Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice

Clara Machado Campolim,Olivia Pizetta Zordão,Jose Donato,Clílton Kraüss De Oliveira Ferreira,Tamires Marques Zanotto,Gisele De Castro,Raquel Patrícia Ataíde Lima,Mariana Matera Veras,Lais Weissmann,Paulo Hilário Nascimento Saldiva,Paula Gabriele Fernandes Quaresma,Patricia Oliveira Prada,Vitor Ferreira Boico,Ana Paula Segantine Dornellas,Young-Bum Kim

doi:10.1038/s41598-020-67040-3

Abstract

A previous study demonstrated that a high-fat diet (HFD), administered for one-three-days, induces hypothalamic inflammation before obesity’s established, and the long term affects leptin signaling/action due to inflammation. We investigate whether exposure to particulate matter of a diameter of ≤2.5 μm (PM2.5) in mice fed with a chow diet leads to similar metabolic effects caused by high-fat feeding. Compared to the filtered air group (FA), one-day-exposure-PM2.5 did not affect adiposity. However, five-days-exposure-PM2.5 increased hypothalamic microglia density, toll-like-receptor-4 (Tlr4), and the inhibitor-NF-kappa-B-kinase-epsilon (Ikbke) expression. Concurrently, fat mass, food intake (FI), and ucp1 expression in brown adipose tissue were also increased. Besides, decreased hypothalamic STAT3-phosphorylation and Pomc expression were found after twelve-weeks-exposure-PM2.5. These were accompanied by increased FI and lower energy expenditure (EE), leading to obesity, along with increased leptin and insulin levels and HOMA. Mechanistically, the deletion of Tlr4 or knockdown of the Ikbke gene in the hypothalamus was sufficient to reverse the metabolic outcomes of twelve-weeks-exposure-PM2.5. These data demonstrated that short-term exposure-PM2.5 increases hypothalamic inflammation, similar to a HFD. Long-term exposure-PM2.5 is even worse, leading to leptin resistance, hyperphagia, and decreased EE. These effects are most likely due to chronic hypothalamic inflammation, which is regulated by Tlr4 and Ikbke signaling.

Highlights

A previous study demonstrated that a high-fat diet (HFD), administered for one-three-days, induces hypothalamic inflammation before obesity’s established, and the long term affects leptin signaling/ action due to inflammation
The expression of the uncoupling protein 1 (Ucp1) gene in brown adipose tissue (BAT) was elevated in mice exposed to PM2.5 compared to mice exposed to filtered air group (FA) (Fig. 1N)
The findings presented here demonstrated that five days of exposure to PM2.5 was sufficient to induce hypothalamic inflammation before the development of obesity, similar to what occurs in mice fed with a HFD13,15

Summary

Introduction

A previous study demonstrated that a high-fat diet (HFD), administered for one-three-days, induces hypothalamic inflammation before obesity’s established, and the long term affects leptin signaling/ action due to inflammation. The deletion of Tlr[4] or knockdown of the Ikbke gene in the hypothalamus was sufficient to reverse the metabolic outcomes of twelve-weeks-exposure-PM2.5 These data demonstrated that short-term exposure-PM2.5 increases hypothalamic inflammation, similar to a HFD. Long-term exposure-PM2.5 is even worse, leading to leptin resistance, hyperphagia, and decreased EE These effects are most likely due to chronic hypothalamic inflammation, which is regulated by Tlr[4] and Ikbke signaling. Since exposure to PM2.5 triggers inflammation in the peripheral tissues and hypothalamus[10,11,16,17], by analogy, we asked if mice exposed to PM2.5 for a short-term while receiving chow diet could induce this effect before obesity was developed

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