Profound hyperglycemia in knockout mutant mice identifies novel function for POU4F2/Brn-3b in regulating metabolic processes

Bitsi, Stavroula; Ali, Houda; Maskell, Lauren; Ounzain, Samir; Mohamed‐Ali, Vidya; Budhram-Mahadeo, Vishwanie

doi:10.1152/ajpendo.00211.2015

Cited by 7 publications

(20 citation statements)

References 40 publications

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“…As a TF, Brn-3b(s) regulates multiple target genes and thereby drive complex cellular effects. Here we show that known Brn-3b target genes, cyclin D1 34 , GLUT4 30 and Bax 40,41 , are increased by AngII in intact hearts, isolated NRVM cultures or H9c2 cells. Time-course studies identify differential expression patterns of Brn-3b target genes following AngII treatment with maximal expression of cyclin D1 and GLUT4 seen at earlier time points when pro-apoptotic Bax expression is low but are reduced by 24 h, when Bax is maximally induced.…”

Section: Discussionmentioning

confidence: 71%

“…For example, cyclin D1 KO mice display attenuated hypertrophy, whereas transgenic mice over-expressing cyclin D1 develop enlarged hearts 16,17 . Similarly, GLUT4, is increased in hypertrophic hearts 30 and may contribute to metabolic switching, from fatty acid to glucose metabolism in stressed hearts 54 . In contrast, induction of Bax and p53 are linked to cardiomyocyte apoptosis in failing hearts 25,62,63 .…”

Section: Discussionmentioning

confidence: 99%

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The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

Mele¹,

Maskell²,

Stuckey

et al. 2019

Cell Death Dis

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Adult hearts respond to increased workload such as prolonged stress or injury, by undergoing hypertrophic growth. During this process, the early adaptive responses are important for maintaining cardiac output whereas at later stages, pathological responses such as cardiomyocyte apoptosis and fibrosis cause adverse remodelling, that can progress to heart failure. Yet the factors that control transition from adaptive responses to pathological remodelling in the heart are not well understood. Here we describe the POU4F2/Brn-3b transcription factor (TF) as a novel regulator of adaptive hypertrophic responses in adult hearts since Brn-3b mRNA and protein are increased in angiotensin-II (AngII) treated mouse hearts with concomitant hypertrophic changes [increased heart weight:body weight (HW:BW) ratio]. These effects occur specifically in cardiomyocytes because Brn-3b expression is increased in AngII-treated primary cultures of neonatal rat ventricular myocytes (NRVM) or foetal heart-derived H9c2 cells, which undergo characteristic sarcomeric re-organisation seen in hypertrophic myocytes and express hypertrophic markers, ANP/βMHC. The Brn-3b promoter is activated by known hypertrophic signalling pathways e.g. p42/p44 mitogen-activated protein kinase (MAPK/ERK1/2) or calcineurin (via NFAT). Brn-3b target genes, e.g. cyclin D1, GLUT4 and Bax, are increased at different stages following AngII treatment, supporting distinct roles in cardiac responses to stress. Furthermore, hearts from male Brn-3b KO mutant mice display contractile dysfunction at baseline but also attenuated hypertrophic responses to AngII treatment. Hearts from AngII-treated male Brn-3b KO mice develop further contractile dysfunction linked to extensive fibrosis/remodelling. Moreover, known Brn-3b target genes, e.g. GLUT4, are reduced in AngII-treated Brn-3b KO hearts, suggesting that Brn-3b and its target genes are important in driving adaptive hypertrophic responses in stressed heart.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

Mele¹,

Maskell²,

Stuckey

et al. 2019

Cell Death Dis

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“…Many studies indicate the molecular mechanisms developing insulin resistance are based on various specific molecules such as cytokines [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. This information [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , ...…”

Section: Introductionmentioning

confidence: 99%

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

Marunaka

2018

IJMS

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Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH under metabolic disorder conditions becomes lower than the normal level. Insulin resistance is one of the most important key factors in pathogenesis of diabetes mellitus, nevertheless the molecular mechanism of insulin resistance occurrence is still unclear. Our studies indicate that lowered interstitial fluid pH occurs in diabetes mellitus, causing insulin resistance via reduction of the binding affinity of insulin to its receptor. Therefore, the key point for improvement of insulin resistance occurring in diabetes mellitus is development of methods or techniques elevating the lowered interstitial fluid pH. Intake of weak organic acids is found to improve the insulin resistance by elevating the lowered interstitial fluid pH in diabetes mellitus. One of the molecular mechanisms of the pH elevation is that: (1) the carboxyl group (R-COO−) but not H+ composing weak organic acids in foods is absorbed into the body, and (2) the absorbed the carboxyl group (R-COO−) behaves as a pH buffer material, elevating the interstitial fluid pH. On the other hand, high salt intake has been suggested to cause diabetes mellitus; however, the molecular mechanism is unclear. A possible mechanism of high salt intake-caused diabetes mellitus is proposed from a viewpoint of regulation of the interstitial fluid pH: high salt intake lowers the interstitial fluid pH via high production of H+ associated with ATP synthesis required for the Na+,K+-ATPase to extrude the high leveled intracellular Na+ caused by high salt intake. This review article introduces the molecular mechanism causing the lowered interstitial fluid pH and insulin resistance in diabetes mellitus, the improvement of insulin resistance via intake of weak organic acid-containing foods, and a proposal mechanism of high salt intake-caused diabetes mellitus.

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“…Brn-3b is a tissue-specific TF [18][19][20][21][22][23][24][25] belonging to the class IV POU (Pit-1; Oct-1; Unc-86) sub-family of homeodomain TFs, and is characterised by a highly conserved POU domain that forms a helix-turn-helix (HTH) DNA binding structure 26 . The POU domain consists of a 60aa homeodomain, POU-HD , with strong similarity to homeobox proteins and 74-82aa POU-specific domain (POU s ), which is unique to POU proteins (Fig.…”

Section: Brn-3b/pou4f2 Transcription Factor (Tf)mentioning

confidence: 99%

“…afferents of dorsal root ganglia (DRG); cranial nerves V, VIII, IX, X and VII 37 . However, subsequent studies have shown Brn-3b expression in other diverse tissues including reproductive tract tissue (testis, ovary and breast epithelium) 22,33,34,[38][39][40][41][42][43][44] , peripheral blood mononuclear cells (PBMC) 23,45,46 , metabolic tissue (adipocytes, skeletal muscle and liver) 20 , cardiovascular tissues e.g. cardiomyocytes 18,19,21,39,47 and vascular smooth muscle cells (VSMC) (Fig.…”

Section: Brn-3b/pou4f2 Transcription Factor (Tf)mentioning

confidence: 99%

Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease

2021

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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.

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Profound hyperglycemia in knockout mutant mice identifies novel function for POU4F2/Brn-3b in regulating metabolic processes

Cited by 7 publications

References 40 publications

The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease

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