Apolipoprotein A-IV Inhibits AgRP/NPY Neurons and Activates Pro-Opiomelanocortin Neurons in the Arcuate Nucleus.
Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However, the mechanisms underlying its anorexigenic effects remain to be identified.



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.



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.



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.
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.|Medical College of Qingdao University, Qingdao, China 266020.
Chunling
C
Yan
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Yanlin
Y
He
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030.
Yuanzhong
Y
Xu
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.|Department of Physiology, Institute of Animal Science, Southern China University of Agriculture, Guangzhou, China.
Gang
G
Shu
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Chunmei
C
Wang
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Yongjie
Y
Yang
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Kenji
K
Saito
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Pingwen
P
Xu
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Antentor Othrell
AO
Hinton
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Xiaofeng
X
Yan
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.|Department of Rheumatology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China.
Likai
L
Yu
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Qi
Q
Wu
Department of Pathology and Laboratory Medicine, University of Cincinnati, 2120 East Galbraith Road, Cincinnati, OH, 45237.
Patrick
P
Tso
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030.
Qingchun
Q
Tong
Children's Nutrition ReseARHh Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.|Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
Yong
Y
Xu
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000072040:Apolipoprotein A-V / Q000378:metabolism / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology*; D001640:Bicuculline / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018682:GABA Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D000072040:Apolipoprotein A-V; D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; D009478:Neuropeptide Y; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D011333:Pro-Opiomelanocortin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; D001640:Bicuculline