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.
Highlights
High-Fat diet (HFD) consumption induces obesity-related metabolic disorders characterized by low-grade inflammation (Mollica et al, 2011)
High-Fat Diet (HFD) consumption produced a significant increase in body weight, body lipids percentage, lipid gain, and body energy compared to the control diet
HFD mice exhibited a decrease in body water and body protein percentage compared to control mice, while protein gain did not change between groups
Summary
High-Fat diet (HFD) consumption induces obesity-related metabolic disorders characterized by low-grade inflammation (Mollica et al, 2011). Mitochondrial dysfunction is related to inflammation and other energy-dependent disturbances, where the generation of ROS exceeds the physiological antioxidant protective activity, causing cellular oxidative damage (Chan, 2006). Neuroinflammation HFD-induced is known to affect BDNF-related pathways in several brain regions (Mi et al, 2017; Zhao et al, 2019). The impaired neurotransmission and cognitive failure associated to neurodegenerative diseases may be related to the dysfunctional synaptic mitochondria that do not satisfy the high energy demands required at the synapses (Reddy and Beal, 2008). We evaluate the mitochondrial function and efficiency, oxidative stress, inflammation, and BDNF pathway both in the brain cortex and in the corresponding synaptosomal fraction of HFD-induced obese mice
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