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Erk1/2 mediates leptin receptor signaling in the ventral tegmental area

Richard Trinko1, Geliang Gan, Xiao-Bing Gao

  • 1Division of Molecular Psychiatry, Ribicoff Research Facilities, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Plos One
|November 15, 2011
PubMed

Insights

Leptin

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Endocrinology

Background:

  • Leptin is a key hormone regulating energy balance.
  • Leptin's action in the ventral tegmental area (VTA) influences feeding behavior.
  • Intracellular signaling pathways mediating leptin's effects in the VTA are not fully understood.

Purpose of the Study:

  • To identify intracellular signaling pathways regulated by leptin in the VTA.
  • To determine the role of specific signaling molecules in leptin's electrophysiological and behavioral effects.

Main Methods:

  • Direct leptin infusion into the VTA of rodents.
  • Assessment of phosphorylated signaling proteins (pSTAT3, pERK1/2, pAKT) via Western blotting or immunohistochemistry.
  • Electrophysiological recordings of VTA dopamine neurons.
  • Pharmacological inhibition of MEK1/2 using U0126 to block ERK1/2 phosphorylation.
  • Behavioral assessment of feeding behavior following VTA leptin administration and U0126 pretreatment.

Main Results:

  • Leptin infusion increased phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and phosphorylated extracellular signal-regulated kinase-1 and -2 (pERK1/2) in the VTA.
  • Phospho-AKT (pAKT) levels remained unaffected by leptin.
  • Inhibition of MEK1/2 with U0126 blocked the leptin-induced decrease in VTA dopamine neuron firing frequency.
  • U0126 pretreatment also abolished the anorexigenic effects of leptin administered to the VTA.
  • U0126 effectively inhibited ERK1/2 phosphorylation but not STAT3 phosphorylation.

Conclusions:

  • Leptin receptor signaling in the VTA involves the activation of both STAT3 and ERK1/2 pathways.
  • Phosphorylated ERK1/2 (pERK1/2) plays a critical role in mediating leptin's electrophysiological effects on VTA dopamine neurons.
  • pERK1/2 signaling is essential for the anorexigenic (appetite-suppressing) effects of leptin acting within the VTA.

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