Impact of Fatty Acid Metabolism in Adipose Tissues and Liver on Insulin Resistance – HepAdialogue

DDysregulation of fat metabolism in liver and adipose tissues is a hallmark of insulin resistance. White and brite/beige adipose tissues, and liver produce proteins and lipids with systemic action on insulin sensitivity. The regulation of the pathways involved in the synthesis, release and use of fatty acids shall influence the secretory capacities of these organs to promote systemic effects on insulin sensitivity. Survey of human data shows that fatty acids are not the only metabolic villains in insulin resistance. There are major gaps in the understanding of the impact of modified fat metabolism in adipocytes and hepatocytes on insulin sensitivity. Therefore, HepAdialogue aims at identifying new mediators of insulin sensitivity which production is influenced by key nodes of regulation in adipose and hepatic lipid metabolic pathways. The partners have identified three proteins that play such a role. In white adipocytes, hormone-sensitive lipase (HSL) independently of its role in adipose tissue lipolysis physically interacts with the glucose-responsive transcription factor, ChREBP, to control de novo lipogenesis and fat cell insulin signaling. ChREBP also influences insulin sensitivity through its major role in the control of de novo fatty acid synthesis in the liver. The nuclear receptor PPARalpha controls fat oxidation. In adipose tissue, it also promotes white-to-brite conversion of fat cells. In the liver, PPARalpha acts as a free fatty acid sensor during adipose tissue lipolysis and controls ketogenesis. Unexpectedly, PPARalpha shares a common transcriptional target with ChREBP, the hepatokine FGF21 which controls brown and white adipose tissue metabolism. Identification of lipids and proteins with putative endocrine action has been initiated by the Partners. In HepAdialogue, it will be completed though combined lipidomics, proteomics and transcriptomics analyses of adipocytes and hepatocytes in vitro and, of fat and liver from adipose-specific and hepatocyte-specific knock out mice in vivo. This part of the work is supported by already established models and preliminary unpublished data. Following validation on complementary models of a short list of secreted lipid and protein species, the influence of adipose factors on hepatocyte glucose metabolism and insulin signaling will be investigated. Conversely, we will study the influence of hepatic factors on adipocyte glucose metabolism and insulin signaling. Regulation of the production of the novel endocrine factors will be investigated in preclinical models of type 2 diabetes and tissue samples from human cohorts. Various pharmacological and nutritional approaches known to impact on the metabolic nodes of lipid metabolism will be used to manipulate the production and levels of the identified factors. Upon project completion, we aim at having identified and validated new secreted molecules with confirmed bioactivity in cell culture. Seeking industrial partnership, the next step will be to test whether the compounds themselves, their precursors or some inhibitors may have the capacity to reverse insulin resistance and associated metabolic disorders and/or to induce browning of white adipose tissues in vivo.