Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus

Kuan-Hui Ethan Chen,Meera G Nair,Nancy M Lainez,Djurdjica Coss

doi:10.1186/s12974-021-02183-2

Kuan-Hui Ethan Chen, Meera G Nair + Show 2 more

Open Access

https://doi.org/10.1186/s12974-021-02183-2

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Abstract

BackgroundObesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. Systemic inflammation is caused by macrophages that infiltrate obese adipose tissues. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia. Since this infiltration contributes to neuroinflammation and neuronal impairment, herein we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice.MethodsC57BL/6J mice were fed HFD (60% kcal from fat) or control diet with matching sucrose levels, for 12–16 weeks. Males and females were analyzed separately to determine sex-specific responses to HFD. Differences in hypothalamic gene expression in HFD-fed male and female mice, compared to their lean controls, in two different areas of the hypothalamus, were determined using the NanoString neuroinflammation panel. Phenotypic changes in macrophages that infiltrated the hypothalamus in HFD-fed mice were determined by analyzing cell surface markers using flow cytometry and compared to changes in macrophages from the adipose tissue and peritoneal cavity. Adipose tissue transplantation was performed to determine the source of hypothalamic macrophages.ResultsWe determined that hypothalamic gene expression profiles demonstrate sex-specific and region-specific diet-induced changes. Sex-specific changes included larger changes in males, while region-specific changes included larger changes in the area surrounding the median eminence. Several genes were identified that may provide partial protection to female mice. We also identified diet-induced changes in macrophage migration into the hypothalamus, adipose tissue, and peritoneal cavity, specifically in males. Further, we determined that hypothalamus-infiltrating macrophages express pro-inflammatory markers and markers of metabolically activated macrophages that were identical to markers of adipose tissue macrophages in HFD-fed mice. Employing adipose tissue transplant, we demonstrate that hypothalamic macrophages can originate from the visceral adipose tissue.ConclusionHFD-fed males experience higher neuroinflammation than females, likely because they accumulate more visceral fat, which provides a source of pro-inflammatory macrophages that migrate to other tissues, including the hypothalamus. Our findings may explain the male bias for neuroinflammation and the metabolic syndrome. Together, our results demonstrate a new connection between the adipose tissue and the hypothalamus in obesity that contributes to neuroinflammation and hypothalamic pathologies.

Highlights

Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation
Initial reports of hypothalamic neuroinflammation in obesity postulated that neuroinflammation is caused by stress and dysfunction of the feeding circuitry neurons, anorexigenic POMC, and orexigenic Neuropeptide Y (NPY), in the arcuate nucleus (ARC), since inflammation was detected in this region [11]
Macrophage influx in the liver and the hypothalamus may contribute to male-biased propensity for obesity-induced pathologies such as heart disease and the metabolic syndrome. In these studies, we identify a connection between macrophage accumulation in the visceral adipose tissue and hypothalamic neuroinflammation in response to obesity

Summary

Introduction

Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia Since this infiltration contributes to neuroinflammation and neuronal impairment, we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice. In addition to activation of microglia, which are resident immune cells of the brain, HFD causes an increase in the number of peripheral macrophages in the hypothalamus of obese animals [9]. Others failed to detect infiltration of peripheral immune cells [15] or argued that the increase is attributed to proliferation of perivascular immune cells [16] To address this discrepancy, here we perform additional analyses to investigate profiles and origin of hypothalamic macrophages in obesity

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