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Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic
Vishwanie S Budhram-Mahadeo1, Matthew R Solomons2, Eeshan A O Mahadeo-Heads2,3
1Molecular Biology Development and Disease, Institute of Cardiovascular Science, University College London, London, UK. v.budhram-mahadeo@ucl.ac.uk.
Abstract:
Metabolic and cardiovascular diseases are highly prevalent and chronic conditions that are closely linked by complex molecular and pathological changes. Such adverse effects often arise from changes in the expression of genes that control essential cellular functions, but the factors that drive such effects are not fully understood. Since tissue-specific transcription factors control the expression of multiple genes, which affect cell fate under different conditions, then identifying such regulators can provide valuable insight into the molecular basis of such diseases. This review explores emerging evidence that supports novel and important roles for the POU4F2/Brn-3b transcription factor (TF) in controlling cellular genes that regulate cardiometabolic function. Brn-3b is expressed in insulin-responsive metabolic tissues (e.g. skeletal muscle and adipose tissue) and is important for normal function because constitutive Brn-3b-knockout (KO) mice develop profound metabolic dysfunction (hyperglycaemia; insulin resistance). Brn-3b is highly expressed in the developing hearts, with lower levels in adult hearts. However, Brn-3b is re-expressed in adult cardiomyocytes following haemodynamic stress or injury and is necessary for adaptive cardiac responses, particularly in male hearts, because male Brn-3b KO mice develop adverse remodelling and reduced cardiac function. As a TF, Brn-3b regulates the expression of multiple target genes, including GLUT4, GSK3β, sonic hedgehog (SHH), cyclin D1 and CDK4, which have known functions in controlling metabolic processes but also participate in cardiac responses to stress or injury. Therefore, loss of Brn-3b and the resultant alterations in the expression of such genes could potentially provide the link between metabolic dysfunctions with adverse cardiovascular responses, which is seen in Brn-3b KO mutants. Since the loss of Brn-3b is associated with obesity, type II diabetes (T2DM) and altered cardiac responses to stress, this regulator may provide a new and important link for understanding how pathological changes arise in such endemic diseases.
Insights
The transcription factor Brn-3b plays a crucial role in metabolic and cardiac health. Loss of Brn-3b leads to metabolic dysfunction and adverse cardiac responses, suggesting its importance in related diseases.
Area of Science:
- Cardiovascular Biology
- Metabolic Regulation
- Molecular Endocrinology
Background:
- Metabolic and cardiovascular diseases are linked by complex molecular changes, often driven by altered gene expression.
- Transcription factors (TFs) regulate cellular functions and gene expression, offering insights into disease mechanisms.
- The POU4F2/Brn-3b TF's role in cardiometabolic function is an emerging area of research.
Purpose of the Study:
- To review the emerging evidence for the role of the POU4F2/Brn-3b transcription factor in cardiometabolic regulation.
- To explore the link between Brn-3b, metabolic dysfunction, and cardiovascular responses.
Main Methods:
- Review of existing scientific literature on Brn-3b function.
- Analysis of data from Brn-3b-knockout (KO) mouse models.
- Examination of Brn-3b target genes involved in metabolic and cardiac processes.
Main Results:
- Brn-3b is essential for normal metabolic function; Brn-3b KO mice exhibit hyperglycemia and insulin resistance.
- Brn-3b is re-expressed in adult cardiomyocytes after stress and is vital for adaptive cardiac responses, especially in males.
- Brn-3b regulates key genes (e.g., GLUT4, GSK3β, SHH) involved in both metabolism and cardiac stress response.
Conclusions:
- Loss of Brn-3b function links metabolic disturbances with adverse cardiovascular outcomes.
- Brn-3b's role in regulating metabolic and cardiac genes suggests it as a potential therapeutic target for obesity, type II diabetes, and heart disease.
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