Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer’s disease (AD). In a recent Brain, Behavior, and Immunity journal study, scientists reviewed in vitro and in vivo evidence associated with PD and leptin. More specifically, the current research focuses on the neuro-metabolic, neuro-immunomodulatory, and neurotrophic activity of leptin and other adipocytokines.
Study: Emerging roles of leptin in Parkinson’s disease: chronic inflammation, neuroprotection and more? Image Credit: Chinnapong / Shutterstock.com
Typically, when PD is diagnosed, half of the dopaminergic axons and neurons within the substantia nigra pars compacta are already lost. Thus, there is an urgent need to identify early PD markers.
The prodromal stage of PD is characterized by hyposmia, constipation, and behavioral disorder. Aside from weight loss, PD patients also experience bone and muscle mass loss, which affects their mobility and increases the risk of falls and fractures.
PD is a progressive disorder, with 70 years the mean age for its onset. The prevalence of PD is about 1% in individuals over the age of 60 years.
Most epidemiological studies on PD have reported that the condition occurs more frequently in men than women. However, the impact of genetic and environmental factors on the development of PD remains unclear.
The role of leptin in brain development
Leptin, primarily secreted by white adipose tissue, is an anorexigenic hormone linked to the hypothalamic regulation of food intake and body fat storage. The secretion of leptin depends on adipose tissue mass and provides negative feedback of bodily energy stores to the brain.
Leptin receptors are expressed in many regions of the brain, including the hippocampus and cortex. Leptin gene (LEP) mutation or changes in the LEPR gene, which encodes for its receptor, causes severe childhood obesity. Leptin is also involved in the promotion of neural structures and plasticity.
A leptin mutant mouse model revealed that leptin deficiency causes smaller brain size and reduced myelin levels, which was remedied after leptin administration. Several studies have indicated the role of leptin in brain development, especially in the maintenance of neural stem cells, induction of neural differentiation, enhancement of neuronal growth, and stimulation of cortical cell death. In addition to leptin, neurotrophic effects have been associated with other adipocytokines, such as adiponectin.
How does leptin influence PD?
Several studies have highlighted the role of leptin in the neuropathological and behavioral phenotype using a transgenic mouse model of AD.
As previously mentioned, adipose tissue is the primary source of the leptin hormone, which is positively correlated with body mass index. This is the reason why PD patients experience changes in body weight.
For example, three years of follow-up following PD diagnosis have reported an increase in fat mass and weight. PD has also been correlated with reduced physical activity.
In the later stages of PD, most patients experience weight loss attributed to elevated energy expenditure. However, the exact underlying mechanism responsible for this weight loss remains unclear.
Nevertheless, some factors that appear to be related to weight loss in PD patients include an altered gut microbiome, reduced gastrointestinal (GI) motility, dysphagia, reduced sense of taste and smell, constipation, and dyskinesia. The cognitive decline also reduces the inclination to eat and drink.
The administration of leptin has been shown to reduce food intake and increase energy consumption in animals challenged with PD. Both short- and long-term fasting significantly reduce leptin concentrations. Reduced leptin levels have been reported in PD patients with weight loss as compared to PD patients without weight loss.
Preclinical studies have revealed a strong neuroprotective role of leptin against neurodegenerative diseases. For example, leptin-deficient mice exhibit reduced neurotransmission capacity due to an overall decrease in dopamine within dopaminergic neurons of the midbrain. A mouse model of PD has also revealed that decreased levels of leptin were associated with weight loss.
Leptin, along with other adipocytokines, plays an important role in the energy homeostasis of the brain and food intake regulation. Several in vitro and in vivo models have demonstrated the neurotrophic effects of leptin, which involve an increase in neurogenesis and protection from dopaminergic lesioning. Additionally, adipocytokines have been associated with peripheral immune signaling.
In the future, more research is needed to validate leptin and other adipokines as therapeutic targets in PD. The authors recommend evaluating different strategies related to leptin signaling activation. Additionally, a large study cohort should assess the precise regulation of leptin and other adipokines in the development of PD.
- Regensburger, M., Chaudhry, S. R., Yasin, H., et al. (2022) Emerging roles of leptin in Parkinson’s disease: chronic inflammation, neuroprotection and more? Brain, Behavior, and Immunity. doi:10.1016/j.bbi.2022.09.010