Egr1 mediates the effect of insulin on leptin transcription in adipocytes

Mohtar, Omar; Özdemir, Cafer; Roy, Debasish; Shantaram, Dharti; Emili, Andrew; Kandror, Konstantin V.

doi:10.1074/jbc.ac119.007855

Cited by 24 publications

(16 citation statements)

References 43 publications

(47 reference statements)

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“…SC-WAT browning in mutant Egr1 −/− mice is characterized by an increased number of beige adipocytes at the expense of white adipocytes 20 . Taken together, our results suggest that Egr1 represses Cebpb , Ucp1 and activates Lep expression in SC-WAT, which is in accordance with previous results showing recruitment of Egr1 to their promoters 20 , 25 . Decreased Lep expression in MAT depot in Egr1 -null mice (MAT, Supplementary Fig.…”

Section: Resultssupporting

confidence: 93%

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

Bléher

Meshko

Cacciapuoti³

et al. 2020

Sci Rep

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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.

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Section: Resultssupporting

confidence: 93%

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

Bléher

Meshko

Cacciapuoti³

et al. 2020

Sci Rep

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“…Consistent with the browning phenotype, transcriptomic analysis in Egr1-deleted adipose tissue shows a concomitant downregulation of the white adipocyte marker, Lep (leptin) and upregulation of the key beige adipocyte marker Ucp1 [77]. Both positive (Lep) and negative (Ucp1) transcriptional regulations have been shown to occur via direct EGR1 recruitment to regulatory regions of these genes [41,77]. The browning process reduces the deleterious consequences of fat accumulation and is seen as possible mechanism to fight against obesity and to improve metabolic health [125].…”

Section: Egr1 Regulates Extracellular Matrix Production In Adipose Timentioning

confidence: 74%

“…Egr1 expression is rapidly but transiently induced by insulin in 3T3-L1 adipose cell line and in mouse adipose tissue [41]. Insulin secretion induces a cascade of intracellular events in the adipocyte cell lineage [42] including the PI3K/Akt pathway responsible for glucose uptake and glycogenesis and the ERK1/2 MAPK pathway, which decreases insulin signalling [43,44].…”

Section: Numerous Extracellular Signals Regulate Egr1 Expression Via mentioning

confidence: 99%

“…Egr1 gain-of-function in epididymal fat induces insulin resistance [133], while Egr1 loss-of-function improves the whole-body insulin sensitivity in diabetic mice [133]. One possible mechanism would be that insulin-induced EGR1 [41,133] directly inhibits Pnpla2 (ATGL, Adipose TriGlyceride Lipase) expression in adipocytes that leads to lipolysis inhibition and promote fat accumulation [94].…”

Section: Egr1 and Fibrosis In Metabolic Diseases Linked To Adipose Timentioning

confidence: 99%

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EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Havis

Duprez

2020

IJMS

334

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Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair.

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“…Expression of Egr-1 is not detectable in resting cells. However, stimulation of insulin receptor-expressing fibroblasts with insulin induces the biosynthesis of Egr-1 ( Figure 2 B) [ 4 , 5 , 6 , 7 ]. The biosynthesis of Egr-1 is also induced following stimulation of other receptor tyrosine kinases such as the epidermal growth factor (EGF) receptor or the BDNF-responsive tyrosine receptor kinase B (TrkB) [ 8 , 9 , 10 ], indicating that receptor tyrosine kinase signaling converges to the activation of the Egr-1 encoding gene.…”

Section: Transcription Factors Under Control Of Insulin Receptor Signalingmentioning

confidence: 99%

Insulin-Responsive Transcription Factors

2021

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The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues.

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Egr1 mediates the effect of insulin on leptin transcription in adipocytes

Cited by 24 publications

References 43 publications

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

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

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Insulin-Responsive Transcription Factors

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