Summary: Weight loss in Parkinson’s disease has been an unresolved clinical puzzle. New research from Fujita Health University indicates that weight loss in Parkinson’s patients stems mainly from targeted fat loss, not muscle wasting, and reflects a fundamental shift in whole-body energy metabolism. The study shows impaired glucose-based energy production (glycolysis and the TCA cycle) that forces the body into an alternative “emergency” energy mode, burning fat and producing ketone bodies to meet energy demands.
This selective fat depletion is not explained solely by reduced food intake. Instead, the findings suggest that a breakdown of the body’s primary biochemical “engine” for converting carbohydrates into ATP triggers reliance on lipid and amino-acid fuels. Clinically, thinness in Parkinson’s disease may therefore signal an internal energy crisis rather than ordinary calorie deficiency.
Key Facts
- Selective Fat Loss: Patients with Parkinson’s disease (PD) show pronounced decreases in body fat while preserving muscle mass in early-to-mid disease stages.
- Main Energy Pathway Failure: Metabolomic profiling revealed reduced glycolytic and TCA cycle metabolites, indicating impaired carbohydrate-driven ATP production.
- Emergency Energy Mode: Elevated ketone bodies and amino-acid catabolism markers show the body shifts to fat and protein breakdown as an alternative fuel source.
Source: Fujita Health University
Weight loss is a common but poorly explained non-motor feature of Parkinson’s disease. Many patients lose weight as symptoms progress, and this decline is linked to worse outcomes and reduced quality of life.
Until now, it has been unclear whether this weight loss primarily reflected sarcopenia, inadequate nutrition, or systemic metabolic changes. The new study clarifies that PD-related weight loss is driven predominantly by loss of body fat while skeletal muscle mass remains relatively intact in early-to-mid stages. At the same time, the body’s pattern of energy production shifts away from glucose metabolism toward lipid- and protein-based fuels.
Parkinson’s is primarily considered a neurodegenerative disorder, but growing evidence points to systemic metabolic involvement. Fatigue, changes in appetite, and declining nutritional status are frequent, yet nutritional recommendations have typically emphasized increased caloric intake. These new results challenge that approach by showing that when carbohydrate-based energy systems fail, simply consuming more calories may not reverse the underlying metabolic problem.
The study was published on November 30, 2025 in the Journal of Neurology, Neurosurgery & Psychiatry and was led by Professor Hirohisa Watanabe of Fujita Health University’s Department of Neurology, with co-authors Dr. Atsuhiro Higashi and Dr. Yasuaki Mizutani.
To determine what is lost in PD-related weight decline and why the body changes fuel sources, the team enrolled 91 people with Parkinson’s disease and 47 age-matched healthy controls. Body composition was measured using bioelectrical impedance analysis to estimate fat mass and muscle mass separately. In parallel, plasma metabolomic profiling using mass spectrometry examined glycolysis intermediates, TCA cycle metabolites, lipid-related compounds, mitochondrial indicators, and ketone bodies.
Compared with controls, patients with PD had lower overall weight and body mass index, primarily due to reduced fat mass. Muscle mass remained largely conserved in the early-to-mid stages, and the rate of sarcopenia was similar to that expected for normal aging. These observations support the conclusion that PD-related weight loss is predominantly a loss of adipose tissue rather than muscle.
Metabolomic analysis exposed a coherent metabolic signature: decreased levels of glycolysis and TCA cycle markers (for example, lactic acid and succinic acid), combined with elevated ketone bodies (acetoacetic acid and 3-hydroxybutyric acid) and increased markers of amino-acid catabolism. This pattern indicates a weakened capacity to generate energy from glucose and a compensatory increase in fat- and protein-derived fuels.
Importantly, ketone body levels correlated inversely with BMI and were higher in patients with more advanced disease, suggesting that the shift to fat-dependent energy production intensifies with disease progression. In practical terms, being thin in PD may reflect an ongoing, hidden metabolic emergency in which the body relies increasingly on fat stores to maintain energy balance.
