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EBioMedicine. 2019 May;43:392-410. doi: 10.1016/j.ebiom.2019.03.087. Epub 2019 Apr 10.

Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course.

Author information

1
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NY, New York, United States of America.
2
Department of Neurology, Icahn School of Medicine at Mount Sinai, NY, New York, United States of America.
3
Advanced Science Research Center at The Graduate Center of The City University of New York and Inter-Institutional Center for Glial Biology at Icahn School of Medicine New York, New York, United States of America.
4
Neuroimmunological Disease Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
5
BERG, LLC. Framingham, MA, United States of America.
6
Department of Chemistry, New York University, NY, New York, United States of America.
7
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, United States of America.
8
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, NY, New York, United States of America; Advanced Science Research Center at The Graduate Center of The City University of New York and Inter-Institutional Center for Glial Biology at Icahn School of Medicine New York, New York, United States of America. Electronic address: patrizia.casaccia@asrc.cuny.edu.

Abstract

BACKGROUND:

Multiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS.

METHODS:

Fifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS.

FINDINGS:

Higher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS.

INTERPRETATION:

High BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes. FUND: This work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.

KEYWORDS:

Epigenetics; Immunity; Lipids; Neurodegeneration; Obesity

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