期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1866, 期 3, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2019.165630
关键词
High fat diet; Myelin; Oligodendrocyte; Mitochondria; Apoptosis
资金
- Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology (CMSAN)
- Eugene and Marcia Applebaum Foundation
- Mayo Clinic Center for Biomedical Discovery (CBD)
- Mayo Clinic Metabolomics Core [U24DK100469, UL1TR000135]
- National Multiple Sclerosis Society [R01NS052741, RG4958]
- Craig H. Neilsen Foundation
- Minnesota State Spinal Cord Injury and Traumatic Brain Injury Research Program
Metabolic syndrome is a key risk factor and co-morbidity in multiple sclerosis (MS) and other neurological conditions, such that a better understanding of how a high fat diet contributes to oligodendrocyte loss and the capacity for myelin regeneration has the potential to highlight new treatment targets. Results demonstrate that modeling metabolic dysfunction in mice with chronic high fat diet (HFD) consumption promotes loss of oligodendrocyte progenitors across the brain and spinal cord. A number of transcriptomic and metabolomic changes in ER stress, mitochondrial dysfunction, and oxidative stress pathways in HFD-fed mouse spinal cords were also identified. Moreover, deficits in TCA cycle intermediates and mitochondrial respiration were observed in the chronic HFD spinal cord tissue. Oligodendrocytes are known to be particularly vulnerable to oxidative damage, and we observed increased markers of oxidative stress in both the brain and spinal cord of HFD-fed mice. We additionally identified that increased apoptotic cell death signaling is underway in oligodendrocytes from mice chronically fed a HFD. When cultured under high saturated fat conditions, oligodendrocytes decreased both mitochondrial function and differentiation. Overall, our findings show that HFD-related changes in metabolic regulators, decreased mitochondrial function, and oxidative stress contribute to a loss of myelinating cells. These studies identify FWD consumption as a key modifiable lifestyle factor for improved myelin integrity in the adult central nervous system and in addition new tractable metabolic targets for myelin protection and repair strategies.
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