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<p>Unintentional weight loss is common among patients with Parkinson’s disease (PD) and is associated with poor quality of life and accelerated disease progression. To explore how early α-synuclein pathology contributes to metabolic dysregulation leading to weight loss in PD, transgenic mice overexpressing human wild-type α-synuclein (α-Syn) and controls were fed a high-fat diet (HFD) chow for 4 months. Compared with controls on HFD, α-Syn mice on HFD exhibited a dramatically leaner phenotype, improved glucose tolerance, a major decrease in fat mass, an increase in energy expenditure, a decrease in insulin signaling in the olfactory bulb, aggravated olfactory and motor dysfunctions, and an increase in mortality. Our results show that high-fat diet in α-Syn mice provides a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. Moreover, a role is proposed for olfactory dysfunction in PD-related unintentional weight loss.</p>

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Metabolic dysregulation and resistance to high-fat diet-induced weight gain in mice overexpressing human wild-type α-synuclein

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月24日

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  • K. C. Biju,
  • Enrique Torres Hernandez,
  • Alison Michelle Stallings,
  • Ada C. Felix-Ortiz,
  • Skanda K. Hebbale,
  • Luke Norton,
  • Michael J. Mader,
  • Robert A. Clark

摘要

Unintentional weight loss is common among patients with Parkinson’s disease (PD) and is associated with poor quality of life and accelerated disease progression. To explore how early α-synuclein pathology contributes to metabolic dysregulation leading to weight loss in PD, transgenic mice overexpressing human wild-type α-synuclein (α-Syn) and controls were fed a high-fat diet (HFD) chow for 4 months. Compared with controls on HFD, α-Syn mice on HFD exhibited a dramatically leaner phenotype, improved glucose tolerance, a major decrease in fat mass, an increase in energy expenditure, a decrease in insulin signaling in the olfactory bulb, aggravated olfactory and motor dysfunctions, and an increase in mortality. Our results show that high-fat diet in α-Syn mice provides a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. Moreover, a role is proposed for olfactory dysfunction in PD-related unintentional weight loss.