A Western diet impairs CNS energy homeostasis and recovery after spinal cord injury: Link to astrocyte metabolism

Abstract

A diet high in fat and sucrose (HFHS), the so-called Western diet promotes metabolic syndrome, a significant comorbidity for individuals with spinal cord injury (SCI). Here we demonstrate that the spinal cord of mice consuming HFHS expresses reduced insulin-like growth factor 1 (IGF-1) and its receptor and shows impaired tricarboxylic acid cycle function, reductions in PLP and increases in astrogliosis, all prior to SCI. After SCI, Western diet impaired sensorimotor and bladder recovery, increased microgliosis, exacerbated oligodendrocyte loss and reduced axon sprouting. Direct and indirect neural injury mechanisms are suggested since HFHS culture conditions drove parallel injury responses directly and indirectly after culture with conditioned media from HFHS-treated astrocytes. In each case, injury mechanisms included reductions in IGF-1R, SIRT1 and PGC-1α and were prevented by metformin. Results highlight the potential for a Western diet to evoke signs of neural insulin resistance and injury and metformin as a strategy to improve mechanisms of neural neuroprotection and repair.

Critical role for astrocyte NAD+glycohydrolase in myelin injury and regeneration

“…In addition, HFD-fed CD38ci mice showed significantly reduced IBA1 immunoreactivity in the ventral grey and white matter of the spinal cord compared to wildtype mice fed a HFD. Although HFD did not significantly increase IBA1immunoreactivity in this study, this is consistent with a recent Western-style diet study from our laboratory and older mice may already have residually higher levels (8,31).…”

“…First, we established increased CD38 expression following HFD consumption. Our previous studies indicate that high fat diets lead to a reduction in oligodendrocytes and their progenitors within the mouse CNS (4,6,8). Next, we demonstrated that CD38 catalytically inactive mice fed a HFD were protected from HFD-mediated loss of oligodendrocytes with concomitant increases in NAD + levels and reduced neuroinflammation and oxidative damage.…”

“…Neuroinflammation and astrogliosis are predominant pathological mediators of neurodegenerative conditions, including MS (9, 41), and astrogliosis is linked to HFDinduced CNS pathology in rodents (8,24). In spinal cord astrocytes of HFD mice, we observed increased CD38 expression and an overall depletion of NAD + .…”

“…Although saturated fat inhibited markers of differentiation in vitro, it was not oligotoxic, suggesting a more complex mechanism at play in vivo (4). Considering the emerging role of astrocytes in the pathology of various neurological disorders (9,11,23) and in the CNS following chronic HFD (7,8,24), along with their known essential metabolic and functional links with oligodendrocytes (25,26), we decided to address the possibility of indirect effects of HFD mediated by astrocytes ( Figure 1A). NAD + is a key mediator of cellular energy status and is involved in mitochondrial function and quality control processes primarily through the activity of sirtuins that require NAD + as a cofactor (19,20,27).…”

“…Astrocyte activation occurs following chronic HFD feeding in the CNS (7,8) and can exert oligotoxic effects (9). Building and maintenance of myelin membranes requires oligodendrocyte fatty acid synthesis, yet oligodendrocytes can utilize lipids from the diet or synthesized by astrocytes (10).…”