ERK1/2 mediates glucose-regulated POMC gene expression in hypothalamic neurons

Area of Science:

• Neuroscience
• Metabolism
• Cell Signaling

Background:

• Hypothalamic glucose-sensing neurons control feeding behavior and metabolic homeostasis.
• AMP-activated protein kinase (AMPK) is a known mediator of glucose signaling.
• The role of other signaling pathways, like ERK1/2, in hypothalamic glucose sensing remains unclear.

Purpose of the Study:

• To investigate the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in hypothalamic glucose sensing.
• To elucidate the signaling mechanisms underlying glucose-regulated neuropeptide expression in the hypothalamus.

Main Methods:

• Primary hypothalamic neurons were differentiated from progenitor cells.
• Glucose treatment effects on POMC, AgRP, and NPY gene expression and AMPK/ERK1/2 phosphorylation were analyzed.
• Specific inhibitors (PD98059 for ERK1/2, compound C for AMPK) were used to block signaling pathways.
• In vivo experiments involved intracerebroventricular (i.c.v.) administration of PD98059 in rats.

Main Results:

• Glucose increased POMC and decreased AgRP/NPY expression, suppressing AMPK phosphorylation.
• Glucose dose-dependently increased ERK1/2 phosphorylation.
• ERK1/2 inhibition partially abolished glucose-induced POMC expression but not AgRP/NPY.
• AMPK inhibition partially reversed low-glucose-suppressed POMC and blunted low-glucose-induced AgRP/NPY expression.
• In vivo, PD98059 attenuated glucose-induced POMC expression in rat hypothalamus.

Conclusions:

• ERK1/2 signaling mediates glucose-induced POMC expression in hypothalamic neurons.
• ERK1/2 plays a role in hypothalamic glucose sensing, distinct from AMPK's role in AgRP/NPY regulation.
• These findings offer new mechanistic insights into hypothalamic glucose sensing and metabolic regulation.