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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #331550
Title: Apolipoprotein A-IV inhibits AgRP/NPY neurons and activates POMC neurons in the arcuate nucleus

Author
item YAN, CHUNLIN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item HE, YANLIN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item XU, YUANZHONG - UNIVERSITY OF HOUSTON
item SHU, GANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item WANG, CHUNMEI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item YANG, YONGJIE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item SAITO, KENJI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item XU, PINGWEN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item HINTON, ANTENTOR - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item YAN, XIAOFENG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item YU, LIKAI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item WU, QI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item TSO, PATRICK - UNIVERSITY OF CINCINNATI
item TONG, QINGCHUN - UNIVERSITY OF HOUSTON
item XU, YONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: Neuroendocrinology Journal
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/9/2015
Publication Date: 1/10/2016
Citation: Yan, C., He, Y., Xu, Y., Shu, G., Wang, C., Yang, Y., Saito, K., Xu, P., Hinton, A., Yan, X., Yu, L., Wu, Q., Tso, P., Tong, Q., Xu, Y. 2016. Apolipoprotein A-IV inhibits AgRP/NPY neurons and activates POMC neurons in the arcuate nucleus. Neuroendocrinology Journal. 103(5):476-488 doi:10.1159/000439436.

Interpretive Summary: Obesity is a serious global health problem. Here we demonstrated that a hormone, namely apolipoprotein A-IV, can effectively reduce food intake and body weight in mice. These results provide pre-clinical evidence for this hormone or its analogs to treat human obesity.

Technical Abstract: 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 vs. 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 mouse hypothalamus, including AgRP/NPY neurons, and food deprivation suppresses 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.