Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity

Elena Hernández-García,Iñaki Robles-Vera,Francisco J Cueto,Emma C L Cook,Ruth Conde-Garrosa,Sara Charro-Zanca,Ana Redondo-Urzainqui,David Sancho,Ivana Nikolić,Salvador Iborra,Guadalupe Sabio

doi:10.1038/s41423-021-00812-7

Elena Hernández-García, Iñaki Robles-Vera + Show 9 more

Open Access

https://doi.org/10.1038/s41423-021-00812-7

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Abstract

Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

Highlights

Natural selection pressures act against high adiposity due to the risk of predation while disfavoring low levels of adiposity because of the risk of starvation and inability to mount energetically demanding immune responses against diseases and pathogens [1]
While it has been assumed that dendritic cell (DC) play a pathogenic role during overnutrition [10], we found that the abundance of cDC1s in visceral adipose tissue was reduced in mice fed an high-fat diet (HFD) and that reduced expression of cDC1-related genes was characteristic of mice prone to gain more weight (GSE4692)
Flt3lKO mice devoid of Conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) gain less weight than WT mice when fed a high-fat diet (HFD) and have reduced numbers of macrophages in their white adipose tissue (WAT) [10], and several studies have suggested that increased inflammatory effector T cells precede the recruitment of macrophages into adipose tissue [58]

Summary

INTRODUCTION

Natural selection pressures act against high adiposity due to the risk of predation while disfavoring low levels of adiposity because of the risk of starvation and inability to mount energetically demanding immune responses against diseases and pathogens [1]. We found that cDC1 infiltration within WAT relied on the general metabolic status of the body and set out to explore the of commensal microbiota in these mice, and around week 18 in females (Fig. S1d and S1e). Both female and male Batf3KO mice at function of cDC1s in obesity. Analysis of immune infiltrates in the WAT of Batf3-deficient mice before the onset of the obese phenotype revealed impaired WAT infiltration whole-body composition by magnetic resonance imaging (MRI) showed an increase in fat mass but not in lean mass in Batf3KO by NKT and NK cells. Directly on adipocytes [29], we investigated whether the presence or loss of Batf in BM-derived cells prevents or promotes weight

RESULTS

Hernández-García et al 3

DISCUSSION

Findings

MATERIALS AND METHODS