Rachel Chang1, Jennifer Hernandez2, Cassandra Gastelum1, Kaitlyn Guadagno2, Lynnea Perez1, Edward J Wagner3,4. 1. Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, USA. 2. College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA. 3. Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, USA, ewagner@westernu.edu. 4. College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA, ewagner@westernu.edu.
Abstract
OBJECTIVE: We examined whether pituitary adenylate cyclase-activating polypeptide (PACAP) excites proopiomelanocortin (POMC) neurons via PAC1 receptor mediation and transient receptor potential cation (TRPC) channel activation. METHODS: Electrophysiological recordings were done in slices from both intact male and ovariectomized (OVX) female PACAP-Cre mice and eGFP-POMC mice. RESULTS: In recordings from POMC neurons in eGFP-POMC mice, PACAP induced a robust inward current and increase in conductance in voltage clamp, and a depolarization and increase in firing in current clamp. These postsynaptic actions were abolished by inhibitors of the PAC1 receptor, TRPC channels, phospholipase C, phosphatidylinositol-3-kinase, and protein kinase C. Estradiol augmented the PACAP-induced inward current, depolarization, and increased firing, which was abrogated by estrogen receptor (ER) antagonists. In optogenetic recordings from POMC neurons in PACAP-Cre mice, high-frequency photostimulation induced inward currents, depolarizations, and increased firing that were significantly enhanced by Gq-coupled membrane ER signaling in an ER antagonist-sensitive manner. Importantly, the PACAP-induced excitation of POMC neurons was notably reduced in obese, high-fat (HFD)-fed males. In vivo experiments revealed that intra-arcuate nucleus (ARC) PACAP as well as chemogenetic and optogenetic stimulation of ventromedial nucleus (VMN) PACAP neurons produced a significant decrease in energy intake accompanied by an increase in energy expenditure, effects blunted by HFD in males and partially potentiated by estradiol in OVX females. CONCLUSIONS: These findings reveal that the PACAP-induced activation of PAC1 receptor and TRPC5 channels at VMN PACAP/ARC POMC synapses is potentiated by estradiol and attenuated under conditions of diet-induced obesity/insulin resistance. As such, they advance our understanding of how PACAP regulates the homeostatic energy balance circuitry under normal and pathophysiological circumstances.
OBJECTIVE: We examined whether pituitary adenylate cyclase-activating polypeptide (PACAP) excites proopiomelanocortin (POMC) neurons via PAC1 receptor mediation and transient receptor potential cation (TRPC) channel activation. METHODS: Electrophysiological recordings were done in slices from both intact male and ovariectomized (OVX) female PACAP-Cre mice and eGFP-POMCmice. RESULTS: In recordings from POMC neurons in eGFP-POMCmice, PACAP induced a robust inward current and increase in conductance in voltage clamp, and a depolarization and increase in firing in current clamp. These postsynaptic actions were abolished by inhibitors of the PAC1 receptor, TRPC channels, phospholipase C, phosphatidylinositol-3-kinase, and protein kinase C. Estradiol augmented the PACAP-induced inward current, depolarization, and increased firing, which was abrogated by estrogen receptor (ER) antagonists. In optogenetic recordings from POMC neurons in PACAP-Cre mice, high-frequency photostimulation induced inward currents, depolarizations, and increased firing that were significantly enhanced by Gq-coupled membrane ER signaling in an ER antagonist-sensitive manner. Importantly, the PACAP-induced excitation of POMC neurons was notably reduced in obese, high-fat (HFD)-fed males. In vivo experiments revealed that intra-arcuate nucleus (ARC) PACAP as well as chemogenetic and optogenetic stimulation of ventromedial nucleus (VMN) PACAP neurons produced a significant decrease in energy intake accompanied by an increase in energy expenditure, effects blunted by HFD in males and partially potentiated by estradiol in OVX females. CONCLUSIONS: These findings reveal that the PACAP-induced activation of PAC1 receptor and TRPC5 channels at VMN PACAP/ARC POMC synapses is potentiated by estradiol and attenuated under conditions of diet-induced obesity/insulin resistance. As such, they advance our understanding of how PACAP regulates the homeostatic energy balance circuitry under normal and pathophysiological circumstances.
Authors: Diego de Almeida Miranda; Juliana Araripe; Nara G de Morais Magalhães; Lucas Silva de Siqueira; Cintya Castro de Abreu; Patrick Douglas Corrêa Pereira; Ediely Pereira Henrique; Pedro Arthur Campos da Silva Chira; Mauro A D de Melo; Péricles Sena do Rêgo; Daniel Guerreiro Diniz; David Francis Sherry; Cristovam W P Diniz; Cristovam Guerreiro-Diniz Journal: Front Psychol Date: 2022-02-04
Authors: Massimo Ubaldi; Nazzareno Cannella; Anna Maria Borruto; Michele Petrella; Maria Vittoria Micioni Di Bonaventura; Laura Soverchia; Serena Stopponi; Friedbert Weiss; Carlo Cifani; Roberto Ciccocioppo Journal: Int J Mol Sci Date: 2021-11-30 Impact factor: 6.208