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Götz, A. ; Lehti, M.* ; Donelan, E.* ; Striese, C. ; Cucuruz, S. ; Sachs, S. ; Yi, C.X.* ; Woods, S.C.* ; Wright, S.D.* ; Tschöp, M.H. ; Gao, Y.* ; Hofmann, S.M.

Circulating HDL levels control hypothalamic astrogliosis via apoA-I.

J. Lipid Res. 59, 1649-1659 (2018)
Publ. Version/Full Text Postprint DOI PMC
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mitochondria ; Inflammation ; High Density Lipoprotein ; Apolipoprotein A-i ; Metabolism ; Dyslipidemia ; Adipose Tissue ; Hypothalamus ; Astrocytes; High-density-lipoprotein; Aortic Endothelial-cells; Alzheimers-disease; Reactive Gliosis; Protein-kinase; Obesity; Inflammation; Astrocytes; Mice; Transcytosis
ISSN (print) / ISBN 0022-2275
e-ISSN 1539-7262
Journal Journal of Lipid Research
Quellenangaben Volume: 59, Issue: 9, Pages: 1649-1659 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Publishing Place 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Regeneration Research (IDR)