GO:0045722 positive regulation of gluconeogenesis

Gluconeogenesis is the metabolic pathway that synthesizes glucose from non-carbohydrate precursors such as lactate, glycerol, and amino acids, primarily in the liver and kidneys. The Gene Ontology term GO:0045722, positive regulation of gluconeogenesis, encompasses any process that activates or increases the frequency, rate, or extent of this pathway. This regulation is critical for maintaining blood glucose levels during fasting and is tightly controlled by hormonal and nutritional signals. Dysregulation of gluconeogenesis is a hallmark of metabolic disorders, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Understanding the positive regulators of gluconeogenesis is therefore essential for developing therapeutic strategies. Recent research has uncovered diverse molecular mechanisms that positively regulate gluconeogenesis. For instance, the transcription factor Foxo1 is a well-known activator of gluconeogenic gene expression, and its reciprocal regulation with TGF-β1 controls hepatic glucose production and energy expenditure. Additionally, the gluconeogenic enzyme PCK1 (phosphoenolpyruvate carboxykinase 1) has been shown to phosphorylate INSIG1/2, thereby promoting lipogenesis and linking glucose production to lipid metabolism. Inter-organ communication also plays a role; hepatic ketone bodies can stimulate renal gluconeogenesis, demonstrating systemic regulation. Given the complexity of these regulatory networks, researchers require robust experimental models to dissect the positive regulation of gluconeogenesis. CRISPR-based gene editing offers powerful tools to create knockout, point-mutation, knock-in, and overexpression cell models, enabling precise interrogation of candidate genes. This article provides a comprehensive overview of GO:0045722, including its definition, key genes, regulatory mechanisms, disease associations, and state-of-the-art research methods.

GO:0045722, positive regulation of gluconeogenesis, is defined as any process that activates or increases the frequency, rate, or extent of gluconeogenesis. This biological process includes the action of transcription factors, signaling pathways, and metabolic enzymes that enhance the synthesis of glucose from non-carbohydrate precursors such as lactate, glycerol, and amino acids. The term is a child of 'regulation of gluconeogenesis' and is distinct from negative regulation (GO:0045721). Synonyms include activation of gluconeogenesis, stimulation of gluconeogenesis, up regulation of gluconeogenesis, up-regulation of gluconeogenesis, and upregulation of gluconeogenesis.

Positive regulation of gluconeogenesis is vital for maintaining blood glucose levels during fasting, exercise, and stress. It ensures that the brain and other glucose-dependent tissues receive an adequate energy supply. However, excessive or inappropriate activation of gluconeogenesis contributes to hyperglycemia in type 2 diabetes and to hepatic steatosis in NAFLD. Therefore, understanding the molecular players that positively regulate this pathway is crucial for identifying therapeutic targets and developing interventions for metabolic diseases.

The following genes and proteins are central to the positive regulation of gluconeogenesis, as supported by published literature.

Positive regulation of gluconeogenesis is controlled by a complex network of hormonal, nutritional, and intracellular signals. Insulin suppresses gluconeogenesis, while glucagon and catecholamines stimulate it. At the transcriptional level, Foxo1 is a key activator that is inhibited by insulin via AKT-mediated phosphorylation. TGF-β1 reciprocally regulates Foxo1, thereby modulating hepatic gluconeogenesis and energy expenditure. Metformin may reduce gluconeogenesis by stimulating the production of cyclic PIP, a natural cAMP antagonist. Additionally, hepatic ketone bodies can regulate renal gluconeogenesis, illustrating inter-organ control. These regulatory mechanisms ensure that glucose production is appropriately matched to physiological demands.

Excessive positive regulation of gluconeogenesis contributes to hyperglycemia in type 2 diabetes. Insulin resistance impairs the ability of insulin to suppress gluconeogenic gene expression, leading to increased hepatic glucose output. The transcription factor Foxo1 is a critical mediator of this process, and its dysregulation is associated with diabetes. Metformin, a first-line therapy, may reduce gluconeogenesis by increasing cyclic PIP, which antagonizes cAMP signaling.

NAFLD is characterized by excessive lipid accumulation in the liver and is often associated with insulin resistance. VEGFB ameliorates insulin resistance in NAFLD via the PI3K/AKT signaling pathway, which may indirectly suppress gluconeogenesis. Additionally, PCK1-mediated phosphorylation of INSIG1/2 links gluconeogenesis to lipogenesis, suggesting that dysregulation of this axis contributes to NAFLD pathogenesis.

The kidneys also contribute to glucose production, and this process can be regulated by hepatic ketone bodies. In conditions such as diabetes, renal gluconeogenesis may be inappropriately activated, exacerbating hyperglycemia. Understanding the inter-organ communication between liver and kidney is therefore important for developing comprehensive therapeutic strategies.

RNA sequencing can quantify changes in the expression of gluconeogenic genes such as PCK1, G6PC, and FBP1 following genetic or pharmacological perturbations. This method is useful for identifying transcriptional networks that positively regulate gluconeogenesis.

Measuring glucose production from labeled precursors (e.g., lactate, pyruvate) using mass spectrometry allows direct assessment of gluconeogenic flux. This is critical for validating the functional impact of candidate regulators.

Mass spectrometry-based proteomics can identify post-translational modifications on gluconeogenic enzymes. For example, phosphorylation of PCK1 and INSIG1/2 can be detected to understand signaling events.

Genome-wide CRISPR knockout or activation screens can uncover novel positive regulators of gluconeogenesis. Such screens have been used to identify genes that modulate metabolic pathways in various cell types.

Researchers studying positive regulation of gluconeogenesis-related genes often need to determine whether a candidate gene is causally involved in the pathway or merely correlated with changes in glucose production. CRISPR-based gene editing provides the necessary tools to establish causality through precise genetic perturbations.

GO:0045722, positive regulation of gluconeogenesis, is a critical biological process that ensures adequate glucose supply during fasting and stress. Its dysregulation contributes to major metabolic diseases, including type 2 diabetes and NAFLD. Advances in CRISPR gene editing and high-throughput screening are accelerating the discovery of novel regulators and therapeutic targets. EDITGENE provides comprehensive services to support research in this field, from custom cell model generation to bioinformatics analysis.