scholarly journals FOXP4 differentially controls cold-induced beige adipocyte differentiation and thermogenesis

2021 ◽  
Author(s):  
Fuhua Wang ◽  
Shuqin Xu ◽  
Tienan Chen ◽  
Shifeng Ling ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Adipocyte Differentiation ◽  
Brown Adipocytes ◽  
Beige Adipocyte ◽  
Forkhead Box ◽  
Beige Adipocytes ◽  
Adipocyte Cell ◽  
Adipocyte Development ◽  
Fibroblastic Cells

Beige adipocytes possess a discrete developmental origin and notable plasticity in thermogenic capacity in response to various environmental cues. But the transcriptional machinery controlling beige adipocyte development and thermogenesis remains largely unknown. By analyzing beige adipocyte-specific knockout mice, we identified a transcription factor, Forkhead Box P4 (FOXP4) that differentially governs beige adipocyte differentiation and activation. Depletion of Foxp4 caused a decline in the frequency of beige preadipocytes by switching their cell fate towards fibroblastic cells at the expense of beige adipocytes. However, we observed that ablation of Foxp4 in differentiated adipocytes profoundly potentiated their thermogenesis upon cold exposure. Of note, the outcome of Foxp4-deficiency on UCP1-mediated thermogenesis was confined to beige adipocytes, rather than to brown adipocytes. Taken together, we submit that FOXP4 primes beige adipocyte cell fate commitment and differentiation by potent transcriptional repression of the thermogenic program.

scholarly journals Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

2020 ◽  
Author(s):  
Xin Cui ◽  
Jia Jing ◽  
Rui Wu ◽  
Qiang Cao ◽  
Fenfen Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Neurotrophic Factor ◽  
Sympathetic Innervation ◽  
Neurite Growth ◽  
Sympathetic Neuron ◽  
Beige Adipocyte ◽  
Diet Induced Obesity ◽  
Neurotrophin 3 ◽  
Beige Adipocytes ◽  
Adipocyte Development

AbstractActivation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.

scholarly journals Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone

Biology ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 57 ◽  
Author(s):  
Kevin J. Phillips
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Metabolic Effects ◽  
Adipose Tissues ◽  
Beige Adipocyte ◽  
Adaptive Thermogenesis ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Beige Cells ◽  
Adipocyte Development

While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.

scholarly journals Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Marianne Bléher ◽  
Berbang Meshko ◽  
Isabelle Cacciapuoti ◽  
Rachel Gergondey ◽  
Yoann Kovacs ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Loss Of Function ◽  
Beige Adipocyte ◽  
Subcutaneous White Adipose Tissue ◽  
Fat Depots ◽  
Beige Adipocytes

Abstract In mice, exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

scholarly journals Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue

2020 ◽  
Author(s):  
Marianne Bléher ◽  
Berbang Meshko ◽  
Rachel Gergondey ◽  
Yoann Kovacs ◽  
Delphine Duprez ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Loss Of Function ◽  
Beige Adipocyte ◽  
Subcutaneous White Adipose Tissue ◽  
Fat Depots ◽  
Beige Adipocytes

AbstractExercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.

scholarly journals Foxp1 controls brown/beige adipocyte differentiation and thermogenesis through regulating β3-AR desensitization

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Pei Liu ◽  
Sixia Huang ◽  
Shifeng Ling ◽  
Shuqin Xu ◽  
Fuhua Wang ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Adipocyte Differentiation ◽  
Beige Adipocyte ◽  
Adaptive Thermogenesis ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Beige Adipocytes ◽  
Treatment Of Obesity ◽  
Deficient Mice ◽  
Specific Deletion

Abstract β-Adrenergic receptor (β-AR) signaling is a pathway controlling adaptive thermogenesis in brown or beige adipocytes. Here we investigate the biological roles of the transcription factor Foxp1 in brown/beige adipocyte differentiation and thermogenesis. Adipose-specific deletion of Foxp1 leads to an increase of brown adipose activity and browning program of white adipose tissues. The Foxp1-deficient mice show an augmented energy expenditure and are protected from diet-induced obesity and insulin resistance. Consistently, overexpression of Foxp1 in adipocytes impairs adaptive thermogenesis and promotes diet-induced obesity. A robust change in abundance of the β3-adrenergic receptor (β3-AR) is observed in brown/beige adipocytes from both lines of mice. Molecularly, Foxp1 directly represses β3-AR transcription and regulates its desensitization behavior. Taken together, our findings reveal Foxp1 as a master transcriptional repressor of brown/beige adipocyte differentiation and thermogenesis, and provide an important clue for its targeting and treatment of obesity.

scholarly journals Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Cui ◽  
Jia Jing ◽  
Rui Wu ◽  
Qiang Cao ◽  
Fenfen Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Neurotrophic Factor ◽  
Sympathetic Innervation ◽  
Neurite Growth ◽  
Sympathetic Neuron ◽  
Beige Adipocyte ◽  
Diet Induced Obesity ◽  
Neurotrophin 3 ◽  
Beige Adipocytes ◽  
Adipocyte Development

AbstractActivation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity.

