TY - JOUR
T1 - High fat diet consumption results in mitochondrial dysfunction, oxidative stress, and oligodendrocyte loss in the central nervous system
AU - Langley, Monica R.
AU - Yoon, Hyesook
AU - Kim, Ha Neui
AU - Choi, Chan Il
AU - Simon, Whitney
AU - Kleppe, Laurel
AU - Lanza, Ian R.
AU - LeBrasseur, Nathan K.
AU - Matveyenko, Aleksey
AU - Scarisbrick, Isobel A.
N1 - Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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 HFD 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.
AB - 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 HFD 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.
KW - Apoptosis
KW - High fat diet
KW - Mitochondria
KW - Myelin
KW - Oligodendrocyte
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U2 - 10.1016/j.bbadis.2019.165630
DO - 10.1016/j.bbadis.2019.165630
M3 - Article
C2 - 31816440
AN - SCOPUS:85076707931
SN - 0925-4439
VL - 1866
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 3
M1 - 165630
ER -