 and TLR4 are partially involved in these outcomes.

Keywords: 1; 2-naphthoquinone; Air pollution; Diesel; Energy balance; Inflammation; Macrophages; PM2.5; White adipose tissue.