HEPATOKINE CONTROL OF METABOLIC CROSSTALK AND INSULIN RESISTANCE

The major goal of this project is to understand how the NAD+-dependent deacetylase SIRT1 regulateshepatokines that are secreted by the liver and how this process slows the progression of non-alcoholic fatty liverdisease (NAFLD) and obesity. Obesity or being overweight affects approximately 70% of U.S. adults andincreases the prevalence of developing NAFLD and Type 2 diabetes. Type 2 diabetes is a life-threateningdisease characterized by peripheral insulin resistance, which dysregulates inter-tissue communication topromote hyperglycemia and dyslipidemia. However, whether the liver controls systemic metabolism byfunctioning as an endocrine organ to engage other metabolic tissues through secreted factors is a noveland under-explored area. Our preliminary studies reveal a series of novel and exciting observations thatsupport our hypothesis. The loss of SIRT1 in the liver leads to an obese phenotype manifested by increased fatmass and decreased energy expenditure. Strikingly, gene expression profiling analyses identify that fibroblastgrowth factor 21 (FGF21)?a ?lean factor? secreted by the liver (called hepatokine)?is the most markedlydownregulated gene in the liver of liver-specific SIRT1 knockout (SIRT1 LKO) mice. Thus, our CentralHypothesis is that hepatic SIRT1-regulated hepatokines have therapeutic implications for NAFLD andobesity through the autocrine regulation of hepatic lipid metabolism and endocrine control of adiposetissue function. Because hepatic and circulating levels of FGF21 are remarkably decreased in SIRT1 LKO mice,we choose to study the role of hepatokines such as FGF21 in SIRT1 action. Using gain- and loss-of-functionmouse models, this central hypothesis will be tested in three Specific Aims: 1) To determine whether hepaticSIRT1, via stimulating the hepatokine FGF21, protects against whole-body insulin resistance and metabolicabnormalities in obesity; 2) To elucidate the molecular mechanisms by which the hepatocyte-derived SIRT1-FGF21 signaling exerts an autocrine effect to ameliorate hepatic steatosis; and 3) To investigate whether hepaticSIRT1-induced FGF21 hormone has an endocrine effect on beige adipocytes and insulin resistance in whiteadipose tissue. This project is an innovative departure from the study of a single tissue or pathway and thus islikely to reveal the mechanisms by which hepatic SIRT1 defects alone give rise to many features of obesity.Innovative aspects of the application also include: the novel concept that SIRT1-mediated regulation ofhepatokines represents the molecular basis for liver and adipose tissue communication, the new mechanisticinsight into that SIRT1 regulates FGF21 transcription via a mechanism involving deacetylation, and thetechnical innovation of RNA-sequencing and metabolomics analyses. Overall, accomplishing this proposal willnot only provide fundamental insight into a previously unrecognized endocrine role of the liver in controllingsystemic and adipose tissue metabolism but will also identify new targets for treating NAFLD and obesity.