Function of astrocyte MyD88 in high-fat-diet-induced hypothalamic inflammation

Sungho Jin,Jae Geun Kim,Kwang Kon Kim,Tae Hwan Lee,Bora Jeong,Dong Hee Kim,Byong Seo Park,Byung Ju Lee,Jeong Woo Park,Dasol Kang

doi:10.1186/s12974-020-01846-w

Sungho Jin, Jae Geun Kim + Show 8 more

Open Access

https://doi.org/10.1186/s12974-020-01846-w

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Abstract

BackgroundA growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. In particular, reactive gliosis accompanied by inflammatory responses in the hypothalamus are pivotal cellular events that elicit metabolic abnormalities. In this study, we examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity.MethodsTo analyze the role of astrocyte MyD88 in obesity pathogenesis, we used astrocyte-specific Myd88 knockout (KO) mice fed a high-fat diet (HFD) for 16 weeks or injected with saturated free fatty acids. Astrocyte-specific gene expression in the hypothalamus was determined using real-time PCR with mRNA purified by the Ribo-Tag system. Immunohistochemistry was used to detect the expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, phosphorylated signal transducer and activator of transcription 3, and α-melanocyte-stimulating hormone in the hypothalamus. Animals’ energy expenditure was measured using an indirect calorimetry system.ResultsThe astrocyte-specific Myd88 KO mice displayed ameliorated hypothalamic reactive gliosis and inflammation induced by injections of saturated free fatty acids and a long-term HFD. Accordingly, the KO mice were resistant to long-term HFD-induced obesity and showed an improvement in HFD-induced leptin resistance.ConclusionsThese results suggest that MyD88 in hypothalamic astrocytes is a critical molecular unit for obesity pathogenesis that acts by mediating HFD signals for reactive gliosis and inflammation.

Highlights

A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity
According to the recent literature, neuroinflammation and reactive gliosis can be observed in the hypothalami of mice exposed to a highfat diet (HFD) before the occurrence of significant body weight gain, and this is sustained with continuous HFD feeding, suggesting that hypothalamic gliosis accompanied by inflammation is a crucial cellular event in obesity pathogenesis [12,13,14,15]
We investigated whether Myeloid differentiation primary response 88 (MyD88) signaling in astrocytes is involved in hypothalamic inflammation and reactive gliosis and whether altering the activity of MyD88 signaling in astrocytes, using mutant mice bearing an astrocyte-specific deletion of Myd88 gene expression, would affect the obesity phenotype and leptin resistance induced by HFD consumption

Summary

Introduction

A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. Reactive gliosis accompanied by inflammatory responses in the hypothalamus are pivotal cellular events that elicit metabolic abnormalities. We examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity. According to the recent literature, neuroinflammation and reactive gliosis can be observed in the hypothalami of mice exposed to a highfat diet (HFD) before the occurrence of significant body weight gain, and this is sustained with continuous HFD feeding, suggesting that hypothalamic gliosis accompanied by inflammation is a crucial cellular event in obesity pathogenesis [12,13,14,15]. Unmasking the underlying mechanism by which an HFD induces hypothalamic inflammation and gliosis is required to better understand the initiation and deterioration of metabolic disorders caused by over-nutrition

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