Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

Abstract

Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

Therapeutic potential of PPARγ natural agonists in liver diseases

“…Semple reviewed the function of PPARγ and its variants in metabolic syndrome . In addition, Jia, Chigurupati and Vallée analysed therapeutic potential of PPARγ agonists in diabetes. PPARγ agonists improve insulin sensitivity and treat complications of diabetes.…”

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation

“…Among the endogenous cell processes capable of promoting mitochondrial functions and the endogenous defense mechanisms there are those triggered by the peroxisome proliferator-activated receptor gamma (PPAR-γ) and by the transcription factor nuclear factor-erythroid 2 (NF-E2)-related factor (NRF2) [ 10 , 11 ].…”

Potential Circadian Rhythms in Oligodendrocytes? Working Together Through Time

“…An intriguing example of the interactions between circadian disorders and MS comes from work on the interplay between the PPARγ and the WNT/β-Catenin signalling pathways [138]. PPARγ is a circadian transcription factor [139], know to regulate rhythmic metabolism, including glucose and lipid metabolism, and to have an anti-inflammatory effect by acting on the levels of NF-κB.…”

“…Impaired OPC differentiation and failure to remyelinate in MS and EAE are, at least in part, a consequence of overactivation of the WNT/β-Catenin signalling pathway. PPARγ absence aggravates EAE pathophysiology, whilst, its agonists have shown anti-inflammatory and neuroprotective effects, in addition to rendering the environment permissive to remyelination and ameliorating both EAE and MS symptoms [138]. Hence, PPARγ agonists appear a promising treatment to promote remyelination by abolishing the prohibitive effects of the WNT/beta-catenin pathway through regulation of NF-κB activity.…”