These results carry important implications for clinical care and research. Raising calorie intake alone may not correct energy deficits if glycolysis and TCA cycle function are impaired. New therapeutic strategies might focus on supporting carbohydrate metabolism, enhancing mitochondrial function, or preventing excessive reliance on ketone metabolism. Such approaches would represent a shift from purely symptomatic, dopamine-centered treatments toward interventions that address whole-body energy homeostasis.
Overall, the study frames Parkinson’s disease as a condition that affects both brain and systemic metabolism. By demonstrating that weight loss reflects selective fat depletion tied to impaired carbohydrate-based energy production, the work provides a clearer basis for identifying patients at risk and developing targeted interventions to prevent metabolic decline.
Funding information
This research was supported by JSPS KAKENHI (Grant Number JP22K07508), the Fujita Mind-Brain Research and Innovation Center for Drug Generation of Japan’s Peak Research Universities Program (Grant Number JPJS00420240019), and the Japan Agency for Medical Research and Development (Grant Number 22dk0207055h0002).
Key Questions Answered:
A: The issue is not only calorie intake but how the body converts those calories into usable energy. Parkinson’s appears to impair glycolysis and the TCA cycle, so glucose is not efficiently transformed into ATP. To compensate, the body mobilizes fat and increases ketone production, leading to selective fat loss despite adequate eating.
A: Yes. Lower BMI in PD patients was associated with higher ketone body levels in this study, suggesting that thinness can be a marker of an internal energy shortfall and escalating metabolic compensation.
A: Simply increasing calories may be insufficient if the underlying glucose-to-ATP pathway is defective. Future research should explore interventions that restore glycolytic and mitochondrial function or otherwise stabilize cellular energy production.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full for accuracy.
- Additional context was provided by editorial staff.
About this neurology and Parkinson’s disease research news
Author: Hisatsugu Koshimizu
Source: Fujita Health University
Contact: Hisatsugu Koshimizu – Fujita Health University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Metabolic profiles associated with fat loss in Parkinson’s disease” by Atsuhiro Higashi, Yasuaki Mizutani, Reiko Ohdake, Yasuhiro Maeda, Junichiro Yoshimoto, Sayuri Shima, Yusuke Seino, Akihiro Ueda, Mizuki Ito, Atsushi Suzuki, and Hirohisa Watanabe.
DOI:10.1136/jnnp-2025-336929
Abstract
Metabolic profiles associated with fat loss in Parkinson’s disease
Background
Weight loss is a significant non-motor symptom of Parkinson’s disease and is linked to poorer clinical outcomes. The mechanisms driving PD-related weight loss remain unclear. This study examined the relationship between body composition and plasma metabolic profiles to clarify underlying causes.
Methods
Ninety-one patients with PD and 47 healthy controls were enrolled between July 2021 and October 2023. Body composition was assessed with bioelectrical impedance analysis. Plasma metabolites—including short- and medium-chain fatty acids, TCA cycle intermediates, ketone bodies, and phospholipids—were quantified by mass spectrometry. Associations between body composition changes and plasma metabolite levels were then analyzed.
Results
Compared with controls, patients with PD had lower body weight (p=0.003), BMI (p=0.001), and body fat mass (p<0.001). Metabolomics showed reduced glycolysis and TCA cycle markers (lactic acid and succinic acid) alongside higher ketone bodies (acetoacetic acid and 3-hydroxybutyric acid), increased amino-acid catabolism markers (2-hydroxybutyric acid and 2-oxobutyric acid), and elevated acetic acid. Acetoacetic acid and 3-hydroxybutyric acid were inversely correlated with BMI in patients, and phosphatidylcholine (40:2) levels increased with more advanced disease stage.
Conclusions
Fat loss in PD is associated with decreased glycolytic activity and increased lipid and amino-acid metabolism, suggesting a shift in energy utilization. These metabolic pathways may offer targets for interventions to prevent or lessen weight loss in Parkinson’s disease.