Abstract
Although several epidemiologic and animal studies have revealed correlations between obesity and neurodegenerative disorders, such as Parkinson disease (PD), the underlying pathological mechanisms of obesity-induced PD remain unclear. Our study aimed to assess the effect of diet-induced obesity on the brain dopaminergic pathway. For five months, starting from weaning, we gave C57BL/6 mice a high-fat diet (HFD) to generate an obese mouse model and investigate whether the diet reprogrammed the midbrain dopaminergic system. Tyrosine hydroxylase staining showed that the HFD resulted in fewer dopaminergic neurons in the substantia nigra (SN), but not the striatum. It also induced neuroinflammation, with increased astrogliosis in the SN and striatum. Dendritic spine density in the SN of HFD-exposed mice decreased, which suggested that prolonged HFD altered dopaminergic neuroplasticity. All three peroxisome proliferator-activated receptor (PPAR) subtype (PPAR-α, PPAR-β/δ, PPAR-γ) levels were significantly reduced in the SN and the ventral tegmental area of HFD mice when compared to those in controls. This study showed that a prolonged HFD induced neuroinflammation, suppressed PPAR levels, caused degeneration of midbrain dopaminergic neurons, and resulted in symptoms reminiscent of human PD. To our knowledge, this is the first study documenting the effects of an HFD on PPARs in dopaminergic neurons.
Highlights
IntroductionHigh fat diets (HFDs) are strongly correlated with obesity and exert detrimental effects on cognitive and behavioral functions
Long-term changes in diet can alter the lipid composition of the brain
We investigated whether high-fat diet (HFD) could lead to inflammation by examining microgliosis and astrogliosis in the substantia nigra (SN) and striatum, as neuroinflammation had been proposed as an important mechanism in neurodegenerative diseases, such as Parkinson disease (PD), and obesity is associated with a chronic inflammatory state
Summary
High fat diets (HFDs) are strongly correlated with obesity and exert detrimental effects on cognitive and behavioral functions. Epidemiologic studies have found that patients with obesity have increased risks of neuropsychiatric disorders, including anxiety and depression [1]. Many cases present with a variety of non-motor symptoms such as anxiety, depression, hallucinations, impulse control disorders, cognitive impairment, as well as autonomic dysfunction [6]. The pathway from the pars compacta of the SN (SNpc) to the striatum is called the nigrostriatal pathway, which regulates motor control and movement, and its dysfunction causes PD [7]. The pathway that originates from the VTA is involved in motivation, reward, emotion, and cognitive functions, and it is called the “brain reward system”; its dysfunction is related to stress, anxiety, schizophrenia, and drug addiction [8]
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