Regulation of Ghrelin Production and Food Intake by Gastric Adenylyl Cyclase Type 8

ABSTRACT Ghrelin is a peptide hormone primarily produced by ghrelin cells in the stomach, playing a vital role in the regulation of eating behavior. Adenyl cyclase 8 (ADCY8), a key downstream signaling factor of G protein‐coupled receptors, is essential for maintaining energy homeostasis by modulating levels of cyclic adenosine monophosphate (cAMP). Nevertheless, how ADCY8 modulates ghrelin levels and affects food intake is not well understood. Our findings demonstrated that Adcy8 −/− mice exhibited elevated levels of ghrelin and increased food consumption under both normal and high‐fat diet conditions. These changes were associated with a reduction in the activity of the cAMP‐PKA‐mTOR signaling pathway within the gastric mucosa. The administration of the ghrelin receptor antagonist d ‐Lys‐3‐GH‐releasing peptide‐6 significantly decreased calorie intake in both wild‐type and Adcy8 −/− mice. Furthermore, forskolin was shown to inhibit ghrelin and calorie intake in normal mice, an effect that was absent in Adcy8 −/− mice. Treatment with forskolin or overexpression of Adcy8 in both primary ghrelin‐producing cells and mHypoE‐42 cells resulted in decreased ghrelin levels, accompanied by activation of the cAMP‐PKA‐mTOR signaling pathway. Conversely, the use of the inhibitor SQ22536 or knockdown of Adcy8 produced opposing effects. In conclusion, gastric ADCY8 regulates the expression and secretion of ghrelin via the cAMP‐PKA‐mTOR signaling pathway, thereby influencing food intake.