This proposal """"""""Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling"""""""" addresses the fundamental mechanism of diabetes by studying fuel hormone's action in the liver. Elevated blood glucagon levels and defective insulin action in patients with type 2 diabetes are responsible for hyperglycemia, but the molecular mechanisms remain elusive. Glucagon and insulin reciprocally control metabolic and cellular homeostasis, in which the liver is a major organ that executes their cellular functions. In the fasting liver, glucagon stimulates gluconeogenesis, degrades macromolecules including glycogen, lipid, and protein, and promotes the autophagic pathway that regulates cellular organelle turnover. In the feeding liver, insulin reverses the catabolic metabolism of glucagon. The metabolic and cellular adaptation from fasting to feeding requires a tight control of gene transcription by opposing effects of the two hormones, and the failure of the adaptation causes hyperglycemia in diabetes. The forkhead transcription factor Foxo1 that regulates multiple biological processes is inhibited by insulin signaling. Insulin phosphorylates Foxo1 at Ser253 in mice or S256 in humans via PKB activation, and triggers Foxo1 nuclear export and cytoplasmic sequestration for ubiquitination. Conversely, glucagon promotes Foxo1 protein stability in the fasting liver or the liver of diabetes when insulin level is decreased or insulin resistance occurs. Foxo1 can mediate the effect of cyclic AMP, the second messenger of glucagon, on expression of gluconeogenic enzymes and autophagic genes, but the role of Foxo1 and its regulation by glucagon, particularly in concert with insulin resistance, in metabolic regulation and cellular function is completely unclear.
In Aim 1, we will use Foxo1 liver-specific knockout mice and examine whether Foxo1 is a key mediator in glucagon signaling to regulate hepatic glucose production, glycogenolysis, lipid and protein homeostasis, mitochondrial turnover and function, autophagy and survival, whereas disruption of Foxo1 prevents the glucagon-induced biological processes that promote the development of diabetes.
In Aim2, we will use mass-spectrometry and phospho-specific antibodies to determine whether Foxo1 phosphorylation at S153 by glucagon and protein kinase PKA promotes nuclear targeting and whether phosphorylation at S276 enhances transcriptional activity in cells.
In Aim 3, we have generated Foxo1- S253A mutant mice mimicking insulin resistance at the Foxo1 level in vivo. Using this unique mouse model, we will determine whether glucagon stimulates the effect of dephosphorylated Foxo1, disrupting metabolic and cellular homeostasis and liver function. In overall, we use Foxo1 gene loss- and gain-of-function approaches to investigate the physiological role of Foxo1 in glucagon action and identify novel molecular mechanisms of Foxo1 activation, which will advance our understanding of the mechanism of diabetes and help develop strategies detecting and inhibiting the glucagon->Foxo1 pathway to control the disease.

Public Health Relevance

This project addresses the fundamental mechanisms of type 2 diabetes mellitus, in which excess glucagon and defective insulin action co-exist and promote metabolic and cellular dysfunction in the liver. Activation of Foxo1 protein by excess glucagon and insulin resistance coordinately plays a central role in controlling hepatic glucose, lipid, protein and amino acid metabolism, regulating liver function and failure in diabetes. Targeting the novel mechanism of Foxo1 activation in glucagon action can provide new strategies developing therapeutic intervention for the treatment of diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
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Texas A&M University
Internal Medicine/Medicine
Schools of Medicine
College Station
United States
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Wu, Yuxin; Pan, Quan; Yan, Hui et al. (2018) Novel Mechanism of Foxo1 Phosphorylation in Glucagon Signaling in Control of Glucose Homeostasis. Diabetes 67:2167-2182
Guo, Cathy A; Guo, Shaodong (2017) Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure. J Endocrinol 233:R131-R143
Qi, Yajuan; Zhu, Qinglei; Zhang, Kebin et al. (2015) Activation of Foxo1 by insulin resistance promotes cardiac dysfunction and ?-myosin heavy chain gene expression. Circ Heart Fail 8:198-208
Qi, Yajuan; Zhang, Kebin; Wu, Yuxin et al. (2014) Novel mechanism of blood pressure regulation by forkhead box class O1-mediated transcriptional control of hepatic angiotensinogen. Hypertension 64:1131-40
Ma, Jieliang; Zhang, Li; Tipton, Aaron R et al. (2014) Structural and functional analysis of the related transcriptional enhancer factor-1 and NF-?B interaction. Am J Physiol Heart Circ Physiol 306:H233-42
Guo, Shaodong (2014) Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol 220:T1-T23
Zhang, Le; He, Siyi; Guo, Shaodong et al. (2014) Down-regulation of miR-34a alleviates mesangial proliferation in vitro and glomerular hypertrophy in early diabetic nephropathy mice by targeting GAS1. J Diabetes Complications 28:259-64
Guo, Shaodong (2014) Decoding insulin resistance and metabolic syndrome for promising therapeutic intervention. J Endocrinol 220:E1-3
Guo, Shaodong (2014) Mechanisms of Heart Failure in Type 2 Diabetes Mellitus. Austin J Clin Cardiol 1:
Guo, Shaodong (2013) Molecular Basis of Insulin Resistance: The Role of IRS and Foxo1 in the Control of Diabetes Mellitus and Its Complications. Drug Discov Today Dis Mech 10:e27-e33

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