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J Lipid Res. 2018 Sep;59(9):1649-1659. doi: 10.1194/jlr.M085456. Epub 2018 Jul 10.

Circulating HDL levels control hypothalamic astrogliosis via apoA-I.

Author information

1
Institutes for Diabetes and Obesity Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
2
Department of Internal Medicine I, University Hospital RWTH Aachen, Aachen, Germany.
3
LIKES Research Centre for Physical Activity and Health, Jyväskylä, Finland.
4
Metabolic Disease Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH.
5
Diabetes and Regeneration Research, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
6
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
7
CSL Behring, King of Prussia, PA.
8
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
9
Nanjing Medical University, College of Pharmacy, Nanjing, China susanna.hofmann@helmholtz-muenchen.de yuanqinggao@njmu.edu.cn.
10
German Center for Diabetes Research (DZD), München-Neuherberg, Germany susanna.hofmann@helmholtz-muenchen.de yuanqinggao@njmu.edu.cn.
11
Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilian Universität, Munich, Germany.

Abstract

Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I-/-) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I-/- compared with apoA-I+/+ mice and was associated with compromised mitochondrial function. apoA-I-/- mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I+/+ controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I-/- mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.

KEYWORDS:

adipose tissue; apolipoprotein A-I; astrocytes; dyslipidemia; high density lipoprotein; hypothalamus; inflammation; metabolism; mitochondria

PMID:
29991652
PMCID:
PMC6121940
[Available on 2019-09-01]
DOI:
10.1194/jlr.M085456

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