High fat diet-induced obesity causes a reduction in brain tyrosine hydroxylase levels and non-motor features in rats through metabolic dysfunction, neuroinflammation and oxidative stress

ABSTRACT

Obesity is a health problem that has been associated with neuroinflammation, decreased cognitive functions and development of neurodegenerative diseases. Parkinson’s disease (PD) is a chronic neurodegenerative condition characterized by motor and non-motor abnormalities, increased brain inflammation, α-synuclein protein aggregation and dopaminergic neuron loss that is associated with decreased levels of tyrosine hydroxylase (TH) in the brain. Diet-induced obesity is a global epidemic and its role as a risk factor for PD is not clear. Herein, we showed that 25 weeks on a high-fat diet (HFD) promotes significant alterations in the nigrostriatal axis of Wistar rats. Obesity induced by HFD exposure caused a reduction in TH levels and increased TH phosphorylation at serine 40 in the ventral tegmental area. These effects were associated with insulin resistance, increased tumor necrosis factor-α levels, oxidative stress, astrogliosis and microglia activation. No difference was detected in the levels of α-synuclein. Obesity also induced impairment of locomotor activity, total mobility and anxiety-related behaviors that were identified in the open-field and light/dark tasks. There were no changes in motor coordination or memory. Together, these data suggest that the reduction of TH levels in the nigrostriatal axis occurs through an α-synuclein-independent pathway and can be attributed to brain inflammation, oxidative/nitrosative stress and metabolic disorders induced by obesity.

KEYWORDS:

• Obesity
• Parkinson’s disease
• tyrosine hydroxylase
• inflammation
• locomotion
• anxiety
• neuroinflammation
• high-fat diet

Acknowledgements

This work was supported by grants received from the following Brazilian public funds: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) #408435/2018-6, Fundação de Amparo à Pesquisa do Estado do RS (FAPERGS) #16/2551-0000499-4 and #17/2551-0000984-3, Propesq-UFRGS and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants received from the following Brazilian public funds: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [grant number 408435/2018-6], Fundação de Amparo à Pesquisa do Estado do RS (FAPERGS) [grant numbers 16/2551-0000499-4 and 17/2551-0000984-3], Propesq-UFRGS and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).