The identification of forkhead transcription factors of the Foxo sub-family as effectors of insulin action on gene expression has filled a yawning gap in our knowledge of insulin signaling, and has identified a cellular biological mechanisms linking hormone signaling to regulation of the cell's transcriptional response through sub-cellular redistribution of transcription factors. Key advances supported by this grant in the past cycle have been: i, demonstration of a key role of Foxo1 in neuropeptide processing and energy balance, linking food intake to work efficiency; ii, identification of G-protein-coupled receptor Gpr17 as a potential modulator of energy balance; iii, identification of an integrative role of hepatic Foxo in the reciprocal regulation of glucokinase vs. glucose-6-phosphatase, with important implications for the design of insulin sensitizers; iv, discovery of the metabolic functions of hepatic Notch; and v, demonstration of its functional interaction with Foxo, establishing a mechanistic link between developmental and nutrient-sensing pathways. We seek to continue our studies with the following aims:
in Aim 1, we propose to investigate whether Foxo1 target Gpr17 is a transcriptional sensor of nutrient and neurotransmitter levels in Npy/AgRP neurons, linking food intake with energy expenditure and hepatic glucose production. To test the hypothesis, we generated mice lacking Gpr17 in AgRP neurons. In preliminary data, we show that these mice have metabolic changes consistent with our original hypothesis. We propose a series of studies to understand the mechanism of Gpr17 action in the CNS and in the periphery, and its functions in metabolic homeostasis.
In Aim 2, we intend to study the corepressor function of Foxo1, using regulation of hepatic glucokinase as a model. The ability of Foxo to repress gene expression has been known for many years, but its effector(s) are unknown. We propose to find the hepatic Foxo1 corepressor(s). We have identified sites of Foxo1 interaction with the glucokinase promoter as well as a candidate corepressor interacting domain. We have established methods to affinity-purify Foxo1 and determine its associated proteins by mass spectrometry. Using these and other techniques in a reconstitution system of Foxo-deficient primary hepatocytes, we plan to identify and functionally characterize the Foxo1 corepressor(s).
Foxo transcription factors are key sensors of the organism's metabolic and hormonal status, and can induce changes in gene expression that account for the protean manifestations of insulin resistance, and its progression to overt diabetes. Based on a body of work developed during the past decade, we will endeavor to understand the integrated physiology of Foxo function in specific tissues, and its biochemical underpinnings. The ultimate goal of this work is to find therapeutic approaches to modify Foxo function. Indeed, whereas Foxo is an attractive biological target to reverse diabetes and metabolic diseases, it is largely intractable as a drug target. Therefore, it is hoped that by parsing its modes of action and interacting partners, new ways to modulate its function can be found.
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|Accili, Domenico (2018) Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67:1701-1709|
|Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44|
|Langlet, Fanny; Haeusler, Rebecca A; Lindén, Daniel et al. (2017) Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Cell 171:824-835.e18|
|Kim-Muller, Ja Young; Kim, Young Jung R; Fan, Jason et al. (2016) FoxO1 Deacetylation Decreases Fatty Acid Oxidation in ?-Cells and Sustains Insulin Secretion in Diabetes. J Biol Chem 291:10162-72|
|Accili, D; Talchai, S C; Kim-Muller, J Y et al. (2016) When ?-cells fail: lessons from dedifferentiation. Diabetes Obes Metab 18 Suppl 1:117-22|
|Cook, Joshua R; Matsumoto, Michihiro; Banks, Alexander S et al. (2015) A mutant allele encoding DNA binding-deficient FoxO1 differentially regulates hepatic glucose and lipid metabolism. Diabetes 64:1951-65|
|Pajvani, Utpal B; Accili, Domenico (2015) The new biology of diabetes. Diabetologia 58:2459-68|
|Cook, Joshua R; Langlet, Fanny; Kido, Yoshiaki et al. (2015) Pathogenesis of selective insulin resistance in isolated hepatocytes. J Biol Chem 290:13972-80|
|Ren, Hongxia; Cook, Joshua R; Kon, Ning et al. (2015) Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin. Diabetes 64:3670-9|
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