PROJECT SUMMARY The delta cell is uniquely positioned in the islet to integrate local signals and circulating nutrient cues to regulate alpha and beta cell function. Delta cells exert inhibitory effects on alpha and beta cells through somatostatin secretion. Paracrine actions of SST form a negative feedback loop to restrain hormone secretion and maintain glucose homeostasis. In type 2 diabetes (T2D), delta cell responses to ambient glucose are disproportionate and consequently alter insulin and glucagon secretion leading to dysglycemia. However, we know relatively little about the mechanisms influencing delta cells in health and disease. Thus, understanding factors that regulate delta cell SST secretion may reveal pathogenic mechanisms contributing to diabetes and direct new therapies to achieve glucose homeostasis. Leptin is a circulating hormone that reduces alpha and beta cell function, but the specific islet cell target and mechanism of action are unclear. While leptin potently inhibits insulin and glucagon secretion, contemporary experiments suggest leptin effects on alpha and beta cells occurs through indirect mechanisms. Of note, the leptin receptor (LepR) is exclusively expressed on delta cells of human islets. Our preliminary data demonstrate leptin stimulates SST secretion from human and mouse islets, corresponding with decreased insulin and glucagon secretion. Our initial studies also show leptin-induced SST requires delta cell LepR expression, and given SST inhibits alpha and beta cell function, suggests an indirect mechanism whereby leptin regulates alpha and beta cells via SST. Thus, our overarching hypothesis is that leptin stimulates delta cell SST secretion to inhibit alpha and beta cell function. Our project goal is to define the mechanism(s) by which leptin regulates delta cell secretion of SST. In Aim 1, we will temporally reduce circulating leptin levels to define the acute impact of leptin on islet function and morphology independent of overt hyperglycemia. Aim 2 will use genetic tools and SST receptor antagonists to establish the leptin specific effects on delta cells and how leptin exerts paracrine effects in islets. Lastly, Aim 3 will employ pharmacologic and genetic interventions with live functional imaging and unbiased approaches to reveal the molecular and transcriptional mechanisms of leptin action in delta cells. These studies are the first to describe leptin effects on pancreatic delta cells and SST secretion. Our project offers a significant advancement in islet biology given how little we know about delta cells. We will define the mechanisms of leptin regulation of delta cells and uncover a unifying mechanism whereby leptin acts indirectly on alpha and beta cells through paracrine SST signaling. Importantly, delta cells play a critical role to maintain balance of insulin and glucagon secretion. As such, our findings are expected to have high impact on the field and will reveal new signaling mechanisms governing i...