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Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates

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Abstract

Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity which might help to better understand underlying processes in human obesity. Eighty Wistar rats, between 30 and 60 days of age, were intracerebrally inoculated with Borna disease virus (BDV-1), a neurotropic negative-strand RNA virus infecting an unusually broad host spectrum including humans. Half of the rats developed fatal encephalitis, while the other half, after 3–4 months, continuously gained weight. At tripled weights, rats were sacrificed by trans-cardial fixative perfusion. Neuropathology revealed prevailing inflammatory infiltrates in the median eminence (ME), progressive degeneration of neurons of the paraventricular nucleus, the entorhinal cortex and the amygdala, and a strikingly high-grade involution of the hippocampus with hydrocephalus. Immune histology revealed that major BDV-1 antigens were preferentially present at glutamatergic receptor sites, while GABAergic areas remained free from BDV-1. Virus-induced suppression of the glutamatergic system caused GABAergic predominance. In the hypothalamus, this shifted the energy balance to the anabolic appetite-stimulating side governed by GABA, allowing for excessive fat accumulation in obese rats. Furthermore, inflammatory infiltrates in the ME and ventro-medial arcuate nucleus hindered free access of appetite-suppressing hormones leptin and insulin. The hormone transport system in hypothalamic areas outside the ME became blocked by excessively produced leptin, leading to leptin resistance. The resulting hyperleptinemic milieu combined with suppressed glutamatergic mechanisms was a characteristic feature of the found metabolic pathology. In conclusion, the study provided clear evidence that BDV-1 induced obesity in the rat model is the result of interdependent structural and functional metabolic changes. They can be explained by an immunologically induced hypothalamic microcirculation-defect, combined with a disturbance of neurotransmitter regulatory systems. The proposed mechanism may also have implications for human health. BDV-1 infection has been frequently found in depressive patients. Independently, comorbidity between depression and obesity has been reported, either. Future studies should address the exciting question of whether BDV-1 infection could be a link, whatsoever, between these two conditions.

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Abbreviations

A:

Amygdala

ACTH:

Adrenocorticotropic hormone

AgRP:

Agouti-related peptide

ARC:

Arcuate nucleus

BBB:

Blood–brain barrier

BDV:

Borna disease virus

BDV-1:

Borna disease virus-1

CART:

Cocaine–amphetamine-regulated transcript

CRH:

Corticotropin-releasing hormone

CRP:

C-reactive protein

d.p.n.:

Days post natum

GABA:

γ-Aminobutyric acid

i.c.:

Intracerebral, intracerebrally

MDD:

Major depressive disorder

ME:

Median eminence

MSH:

Melanocyte-stimulating hormone

NPY:

Neuropeptide Y

OW:

Overweight

Oxy:

Oxytocin

p.i.:

Post infection

POMC:

Pro-opiomelanocortin

PVN:

Paraventricular nucleus

SOM:

Somatostatin

SON:

Supraoptic nucleus

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Acknowledgements

This study was financed by the Deutsche Forschungsgemeinschaft (DFG) by grants to Georg Gosztonyi (No. Go 426/3-1) and to Hanns Ludwig (No. Lu 142/5-1, -2, -3) as well as by a grant from the European Union (No. BMH-1-CT 94-1791). Thanks are due to Professor Hans-Hasso Frey for supporting our study with anorectica. We are also grateful to Ms Renate Ehrnsperger and Ms Rita Benz for their excellent technical assistance.

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Authors and Affiliations

  1. Institute of Neuropathology, Charité, University Medicine Berlin, 10117, Berlin, Germany

    Georg Gosztonyi

  2. Freelance Bornavirus Workgroup, 14163, Berlin, Germany

    Hanns Ludwig & Liv Bode

  3. Landesbetrieb Hessisches Landeslabor, 35392, Giessen, Germany

    Moujahed Kao

  4. Division of Pathology, Martin Luther Hospital, 12351, Berlin, Germany

    Manfred Sell

  5. Department of Cell and Developmental Biology, University of North Carolina At Chapel Hill, Chapel Hill, NC, 27599, USA

    Peter Petrusz

  6. Neuromorphological and Neuroendocrine Research Laboratory, Semmelweis University, 1094, Budapest, Hungary

    Béla Halász

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  1. Georg Gosztonyi
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Gosztonyi, G., Ludwig, H., Bode, L. et al. Obesity induced by Borna disease virus in rats: key roles of hypothalamic fast-acting neurotransmitters and inflammatory infiltrates. Brain Struct Funct 225, 1459–1482 (2020). https://doi.org/10.1007/s00429-020-02063-0

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