Characterizing the Therapeutic Potential of the Adropin‐GPR19 Signaling Pathway in MAFLD

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Mushala, Bellina, Xie, Bingxian, Sipula, Ian, Jurczak, Michael, Scott, Iain
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.L7527

Obesity is the second leading cause of preventable death in the United States, and serves as a fundamental risk factor in various pathologies including metabolic‐associated fatty liver disease (MAFLD). The cellular and molecular mechanisms that drive obesity‐related disease in different tissues are not fully elucidated, and this represents an impediment to the development of effective and efficient treatments. Adropin is a nutritionally regulated liver‐ and brain‐derived peptide hormone that modulates metabolic homeostasis in several tissues. Adropin levels are significantly reduced in obese human subjects, and this decrease is linked to increased adiposity, impaired glucose homeostasis, and liver injury. Recent reports show that MAFLD patients exhibit a marked decrease in serum adropin levels, however the functional significance of this is unknown. Various studies suggest that a class A orphan G‐coupled protein receptor, GPR19, mediates adropin signal transduction, therefore we hypothesized that GPR19 may be the putative cellular receptor that permits adropin function in the liver. To investigate this, we used a novel whole‐body GPR19 knockout mouse to perform a preliminary characterization of the effects of GPR19 depletion on hepatic and whole‐body physiology. Using in vivo metabolic approaches, we report that GPR19 KO mice exhibit glucose intolerance, altered hepatic energy metabolism, and histological liver injury. Together, these data suggest that GPR19 KO mice display pathogenic events that promote a MAFLD phenotype, indicating that GPR19 may be critical for the protective effects of adropin signaling in the liver. These findings further define the fundamental role of the adropin‐GPR19 signaling pathway in the regulation of metabolic homeostasis, and thus highlight a potential target for therapeutic interventions in MAFLD.