A High-fat Diet Induces a Loss of Midbrain Dopaminergic Neuronal Function That Underlies Motor Abnormalities

Abstract

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.

Impact of early exposure to a cafeteria diet on prefrontal cortex monoamines and novel object recognition in adolescent rats

“…Alternatively, DA synthesis could be affected by an obesogenic diet. In mice, fed on a high fat diet, the expression of midbrain tyrosine hydroxylase (TH) was reduced [81], however increased in the hypothalamus [76]. TH is the rate limiting enzyme in DA synthesis, and a reduced activity could undelay the reduced DA concentrations as observed in the present study.…”

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

“…Regarding the motor aspects, several studies revealed that HFDs decreased motor function and movement in the OFT. Mice fed an HFD for 20 weeks exhibited decreased movement in the OFT and an increase in the number of missteps in a vertical grid test when compared to mice fed a normal diet [24]. Another study showed that, as compared to lean mice, DIO mice with their activity levels measured using the OFT every two weeks had fewer and slower movements beginning at week 4 and persisting through week 18 [25].…”

“…As DA neurons possess a large amount of GAP-43, and decreased GAP-43 in nigrostriatal DA neurons was observed in an animal model of the presymptomatic period of PD [34], this supports our finding of HFD-induced reduction of dendritic spine density in the SN and striatum. Other proposed mechanisms linking HFD to alterations in the DA system include oxidative stress [35], mitochondrial dysfunction [36], and decreased phosphorylation of c-Jun N-terminal kinase [24] and Akt [37]. SN was found to be more vulnerable to changes in energy state such as glucose signaling as compared to the striatum and cerebral cortex while using db/db and HFD models [26].…”

Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

“…After being given a HFD for 20 weeks, mice displayed reduced locomotion in the open field test and increased missteps in a vertical grid test. These changes were associated with TH depletion in the SN and striatum ( Jang et al, 2017 ). Kao et al (2019) recently demonstrated that mice fed a HFD (60% fat) for 20 weeks presented decreased locomotor function, loss of dopaminergic neurons in the SN, and dendritic spine density reduction.…”