Anatomical Regulation of Glucose and Lipid Metabolism by Insulin Signaling in Hepatocytes

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Abstract This application is entitled ‘Anatomical regulation of glucose and lipid metabolism by insulin signaling in hepatocytes’. The liver is a multitasking organ, performing diverse functions that are critical for maintaining glucose and lipid homeostasis. Previous studies of hepatic insulin signaling have been done with the assumption that all hepatocytes are equivalent. Recently single-cell transcriptomics has revealed that around half of hepatocyte genes are expressed in a zoned manner, in which periportal hepatocytes might coordinate fasting metabolism, whereas pericentral hepatocytes might manage postprandial metabolism. A clear understanding of how insulin signaling coordinates energy homeostasis at spatial levels is necessary. This proposal brings our focus to the important problem of how anatomical segregation of insulin signaling in the liver regulates glucose and lipid metabolism in physiological and pathological conditions. By using promoter knock-in mouse models, we will perform the functional study in vivo by using Gls2CreER mouse line to target periportal hepatocytes and Cyp1a2CreER mouse line to target pericentral hepatocytes. This real-time molecular strategy is innovative as previous work that has relied upon static approaches. By intercrossing with floxed mice targeting insulin signaling components, this project has the potential to reveal important insight into the anatomical segregation of insulin signaling in the liver to control energy homeostasis. First, impaired insulin signal transduction in periportal hepatocytes is expected to promote hepatic glucose production but might retain insulin sensitivity in pericentral hepatocytes for lipid metabolism, producing the pathological combination of hyperglycemia and hyperlipidemia. This strategy might provide an innovative model to investigate the metabolic features of insulin resistance in humans. Second, our preliminary data shows that total hepatic insulin signaling deficiency impairs hepatic de novo lipogenesis and prevents diet-induced fatty liver in mice, which contradicts the excess lipogenesis in insulin-resistant humans. Direct investigation of insulin signaling in pericentral hepatocytes can reveal the relationship between insulin resistance and NAFLD. Third, selective insulin resistance has implications for therapy; however, how to precisely target this paradox is still unresolved. It would be desirable to employ drug targets that could alleviate both T2D and NAFLD. Thus, we propose to identify novel candidate genes that contribute to HFD-induced hyperglycemia and hepatic steatosis. Together, the proposed experiments can discern the function of insulin signaling in the regulation of glucose and lipid metabolism in the periportal and pericentral hepatocytes, which would reveal foundational mechanisms coordinated by hepatic insulin action that moderate glucose and lipid metabolism under physiological and pathological conditions.