High-Fat Diet Induces Neuroinflammation and Mitochondrial Impairment in Mice Cerebral Cortex and Synaptic Fraction

Abstract

Brain mitochondrial dysfunction is involved in the development of neurological and neurodegenerative diseases. Mitochondria specifically located at synapses play a key role in providing energy to support synaptic functions and plasticity, thus their defects may lead to synaptic failure, which is a common hallmark of neurodegenerative diseases. High-Fat Diet (HFD) consumption increases brain oxidative stress and impairs brain mitochondrial functions, although the underlying mechanisms are not completely understood. The aim of our study is to analyze neuroinflammation and mitochondrial dysfunctions in brain cortex and synaptosomal fraction isolated from a mouse model of diet-induced obesity. Male C57Bl/6 mice were divided into two groups fed a standard diet or HFD for 18 weeks. At the end of the treatment, inflammation (detected by ELISA), antioxidant state (measured by enzymatic activity), mitochondrial functions and efficiency (detected by oxidative capacity and Seahorse analysis), and brain-derived neurotrophic factor (BDNF) pathway (analyzed by western blot) were determined in brain cortex and synaptosomal fraction. In HFD animals, we observed an increase in inflammatory parameters and oxidative stress and a decrease in mitochondrial oxidative capacity both in the brain cortex and synaptosomal fraction. These alterations parallel with modulation of BDNF, a brain key signaling molecule that is linking synaptic plasticity and energy metabolism. Neuroinflammation HFD-dependent negatively affects BDNF pathway and mitochondrial activity in the brain cortex. The effect is even more pronounced in the synaptic region, where the impaired energy supply may have a negative impact on neuronal plasticity.

Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

“…The prefrontal cortex is important for executing inhibitory control (e.g., resisting strong appetite impulse), and neural responses in this area are significantly attenuated in obese individuals [ 41 , 42 ]. Cavaliere and colleagues [ 43 ] have revealed that inflammatory and oxidative stress markers such as TNF-α, IL-1β, and malondialdehyde were significantly elevated in synaptosomes in the cortex of obese mice fed a HFD for 18 weeks compared to those in a chow-fed lean control group. Antioxidant glutathione (GSH) was found to be markedly reduced, and the ratio of GSH to its oxidized form GSSG, a readout for antioxidant activity, was decreased, as expected in diet-induced obese mice.…”

Decreased Metabolic Flexibility in Skeletal Muscle of Rat Fed with a High-Fat Diet Is Recovered by Individual CLA Isomer Supplementation via Converging Protective Mechanisms

“…We demonstrated that the beneficial effects exhibited by CLA isomers can be attributed to the activation of different regulatory pathways. Further experiments will be needed to investigate the different effects of dietary C9 or C10 supplementation in modulating cellular and mitochondrial ROS production [87][88][89] and to prevent oxidative DNA damage [90]. Moreover, additional experiments will be necessary for better investigating the involvement of additional genes metabolically linked to PPAR-α (i.e.…”

Interplay between Peripheral and Central Inflammation in Obesity-Promoted Disorders: The Impact on Synaptic Mitochondrial Functions

“…In general, multi-organ damage due to inflammation and oxidative stress, hallmarks of both aging and obesity, highlight that these two processes are tightly interconnected [ 47 ]. The systemic impact of metabolic inflammation involves also the central nervous system [ 48 ]. The brain has been considered for a long time to be an organ protected from systemic inflammation by the blood–brain barrier, but more recent data indicate a tight association between obesity and neurodegeneration.…”

“…HFD-dependent neuroinflammation and oxidative stress play a key role in the alteration of the BDNF levels not only in the hippocampus but also in several brain regions [ 48 , 99 , 100 , 101 ]. In particular, BDNF may be linked to neuroinflammation through NF-κB, although the exact regulatory mechanisms are not completely understood [ 91 , 102 ].…”