UCLA

The communication between adipocytes and liver plays a crucial role in the physiological regulation of metabolism and understanding the basis of this dynamic inter-organ communication has the potential to advance clinical therapies. This is particularly important for conditions like obesity, fatty liver disease, and type 2 diabetes, which have emerged as global metabolic disorders. Consequently, the investigation of the communication between the liver and adipose tissue has been a hot point in metabolic research for many years (Azzu, Vacca et al. 2020).Numerous studies have investigated adipose tissue and its secretome composition, however, a comprehensive global analysis of the lipidome was still absent. In this study, we used the beta-3-adrenergic receptor agonist, CL-316,243 (CL), to stimulate adipose tissue lipolysis in both in vivo and in vitro settings (Zhang, Williams et al. 2023). A single dose of CL treatment was deemed an appropriate model to mimic acute adipose tissue lipolysis. Additionally, we conducted a time course analysis to investigate the dynamic changes in the adipose tissue lipolysis lipidome and its impact on hepatic lipidome, considering the lipid flux originating from adipose tissue lipolysis. We also utilized ATGL adipose tissue-specific knockout mice as a model to underscore the significance of adipose tissue lipolysis in hepatic lipid remodeling (Kim, Tang et al. 2016). Our study provides a comprehensive perspective on how adipose tissue lipolysis remodels the hepatic lipidome. Furthermore, we identified specific lipid alterations of interest, including the accumulation of linoleic acid and the release of odd-chain free fatty acids. Another pivotal aspect of the study on the interaction between adipose tissue and the liver is how the liver responds to adipose tissue lipolysis. In this investigation, we applied RNA-seq and subsequent bioinformatic analysis to detect novel hepatic regulators. In addition to the well-established regulators such as PPARa, HNF4a, and SREBP1c, we identified hepatic glucocorticoid receptor (GR) as another critical transcription factor involved in this process, which is activated by the hypothalamic-pituitary adrenal (HPA) axis. Furthermore, it appears that hepatic GR plays a crucial role in regulating ketogenesis and triglyceride accumulation during adipose tissue lipolysis. Notably, our research revealed that Plin5 serves as a downstream target whose expression is controlled by hepatic GR directly. And absence of hepatic Plin5 also impedes ketogenesis. This suggests that the Adipose-HPA-GR-PLIN5 axis may represent an important regulatory pathway in ketogenesis. In addition to RNA-seq, we employed Assay of Transposase-Accessible Chromatin ATAC-seq as an additional tool to investigate hepatic regulators. Our findings suggest that a novel transcription factor, Elk4, may potentially have a role in hepatic metabolism, specifically in glucose metabolism and pyruvate metabolism. However, given the limited knowledge available about Elk4, further research is warranted to understand more about its functions and mechanisms.