Pituitary Adenylate Cyclase-Activating Polypeptide in the Ventromedial Hypothalamus Is Responsible for Food Intake Behavior by Modulating the Expression of Agouti-Related Peptide in Mice
Pituitary adenylate cyclase-activating polypeptide (PACAP) is abundantly expressed in the hypothalamus and contributes to hypothalamic functions, including appetite regulation. Although food intake is suggested to be decreased in PACAP (−/−) mice, the detailed mechanisms are still being discussed. We sought to investigate this link. The food consumption at 8 h after refeeding in the (−/−) mice who had fasted for 2 days was significantly lower than in the PACAP (+/+) mice. The nocturnal and daily food intake of (−/−) mice was significantly lower than those of (+/+) mice, but the diurnal food intake showed a tendency to increase. mRNA expression levels of agouti-related peptide (AgRP) were decreased, but those of proopiomelanocortin (POMC) were increased in the hypothalamus of (−/−) mice 4 h after refeeding. Furthermore, intracerebroventricular administration of a PACAP receptor antagonist, PACAP6–38 (1 nmol/4 μL/mouse), decreased food intake and body weight 1, 2, and 4 h after refeeding, as well as expression levels of AgRP at 4 h after refeeding in (+/+) mice. The selective overexpression of PACAP by the infection of an adeno-associated virus in the ventromedial hypothalamus (VMH) resulted in an increase in food intake and AgRP expression in the nocturnal period in addition to the increased food intake at 8 h after refeeding. These results suggest that food intake behavior in mice is triggered by the increase in PACAP expression in the VMH via modulation of AgRP expression in the hypothalamus, pointing to PACAP inhibition as a potential strategy for the development of anti-obesity drugs.
KeywordsPituitary adenylate cyclase-activating polypeptide Ventromedial hypothalamus Appetite Agouti-related peptide Food intake
Bed nucleus of the stria terminalis
Cocaine- and amphetamine-regulated transcript
Steroidogenic factor 1
Pituitary adenylate cyclase-activating polypeptide
We would like to thank Ms. Izumi Fujisima and Mr. Tetsuya Kawamura for their technical contribution and all the staff members of the Joint Research Laboratory and the Division of Laboratory Animal Sciences, Kagoshima University for their help with animal care and the use of the facilities. We are also grateful to the Ministry of Agriculture and Rural Development, Vietnam, for the doctoral scholarship to T.T.N.
T.T.N carried out the experiments, performed statistical analysis, and drafted the manuscript. YK carried out the experiments, performed behavioral studies, and wrote the manuscript. TK and AM conceived of and participated in the design of the study and wrote the manuscript. TN, NS, and HH participated in the design of the study and reviewed the manuscript. All authors read and approved of the final manuscript.
This work was supported by a Grant-in-Aid for Scientific Research (C), Japan Society for the Promotion of Science (JSPS) (JSPS KAKENHI Grant No. 17K08310, 17 K08599 and JP19K07121), a Grant-in-Aid for Scientific Research (B) (Grant No. JP17H03989), MEXT KAKENHI, (grant number JP18H05416), and AMED (grant No. JP19dm0107122h0004 and JP19dm0207061h0003).
Compliance with Ethical Standards
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Specifically, all experiments in the present study were approved by the Experimental Animal Research Committee of Kagoshima University (Approval numbers: MD17054 and MD18105) and the Gene Recombination Experiment Safety Committee of Kagoshima University (Approval number: S28006).
Conflict of Interest
The authors declare that they have no conflict of interest.
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