Apolipoprotein A-IV Inhibits AgRP/NPY Neurons and Activates Pro-Opiomelanocortin Neurons in the Arcuate Nucleus

Neuroendocrinology. 2016;103(5):476-488. doi: 10.1159/000439436. Epub 2015 Aug 25.


Background/aims: Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However, the mechanisms underlying its anorexigenic effects remain to be identified.

Methods: We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) and in neurons that express pro-opiomelanocortin (POMC). We then compared anorexigenic effects of apoA-IV in wild-type mice and in mutant mice lacking melanocortin 4 receptors (MC4Rs; the receptors of AgRP and the POMC gene product). Finally, we examined expression of apoA-IV in mouse hypothalamus and quantified its protein levels at fed versus fasted states.

Results: We demonstrate that apoA-IV inhibited the firing rate of AgRP/NPY neurons. The decreased firing was associated with hyperpolarized membrane potential and decreased miniature excitatory postsynaptic current. We further used c-fos immunoreactivity to show that intracerebroventricular (i.c.v.) injections of apoA-IV abolished the fasting-induced activation of AgRP/NPY neurons in mice. Further, we found that apoA-IV depolarized POMC neurons and increased their firing rate. In addition, genetic deletion of MC4Rs blocked anorexigenic effects of i.c.v. apoA-IV. Finally, we detected endogenous apoA-IV in multiple neural populations in the mouse hypothalamus, including AgRP/NPY neurons, and food deprivation suppressed hypothalamic apoA-IV protein levels.

Conclusion: Our findings support a model where central apoA-IV inhibits AgRP/NPY neurons and activates POMC neurons to activate MC4Rs, which in turn suppresses food intake.

Publication types

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

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Agouti-Related Protein / genetics
  • Agouti-Related Protein / metabolism
  • Animals
  • Apolipoprotein A-V / metabolism
  • Apolipoprotein A-V / pharmacology*
  • Arcuate Nucleus of Hypothalamus / cytology*
  • Bicuculline / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • GABA Agents / pharmacology
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / genetics
  • In Vitro Techniques
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Pro-Opiomelanocortin / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Agouti-Related Protein
  • Agrp protein, mouse
  • Apolipoprotein A-V
  • Excitatory Amino Acid Antagonists
  • GABA Agents
  • Neuropeptide Y
  • Sodium Channel Blockers
  • Tetrodotoxin
  • Pro-Opiomelanocortin
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-amino-5-phosphopentanoic acid
  • Valine
  • Bicuculline