Document Type
Article
Publication Date
3-2022
Publisher
American Physiological Society
Source Publication
American Journal of Physiology: Endocrinology and Metabolism
Source ISSN
1522-1555
Original Item ID
DOI: 10.1152/ajpendo.00320.2021
Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) exerts pleiotropic effects on ventromedial nuclei (VMN) of the hypothalamus and its control of feeding and energy expenditure through the type I PAC1 receptor (PAC1R). However, the endogenous role of PAC1Rs in the VMN and the downstream signaling responsible for PACAP’s effects on energy balance are unknown. Numerous studies have revealed that PAC1Rs are coupled to both Gαs/adenylyl cyclase/protein kinase A (Gαs/AC/PKA) and Gαq/phospholipase C/protein kinase C (Gαq/PLC/PKC), while also undergoing trafficking following stimulation. To determine the endogenous role of PAC1Rs and downstream signaling that may explain PACAP’s pleiotropic effects, we used RNA interference to knockdown VMN PAC1Rs and pharmacologically inhibited PKA, PKC, and PAC1R trafficking. Knocking down PAC1Rs increased meal sizes, reduced total number of meals, and induced body weight gain. Inhibition of either PKA or PKC alone in awake male Sprague–Dawley rats, attenuated PACAP’s hypophagic and anorectic effects during the dark phase. However, PKA or PKC inhibition potentiated PACAP’s thermogenic effects during the light phase. Analysis of locomotor activity revealed that PKA inhibition augmented PACAP’s locomotor effects, whereas PKC inhibition had no effect. Finally, PACAP administration in the VMN induces surface PAC1R trafficking into the cytosol which was blocked by endocytosis inhibitors. Subsequently, inhibition of PAC1R trafficking into the cytosol attenuated PACAP-induced hypophagia. These results revealed that endogenous PAC1Rs uniquely engage PKA, PKC, and receptor trafficking to mediate PACAP’s pleiotropic effects in VMN control of feeding and metabolism.
Recommended Citation
Maunze, Brian; Wood Bruckner, Katherine; Desai, Nikhil Nilesh; Chen, Christopher; Chen, Fanghong; Baker, David; and Choi, Sujean, "Pituitary Adenylate Cyclase-Activating Polypeptide Receptor Activation in the Hypothalamus Recruits Unique Signaling Pathways Involved in Energy Homeostasis" (2022). Biomedical Sciences Faculty Research and Publications. 248.
https://epublications.marquette.edu/biomedsci_fac/248
Comments
Accepted version. American Journal of Physiology: Endocrinology and Metabolism, Vol. 322, No. 3 (March 2022): E199-E210. DOI. © 2022 American Physiological Society. Used with permission.