Does leptin play a role in Parkinson’s disease?

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 examined in vitro and live evidence associated with PM and leptin. Specifically, 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

Parkinson’s disease

Typically, when PD is diagnosed, half of the axons and dopaminergic neurons in the substantia nigra pars compacta are already lost. It is therefore urgent to identify early markers of PD.

The prodromal stage of PD is characterized by hyposmia, constipation and behavioral disturbances. Besides weight loss, Parkinson’s patients also experience loss of bone and muscle mass, which affects their mobility and increases the risk of falls and fractures.

PD is a progressive disease, with an average age of onset of 70 years. The prevalence of PD is about 1% in people over 60 years old.

Most epidemiological studies on PD have reported that the disease occurs more frequently in men than in women. However, the impact of genetic and environmental factors on the development of PD remains unclear.

The role of leptin in brain development

Leptin, mainly secreted by white adipose tissue, is an anorectic hormone related to the hypothalamic regulation of food intake and body fat storage. Leptin secretion is dependent on adipose tissue mass and provides negative feedback from body energy stores to the brain.

Leptin receptors are expressed in many regions of the brain, including the hippocampus and cortex. Mutation of the leptin gene (LEP) or changes in the LEPR gene, which codes for its receptor, cause severe childhood obesity. Leptin is also involved in promoting neuronal structures and plasticity.

A leptin mutant mouse model revealed that leptin deficiency leads to smaller brain size and reduced myelin levels, which was corrected after leptin administration. Several studies have indicated the role of leptin in brain development, particularly in maintaining neural stem cells, inducing neural differentiation, enhancing neuronal growth, and stimulating 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 mentioned earlier, fat tissue is the primary source of the hormone leptin, which is positively correlated with body mass index. This is the reason why Parkinson’s patients experience changes in body weight.

For example, three years of follow-up after the diagnosis of PD 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 high 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 Parkinson’s patients include altered gut microbiome, reduced gastrointestinal (GI) motility, dysphagia, decreased taste and smell, constipation, and dyskinesia. Cognitive decline also reduces the desire to eat and drink.

Leptin administration has been shown to reduce food intake and increase energy consumption in animals with PD. Both short-term and long-term fasting significantly reduce leptin concentrations. Reduced leptin levels have been reported in Parkinsonian patients with weight loss compared to Parkinsonian 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 in midbrain dopaminergic neurons. A mouse model of PD also revealed that decreased leptin levels were associated with weight loss.

conclusion

Leptin, along with other adipocytokines, plays an important role in brain energy homeostasis and the regulation of food intake. Several in vitro and live models have shown the neurotrophic effects of leptin, which involve increased neurogenesis and protection against dopaminergic damage. 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 the activation of leptin signaling. Additionally, a large study cohort should assess the precise regulation of leptin and other adipokines in the development of PD.

Journal reference:

  • Regensburger, M., Chaudhry SR, 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

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