In the complex landscape of neurodegenerative disorders, Parkinson’s disease (PD) stands out due to its multifaceted symptoms that extend beyond its hallmark motor impairments. Recent advances in neuroendocrinology highlight the vital role of peripheral hormones in the modulation of neurological functions. Among these, ghrelin—a gut-derived peptide hormone primarily known for its role in hunger signaling—has emerged as a compelling candidate influencing disease pathology and progression in PD. A newly released systematic review and meta-analysis spearheaded by Gouveia, dos Santos-Júnior, and Frasnelli meticulously evaluates fasting and postprandial ghrelin levels in Parkinson’s disease patients, shedding light on potential connections between energy metabolism, neuroprotection, and PD pathophysiology.
Parkinson’s disease is traditionally characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, manifesting primarily as bradykinesia, rigidity, and tremor. However, non-motor symptoms including gastrointestinal dysfunction and altered metabolic states frequently precede motor signs and substantially impact quality of life. Ghrelin, secreted mainly by the stomach’s oxyntic glands during fasting states, enhances appetite through hypothalamic pathways and exhibits neuroprotective properties by stimulating dopamine neuron survival and neural plasticity. The hormone’s dual role offers a tantalizing link connecting metabolic disturbances with neurodegeneration, warranting comprehensive evaluation in the context of PD.
The systematic review encompasses numerous studies investigating circulating ghrelin concentrations during fasting and after meal consumption, comparing results between PD patients and healthy controls. The meta-analytical approach enables a robust aggregated effect size, integrating heterogeneous datasets to account for variability in sample size, disease stage, and assay methodologies. Notably, fasting ghrelin levels show consistent deviation in PD cohorts, suggesting potential dysregulation of appetite signaling and energy balance in the disease state. In contrast, postprandial ghrelin responses, which typically decrease to signal satiety, reveal a more complex pattern that may implicate altered gastrointestinal feedback mechanisms in PD.
Understanding the implications of these hormonal variations necessitates a grasp of ghrelin’s biochemical and physiological underpinnings. Ghrelin acts primarily through the growth hormone secretagogue receptor (GHS-R1a), expressed both centrally and peripherally. It exerts orexigenic (appetite-stimulating) effects by triggering neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons in the arcuate nucleus. Beyond appetite, ghrelin enhances dopaminergic neuron viability through anti-apoptotic signaling cascades involving phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways. Animal models of PD have further demonstrated administration of ghrelin or its analogs mitigates neurotoxicity induced by MPTP, a neurotoxin that replicates PD features.
The meta-analysis consolidates biochemical assays measured by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) across diverse patient populations. Variations in ghrelin isoforms—acylated (active) versus desacylated (inactive) ghrelin—underscore the complexity of interpreting plasma levels, with active ghrelin fluctuations likely more relevant to neuronal effects. Several studies included report significant reductions in total and active ghrelin levels in fasting PD patients, potentially contributing to decreased appetite and unintentional weight loss commonly observed in these individuals. This correlates with clinical data wherein weight loss and malnutrition correlate with poorer outcomes and faster disease progression.
Postprandial ghrelin dynamics are equally intriguing. In healthy individuals, ghrelin secretion decreases sharply after meal ingestion, providing negative feedback to termination of hunger. However, PD patients often exhibit blunted or delayed suppression of ghrelin post-meal, potentially reflecting impaired vagal nerve signaling or gastrointestinal autonomic dysfunction, two issues prevalent in PD. These impairments not only affect nutrition but may also influence central nervous system homeostasis through altered gut-brain axis communication, reinforcing the concept that PD is a systemic disorder rather than solely a central neurodegenerative process.
Moreover, the interplay between ghrelin and dopamine regulation in PD provides fertile ground for future therapeutic exploration. Dopaminergic loss in PD is intricately tied to reward and motivational pathways that modulate feeding behavior. Ghrelin enhances striatal dopamine release and may counterbalance deficits arising from neurodegeneration. This hormonal modulation could explain the observed correlations between ghrelin levels and motor symptom severity or cognitive decline in PD populations. Targeting ghrelin pathways might, therefore, hold promise not only for symptomatic relief but for disease modification.
The review also highlights notable methodological challenges inherent in the existing literature, such as heterogeneity in patient cohorts, differences in fasting duration, timing of postprandial sampling, and assay sensitivity. These factors contribute to discrepancies in reported ghrelin concentrations and underscore the necessity for standardized protocols in future research. The authors recommend longitudinal studies with repeated ghrelin measurements, combined with neuroimaging and comprehensive clinical phenotyping, to unravel cause-effect relationships and temporal dynamics more definitively.
From a translational perspective, understanding ghrelin’s role could revolutionize nutritional and pharmacological interventions in PD. Patients often struggle with gastrointestinal motility issues, dysphagia, and reduced appetite, culminating in energy deficits that exacerbate neurodegeneration. Strategies aimed at correcting ghrelin imbalances—through ghrelin mimetics, receptor agonists, or dietary modulation—may enhance nutritional status, exert neuroprotective effects, and ultimately improve clinical outcomes. Additionally, monitoring ghrelin as a biomarker could provide invaluable insights into disease stage, prognosis, and response to treatments.
Intriguingly, the gut-brain axis paradigm of PD etiology gains further support through this meta-analytical lens. The gastrointestinal tract, often regarded as the origin of alpha-synucleinopathies that propagate to the central nervous system, also serves as a principal source of ghrelin, intertwining metabolic and neurodegenerative pathways. This complex neuroendocrine crosstalk underscores the inadequacy of viewing PD as an isolated brain disorder. Holistic approaches encompassing systemic physiological changes are paramount to designing effective therapeutic modalities.
In conclusion, the comprehensive synthesis presented by Gouveia and colleagues establishes heightened awareness of the critically altered fasting and postprandial ghrelin profiles in Parkinson’s disease. These findings illuminate the hormone’s potential dual role—both as a mediator of disease symptomatology and as a candidate for neuroprotective therapy. The nuanced understanding of metabolic-hormonal dysregulation in PD serves as a call to action for integrated research efforts that bridge endocrinology, neurology, and nutrition science.
Further research is imperative to decode the mechanisms linking ghrelin alterations to dopaminergic neurodegeneration and clinical manifestations. High-resolution longitudinal studies, advanced neurochemical imaging, and interventional trials with ghrelin analogs await prioritization. Such endeavors may pave pathways toward precision medicine approaches, where metabolic markers guide personalized therapeutic regimes in Parkinson’s disease.
By framing ghrelin not only as an appetite hormone but also as an influential neuroendocrine modulator, this emerging field transforms our comprehension of Parkinson’s disease from a purely neurological deficit to a complex systemic disorder impacted by metabolic status. The scientific community—and patients alike—stand to benefit enormously from these novel insights unveiling new horizons beyond traditional motor symptom management.
Subject of Research: Ghrelin hormone levels in fasting and postprandial states within Parkinson’s disease patients and their implications on disease pathology and progression.
Article Title: Fasting and postprandial Ghrelin levels in Parkinson’s disease: a systematic review and meta-analysis.
Article References:
Gouveia, H.J.C.B., dos Santos-Júnior, O.H. & Frasnelli, J. Fasting and postprandial Ghrelin levels in Parkinson’s disease: a systematic review and meta-analysis. npj Parkinsons Dis. 11, 212 (2025). https://doi.org/10.1038/s41531-025-01066-0
Image Credits: AI Generated
