The PACAP/PAC1 Receptor System and Feeding

Abstract

Pituitary adenylyl cyclase activating polypeptide (PACAP) belongs to the vasoactive intestinal polypeptide (VIP)/secretin/glucagon superfamily. PACAP is present in two forms (PACAP-38 and PACAP-27) and binds to three guanine-regulatory (G) protein-coupled receptors (PAC1, VPAC1, and VPAC2). PACAP is expressed in the central and peripheral nervous systems, with high PACAP levels found in the hypothalamus, a brain region involved in feeding and energy homeostasis. PAC1 receptors are high-affinity and PACAP-selective receptors, while VPAC1 and VPAC2 receptors show a comparable affinity to PACAP and VIP. PACAP and its receptors are expressed in the central and peripheral nervous systems with moderate to high expression in the hypothalamus, amygdala, and other limbic structures. Consistent with their expression, PACAP is involved in several physiological responses and pathological states. A growing body of literature suggests that PACAP regulates food intake in laboratory animals. However, there is no comprehensive review of the literature on this topic. Thus, the purpose of this article is to review the literature regarding the role of PACAP and its receptors in food intake regulation and to synthesize how PACAP exerts its anorexic effects in different brain regions. To achieve this goal, we searched PubMed and reviewed 68 articles regarding the regulatory action of PACAP on food intake. Here, we present the literature regarding the effect of exogenous PACAP on feeding and the role of endogenous PACAP in this process. We also provide evidence regarding the effect of PACAP on the homeostatic and hedonic aspects of food intake, the neuroanatomical sites where PACAP exerts its regulatory action, which PACAP receptors may be involved, and the role of various signaling pathways and neurotransmitters in hypophagic effects of PACAP.

Asprosin promotes feeding through SK channel–dependent activation of AgRP neurons

“…We have previously reported that asprosin failed to directly regulate some neuron types including POMC-expressing neurons, serotonin neurons, dopamine neurons, steroidogenic factor-1 neurons, and neuron populations in the paraventricular hypothalamic nucleus neurons ( 2 ), which are relevant for feeding and glucose homeostasis. However, some other neuron types—including the cannabinoid receptor 1–expressing neurons ( 53 ), pituitary adenylate cyclase–activating polypeptide–releasing neurons ( 54 ), neuronal nitric oxide synthase–expressing neurons ( 55 , 56 ), and brain-derived neurotrophic factor–releasing neurons ( 57 )—in the ventral medial of hypothalamus (VMH) have been identified for the regulation of food intake, glucose homeostasis, and energy expenditure. It is possible that apsrosin also acts on those VMH neuron populations to further regulate feeding behavior and glucose homeostasis.…”

Anorexigenic neuropeptides as anti-obesity and neuroprotective agents

“…PACAP is a 38-amino-acid or 27-amino-acid neuropeptide produced and released both in the periphery and the CNS, especially in the VMN, or in the LHA and PVN in the hypothalamus [ 148–150 ]. PACAP binds to three GPCRs: PAC1R, VPAC1, and VPAC2 [ 151 ]. Its metabolic pathways are linked to the regulation of body weight and the development of obesity and metabolic syndrome.…”

The Role of G Protein–Coupled Receptors and Receptor Kinases in Pancreaticβ-Cell Function and Diabetes

“…Together, these findings raise the intriguing possibility that PACAP and PAC1R signaling may have critical roles in β -cell function. Moreover, β -cell production and release of proteolytically mature PACAP-38 in response to glucose may represent a mechanism to ensure its own insulin release but also to communicate the feeding state to PAC1 receptors in the hypothalamus and other brain regions that control feeding behavior ( Sekar et al, 2017 ; Sureshkumar et al, 2021 ). It is worth noting that there was a discrepancy in the mRNA and protein expression, with ADCYAP1 mRNA specifically enriched in β cells, whereas PACAP protein was detected in δ cells via immunohistochemistry ( Elgamal et al, 2023 ; Yang et al, 2023 ).…”