The role of FoxK1 in insulin signaling and adipose tissue metabolism
Final Report Abstract
Insulin is a central hormone in the regulation of systemic metabolism. Patients with obesity and metabolic syndrome are characterized by a state of Insulin resistance, which contributes to their adverse metabolic manifestations such as hypertension, hyperglycemia, dyslipidemia and fatty liver development. Despite many years of work, it remains elusive many aspects of the Insulin signaling pathway and how its alterations led to Insulin resistance. In the present project, we aimed to characterize the rote of the transcription factor FOXK1, a novel factor recently found to bind to Insulin receptor and to translocate to the nucleus upon Insulin stimulation. Due to some issues, we needed to change the tissue of interest to the liver. By using liver-specific FOXK1 knockout mice as well as in vitro hepatocytes silenced for this factor, we haue shown that this transcription factor regulates a large set of genes in both basal and Insulin-stimulated conditions. Among those are genes involved in fatty acid and cholesterol metabolism, cell adhesion/communication factors and cell growth/proliferation pathways. Mice deficient for this factor in the liver showed reduced liver weight associated to diminished fasting blond glucose and a mild improvement in glucose tolerance. Preliminary chromatin i mmunoprecipitation experiments showed that FOXK1 can bind directly to the promoters of genes regulated by Insulin, suggesting that this factor represents a new identified branch of the Insulin signaling pathway. Additionally, we identified an unknown Insulin action, which consist in the regulation of miRNAs content of exosomes. This might represent a completely novel mechanism by which Insulin can regulate gene expression in distant tissues. Moreover, by miRNA profile experiments of exosomes and cellular bodies from various Gell types we showed that around half of the expressed miRNAs by any given cell type is subjected to a selective exosomal sorting or cellular retention. We haue also identified general and celltype-specific sequence motifs that determine these processes. Mutagenesis experiments introducing these motifs increased the exosomal sorting of miRNAs. These newly identified motifs Gould represent a novel strategy for the generation of administrable exosomes loaded with miRNAs specifically targeting genes dysregulated in human diseases.
Publications
- Extracellular miRNAs: From Biomarkers to Mediators of Homeostasis and Disease. Cell Metabolism, August 2019
Mori M, Ludwig R, Garcia-Martin R, Brandao BB, Kahn CR
(See online at https://doi.org/10.1016/j.cmet.2019.07.011) - Multi-dimensional transcriptional remodeling by physiological Insulin in vivo, Cell Reports, 2019, Mar 19;26(12):3429-3443
Batista T, Garcia-Martin R, Cai W, Konishi M, O'Neill BT, Sakaguchi M, Kim JH, Jung DY, Kim JK, Kahn CR
(See online at https://doi.org/10.1016/j.celrep.2019.02.081)