Growth factor regulation of uncoupling protein-1 mRNA expression in brown adipocytes

2002 ◽  
Vol 282 (1) ◽  
pp. C105-C112 ◽  
Author(s):  
Bibian García ◽  
Maria-Jesús Obregón
Keyword(s):  
Growth Factor ◽  
Adipocyte Differentiation ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Mrna Levels ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Proliferation And Differentiation ◽  
Epidermal Growth ◽  
Continuous Presence

To study the effect of the mitogens epidermal growth factor (EGF), acidic and basic fibroblast growth factors (aFGF and bFGF), and vasopressin on brown adipocyte differentiation, we analyzed the expression of uncoupling protein-1 (UCP-1) mRNA. Quiescent brown preadipocytes express high levels of UCP-1 mRNA in response to triiodothyronine (T3) and norepinephrine (NE). The addition of serum or the mitogenic condition aFGF + vasopressin + NE or EGF + vasopressin + NE decreases UCP-1 mRNA. A second addition of mitogens further decreases UCP-1 mRNA. Treatment with aFGF or bFGF alone increases UCP-1 mRNA, whereas the addition of EGF or vasopressin dramatically reduces UCP-1 mRNA levels. The continuous presence of T3 increases UCP-1 mRNA levels in cells treated with EGF, aFGF, or bFGF. The effect of T3 on the stimulation of DNA synthesis also was tested. T3 inhibits the mitogenic activity of aFGF and bFGF. In conclusion, mitogens like aFGF or bFGF allow brown adipocyte differentiation, whereas EGF and vasopressin inhibit the differentiation process. T3 behaves as an important hormone that regulates both brown adipocyte proliferation and differentiation.

scholarly journals The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML

2012 ◽  
Vol 210 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Florian H. Heidel ◽  
Lars Bullinger ◽  
Patricia Arreba-Tutusaus ◽  
Zhu Wang ◽  
Julia Gaebel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Determinant ◽  
Lethal Giant Larvae ◽  
Evolutionarily Conserved ◽  
Human Acute Myeloid Leukemia ◽  
Early Growth Response 1

A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1−/− HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.

scholarly journals Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2.

1996 ◽  
Vol 16 (3) ◽  
pp. 952-959 ◽  
Author(s):  
J J Hsieh ◽  
T Henkel ◽  
P Salmon ◽  
E Robey ◽  
M G Peterson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Epstein Barr Virus ◽  
Cell Fate Decisions ◽  
Barr Virus ◽  
Amino Acid Region ◽  
Nuclear Events ◽  
Epstein Barr

The Notch/Lin-12/Glp-1 receptor family participates in cell-cell signaling events that influence cell fate decisions. Although several Notch homologs and receptor ligands have been identified, the nuclear events involved in this pathway remain incompletely understood. A truncated form of Notch, consisting only of the intracellular domain (NotchIC), localizes to the nucleus and functions as an activated receptor. Using both an in vitro binding assay and a cotransfection assay based on the two-hybrid principle, we show that mammalian NotchIC interacts with the transcriptional repressor CBF1, which is the human homolog of Drosophila Suppressor of Hairless. Cotransfection assays using segments of mouse NotchIC and CBF1 demonstrated that the N-terminal 114-amino-acid region of mouse NotchIC contains the CBF1 interactive domain and that the cdc10/ankyrin repeats are not essential for this interaction. This result was confirmed in immunoprecipation assays in which the N-terminal 114-amino-acid segment of NotchIC, but not the ankyrin repeat region, coprecipitated with CBF1. Mouse NotchIC itself is targeted to the transcriptional repression domain (aa179 to 361) of CBF1. Furthermore, transfection assays in which mouse NotchIC was targeted through Gal4-CBF1 or through endogenous cellular CBF1 indicated that NotchIC transactivates gene expression via CBF1 tethering to DNA. Transactivation by NotchIC occurs partially through abolition of CBF1-mediated repession. This same mechanism is used by Epstein-Barr virus EBNA2. Thus, mimicry of Notch signal transduction is involved in Epstein-Barr virus-driven immortalization.

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