CREB-regulated transcription coactivator 2, known as CRTC2, is a protein that plays a role in cellular processes by influencing gene expression. This protein belongs to a family of transcription coactivators that promote the transcription of genes targeted by the cAMP response element-binding protein (CREB). CRTC2 is involved in maintaining overall cellular balance by coupling nutrient and hormonal signals to gene expression programs.
CRTC2’s Central Role in Glucose Regulation
CRTC2’s primary function is its involvement in gluconeogenesis, the process where the liver produces glucose from non-carbohydrate sources. By interacting with the CREB protein, CRTC2 activates the transcription of gluconeogenic genes. This directly influences the liver’s glucose output, which is important during fasting to maintain blood glucose levels.
Hormones like insulin and glucagon regulate CRTC2 activity in response to blood glucose fluctuations. Under conditions of elevated blood glucose, insulin works to inhibit CRTC2 activity, helping to reduce glucose production. Conversely, when blood glucose levels are low, glucagon activates CRTC2, promoting glucose release from the liver. This hormonal regulation ensures that glucose levels remain within a healthy range.
CRTC2’s regulation involves its movement within the cell. Normally, CRTC2 is in the cytoplasm, inactive due to phosphorylation. When activated by signals like elevated cAMP or calcium, CRTC2 dephosphorylates and moves into the nucleus. There, it binds to CREB and enhances target gene transcription, increasing glucose production.
Under conditions of high blood sugar, CRTC2 can undergo a modification called O-linked glycosylation. This modification can counteract the inhibitory phosphorylation, essentially locking CRTC2 in an active state. This prolonged activation further stimulates glucose production in the liver, potentially contributing to glucose intolerance.
CRTC2’s Diverse Functions Beyond Glucose
Beyond its well-established role in glucose regulation, CRTC2 influences other metabolic pathways, including lipid metabolism. It plays a part in the synthesis of fatty acids and the storage of triglycerides, highlighting its broader impact on how the body manages and stores fats.
CRTC2 also contributes to overall energy balance within the body. It can affect mitochondrial function, which are the powerhouses of cells responsible for energy production. Its influence on mitochondrial biogenesis suggests a role in ensuring cells have the necessary machinery for efficient energy conversion.
CRTC2 has been linked to other physiological processes, such as inflammatory responses and stress pathways. It integrates signals from both fasting and endoplasmic reticulum stress pathways. Through its association with ATF6α, CRTC2 promotes the expression of glucose-producing genes and induces genes related to endoplasmic reticulum quality control. This dual function fine-tunes the liver’s glucose output, especially during metabolic stress.
These diverse functions underscore that CRTC2 is not solely a glucose regulator but a broader metabolic sensor. Its ability to respond to different cellular signals means it can coordinate various metabolic processes.
CRTC2 and Metabolic Imbalance
Dysregulation of CRTC2 can contribute to various metabolic disorders. It has strong links to Type 2 Diabetes, where increased CRTC2 activity leads to excessive hepatic glucose production. This overproduction contributes to persistently high blood sugar levels, a hallmark of Type 2 Diabetes, and can worsen insulin resistance.
An imbalance in CRTC2 function is also connected to conditions like non-alcoholic fatty liver disease (NAFLD) and obesity. Since CRTC2 influences lipid metabolism, its malfunction can exacerbate the accumulation of fat in the liver, a characteristic of NAFLD. In obesity, altered CRTC2 activity might contribute to the disrupted energy balance and fat storage patterns observed in affected individuals. For instance, when CRTC2 remains overly active, it can promote both glucose and lipid production, contributing to metabolic overload.
Proper CRTC2 function is important for maintaining metabolic health. When its regulatory mechanisms are disrupted, whether through genetic variations or environmental factors, it can lead to a cascade of metabolic disturbances. For example, single nucleotide polymorphisms in the CRTC2 gene have been associated with an increased risk of Type 2 Diabetes. Understanding how CRTC2’s activity is controlled and what causes its dysregulation is a focus in addressing these metabolic conditions.