Opioidergic Regulation of AgRP Neurons

Opioids are generally known to promote hedonic consumption. Although much of the existing evidence is primarily based on studies in mesolimbic pathway, endogenous opioids and their receptors are widely expressed in hypothalamic appetite circuits; however, their role in homeostatic feeding remains unclear. The objective of this study is to understand the role of mediobasal hypothalamic opioid signaling in appetite regulation. We hypothesize that opioids may act as negative regulators of appetite through suppression of hunger neurons. Here we used a novel fluorescent opioid sensor, deltaLight for in vivo imaging of opioid dynamics along with ex vivo electrophysiology to study opioid's impact on appetite neurons. We report that mediobasal hypothalamic opioid levels rapidly increase by feeding, which, in turn, directly inhibit AgRP neurons through mu-opioid receptor (MOR). AgRP specific MOR expression increases by energy surfeit and contributes to opioid induced suppression of appetite. Conversely, its antagonists diminish suppression of AgRP neuron activity by food and satiety hormones. Mice with AgRP neuron specific ablation of MOR expression increased preference for palatable food consumption when given the choice. These results define AgRP neuron specific MOR signaling as a key mediator of diet choice thorough post-ingestive signals. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.