Dectin-1 Activation Exacerbates Obesity and Insulin Resistance in the Absence of MyD88

Ângela Castoldi ,Niels Olsen Saraiva Câmara,Mariane Tami Amano,Marcelo A Mori,Christian Hoffmann,Marcela Teatin Latância,Aline Ignácio,Meire Ioshie Hiyane,Rafael Ribeiro Almeida,Marina Barguil Macêdo,Joanna Darck Carola Correia Lima,Thiago Belchior,Jennifer Lee,Marina Burgos Da Silva,Marília Seelaender,Gordon D Brown,Marcelli Terumi Miyagi,Vinícius Andrade-Oliveira ,Pedro M Moraes‐Vieira ,Luis Alberto Luévano‐Martínez ,Flávio Vieira Loures ,Jonas Weissmann Gaiarsa ,Tárcio Teodoro Braga ,Cristhiane Fávero De Aguiar ,William T Festuccia ,José Antônio Tavares De Albuquerque

doi:10.1016/j.celrep.2017.05.059

Abstract

SUMMARYThe underlying mechanism by which MyD88 regulates the development of obesity, metainflammation, and insulin resistance (IR) remains unknown. Global deletion of MyD88 in high-fat diet (HFD)-fed mice resulted in increased weight gain, impaired glucose homeostasis, elevated Dectin-1 expression in adipose tissue (AT), and proinflammatory CD11c+ AT macrophages (ATMs). Dectin-1 KO mice were protected from diet-induced obesity (DIO) and IR and had reduced CD11c+ AT macrophages. Dectin-1 antagonist improved glucose homeostasis and decreased CD11c+ AT macrophages in chow- and HFD-fed MyD88 KO mice. Dectin-1 agonist worsened glucose homeostasis in MyD88 KO mice. Dectin-1 expression is increased in AT from obese individuals. Together, our data indicate that Dectin-1 regulates AT inflammation by promoting CD11c+ AT macrophages in the absence of MyD88 and identify a role for Dectin-1 in chronic inflammatory states, such as obesity. This suggests that Dectin-1 may have therapeutic implications as a biomarker for metabolic dysregulation in humans.

Highlights

Obesity is characterized by excessive accumulation of white adipose tissue (AT) due in part to increased food intake, decreased energy expenditure, and changes in lifestyle (Mokdad et al, 2003)
Toll-like receptors (TLRs) can signal through myeloid differentiation primary response gene 88 (MyD88) (Adachi et al, 1998), an adaptor molecule expressed in immune cells, epithelial cells, and adipocytes (Bhinder et al, 2014; Everard et al, 2014; Hoshi et al, 2012; Yu et al, 2014)
Absence of MyD88 Signaling Exacerbates ObesityInduced insulin resistance (IR) and Polarization of AT Macrophages toward a Proinflammatory Phenotype MyD88 signaling is a critical component for TLR signaling

Summary

Introduction

Obesity is characterized by excessive accumulation of white adipose tissue (AT) due in part to increased food intake, decreased energy expenditure, and changes in lifestyle (Mokdad et al, 2003). According to the World Health Organization (WHO), 39% of adults over 18 years are overweight and 13% are clinically obese (WHO, 2015). A significant number of obese people are insulin resistant, and obesity is strongly correlated with systemic low-grade inflammation (Belkina and Denis, 2010), highlighting the role of the immune system in the development of insulin resistance (IR). Innate immune receptors, such as Toll-like receptors (TLRs), are expressed in adipocytes and AT macrophages (ATMs) and are important molecules that orchestrate inflammationinduced IR. Some studies showed that whole-body MyD88-deficient mice develop exacerbated IR in the absence

Results

Discussion

Conclusion