Dynamic, sex- and diet-specific pleiotropism in the PAC1 receptor-mediated regulation of arcuate proopiomelanocortin and Neuropeptide Y/Agouti related peptide neuronal excitability by anorexigenic ventromedial nucleus PACAP neurons.

This study furthers the investigation of how pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1 receptor (PAC1R) regulate the homeostatic energy balance circuitry. We hypothesized that apoptotic ablation of PACAP neurones in the hypothalamic ventromedial nucleus (VMN) would affect both energy intake and energy expenditure. We also hypothesized that selective PAC1R knockdown would impair the PACAP-induced excitation in anorexigenic proopiomelanocortin (POMC) neurones and inhibition of orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurones in the hypothalamic arcuate nucleus (ARC).

The vital role of arcuate nociceptin/orphanin FQ neurones in mounting an oestradiol-dependent adaptive response to negative energy balance via inhibition of nearby proopiomelanocortin neurones.

We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQ ) inhibit proopiomelanocortin (POMC ) neurones in a diet- and hormone-dependent manner to promote a more extensive rebound hyperphagia upon re-feeding following an 18 h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum-feeding or fasting conditions. N/OFQ neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to ad libitum-feeding conditions.

The PACAP Paradox: Dynamic and Surprisingly Pleiotropic Actions in the Central Regulation of Energy Homeostasis.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in the central and peripheral nervous systems, and years of accompanying experimental evidence, indicates that PACAP plays crucial roles in diverse biological processes ranging from autonomic regulation to neuroprotection. In addition, PACAP is also abundantly expressed in the hypothalamic areas like the ventromedial and arcuate nuclei (VMN and ARC, respectively), as well as other brain regions such as the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and ventral tegmental area (VTA) - suggesting that PACAP is capable of regulating energy homeostasis both the homeostatic and hedonic energy balance circuitries.