Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease

J Neurosci. 2016 Mar 9;36(10):3049-63. doi: 10.1523/JNEUROSCI.4373-15.2016.


Calorie restriction (CR) is neuroprotective in Parkinson's disease (PD) although the mechanisms are unknown. In this study we hypothesized that elevated ghrelin, a gut hormone with neuroprotective properties, during CR prevents neurodegeneration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. CR attenuated the MPTP-induced loss of substantia nigra (SN) dopamine neurons and striatal dopamine turnover in ghrelin WT but not KO mice, demonstrating that ghrelin mediates CR's neuroprotective effect. CR elevated phosphorylated AMPK and ACC levels in the striatum of WT but not KO mice suggesting that AMPK is a target for ghrelin-induced neuroprotection. Indeed, exogenous ghrelin significantly increased pAMPK in the SN. Genetic deletion of AMPKβ1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects. We consider targeting AMPK in dopamine neurons may recapitulate neuroprotective effects of CR without requiring dietary intervention.

Keywords: AMPK; calorie restriction; ghrelin; stereology; substantia nigra.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Calcium-Binding Proteins / metabolism
  • Caloric Restriction*
  • Cell Count
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Ghrelin / genetics
  • Ghrelin / metabolism*
  • Ghrelin / pharmacology
  • Glial Fibrillary Acidic Protein / metabolism
  • MPTP Poisoning / chemically induced
  • MPTP Poisoning / pathology*
  • MPTP Poisoning / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Neurons / drug effects
  • Parkinson Disease / physiopathology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Tyrosine 3-Monooxygenase / metabolism


  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Ghrelin
  • Glial Fibrillary Acidic Protein
  • Microfilament Proteins
  • Tyrosine 3-Monooxygenase
  • AMP-Activated Protein Kinases