Egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice

AbstractBeige adipocyte differentiation within white adipose tissue, referred to as browning, is seen as a possible mechanism for increasing energy expenditure. The molecular regulation underlying the thermogenic browning process has not been entirely elucidated. Here, we identify the zinc finger transcription factor EGR1 as a negative regulator of the beige fat program. Loss of Egr1 in mice promotes browning in the absence of external stimulation and activates Ucp1 that encodes the key thermogenic mitochondrial uncoupling protein-1. Moreover, EGR1 is recruited to the proximal region of the Ucp1 promoter in subcutaneous inguinal white adipose tissue. Transcriptomic analysis of subcutaneous inguinal white adipose tissue in the absence of Egr1 identifies the molecular signature of white adipocyte browning downstream of Egr1 deletion and highlights a concomitant increase of beige differentiation marker and decrease in extracellular matrix gene expression. Conversely, Egr1 overexpression in mesenchymal stem cells decreases beige adipocyte differentiation, while increasing extracellular matrix production. These results uncover the role of Egr1 in blocking energy expenditure via direct Ucp1 transcription regulation and highlight Egr1 as a therapeutic target for counteracting obesity.

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

Scientific Reports ◽

10.1038/s41598-020-72698-w ◽

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.

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

10.1101/2020.06.03.131342 ◽

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.

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Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1519358112 ◽

2015 ◽

Vol 112 (45) ◽

pp. 14006-14011 ◽

Cited By ~ 22

Author(s):

Yifei Miao ◽

Wanfu Wu ◽

Yubing Dai ◽

Laure Maneix ◽

Bo Huang ◽

...

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Energy Expenditure ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Thyroid Stimulating Hormone ◽

Vital Role ◽

Normal Diet ◽

Subcutaneous White Adipose Tissue ◽

Brown Adipose

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

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CD137 negatively affects “browning” of white adipose tissue during cold exposure

Journal of Biological Chemistry ◽

10.1074/jbc.ac119.011795 ◽

2020 ◽

Vol 295 (7) ◽

pp. 2034-2042 ◽

Cited By ~ 2

Author(s):

Raj Kamal Srivastava ◽

Annalena Moliner ◽

Ee-Soo Lee ◽

Emily Nickles ◽

Eunice Sim ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Cold Exposure ◽

Uncoupling Protein ◽

Surface Protein ◽

Negative Regulator ◽

Subcutaneous White Adipose Tissue ◽

Brown Adipose ◽

Beige Adipocytes ◽

A Cell

Prolonged cold exposure stimulates the formation of brownlike adipocytes expressing UCP1 (uncoupling-protein-1) in subcutaneous white adipose tissue which, together with classical brown adipose tissue, contributes to maintaining body temperature in mammals through nonshivering thermogenesis. The mechanisms that regulate the formation of these cells, alternatively called beige or brite adipocytes, are incompletely understood. Here we report that mice lacking CD137, a cell surface protein used in several studies as a marker for beige adipocytes, showed elevated levels of thermogenic markers, including UCP1, increased numbers of beige adipocyte precursors, and expanded UCP1-expressing cell clusters in inguinal white adipose tissue after chronic cold exposure. CD137 knockout mice also showed enhanced cold resistance. These results indicate that CD137 functions as a negative regulator of “browning” in white adipose tissue and call into question the use of this protein as a functional marker for beige adipocytes.

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RANKL induces beige adipocyte differentiation in preadipocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00397.2019 ◽

2020 ◽

Vol 318 (6) ◽

pp. E866-E877

Author(s):

Flávia Sayuri Matsuo ◽

Paulo Henrique Cavalcanti de Araújo ◽

Ryerson Fonseca Mota ◽

Ana Júlia Rossoni Carvalho ◽

Mariana Santos de Queiroz ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Stromal Vascular Fraction ◽

Nuclear Factor Κb ◽

Whole Body ◽

Brown Adipocyte ◽

Marker Genes ◽

Beige Adipocyte ◽

White Adipocyte

The receptor activator of nuclear factor-κB (NF-κB) (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) are a triad of proteins that regulate bone metabolism, and serum OPG is considered a biomarker for cardiovascular diseases and Type 2 diabetes; however, the implications of OPG in adipose tissue metabolism remains elusive. In this study, we investigate RANK-RANKL-OPG signaling in white adipose tissue browning. Histological analysis of osteoprotegerin knockout (OPG−/−) mice showed subcutaneous white adipose tissue (sWAT) browning, resistance for high-fat diet-induced weight gain, and preserved glucose metabolism compared with wild-type (WT) mice. Stromal vascular fraction (SVF) cells from sWAT of OPG−/− mice showed multilocular morphology and higher expression of brown adipocyte marker genes compared with those from the WT group. Infusion of RANKL induced browning and elevated respiratory rates in sWAT, along with increased whole body oxygen consumption in mice measured by indirect calorimetry. Subcutaneous WAT-derived SVF and 3T3-L1 cells, but not mature white adipocytes, differentiated into beige adipose tissue in the presence of RANKL. Moreover, SVF cells, even under white adipocyte differentiation, showed multilocular lipid droplet, lower lipid content, and increased expression of beige adipocyte markers with RANKL stimulation. In this study, we show for the first time the contribution of RANKL to increase energy expenditure by inducing beige adipocyte differentiation in preadipocytes.

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Regulatory circuits controlling white versus brown adipocyte differentiation

Biochemical Journal ◽

10.1042/bj20060402 ◽

2006 ◽

Vol 398 (2) ◽

pp. 153-168 ◽

Cited By ~ 119

Author(s):

Jacob B. Hansen ◽

Karsten Kristiansen

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Whole Body ◽

Brown Adipocyte ◽

Ample Evidence ◽

Regulatory Circuits ◽

Brown Adipose ◽

Key Factor

Adipose tissue is a major endocrine organ that exerts a profound influence on whole-body homoeostasis. Two types of adipose tissue exist in mammals: WAT (white adipose tissue) and BAT (brown adipose tissue). WAT stores energy and is the largest energy reserve in mammals, whereas BAT, expressing UCP1 (uncoupling protein 1), can dissipate energy through adaptive thermogenesis. In rodents, ample evidence supports BAT as an organ counteracting obesity, whereas less is known about the presence and significance of BAT in humans. Despite the different functions of white and brown adipocytes, knowledge of factors differentially influencing the formation of white and brown fat cells is sparse. Here we summarize recent progress in the molecular understanding of white versus brown adipocyte differentiation, including novel insights into transcriptional and signal transduction pathways. Since expression of UCP1 is the hallmark of BAT and a key factor determining energy expenditure, we also review conditions associated with enhanced energy expenditure and UCP1 expression in WAT that may provide information on processes involved in brown adipocyte differentiation.

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Promoting Effect of α-Tocopherol on Beige Adipocyte Differentiation in 3T3-L1 Cells and Rat White Adipose Tissue

Journal of Oleo Science ◽

10.5650/jos.ess16137 ◽

2017 ◽

Vol 66 (2) ◽

pp. 171-179 ◽

Cited By ~ 11

Author(s):

Rieko Tanaka-Yachi ◽

Chie Takahashi-Muto ◽

Kazuya Adachi ◽

Yukina Tanimura ◽

Yoshinori Aoki ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Promoting Effect ◽

Beige Adipocyte

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Acetylation of Histone and Modification of Gene Expression via HDAC Inhibitors Affects the Obesity

Biomedical & Pharmacology Journal ◽

10.13005/bpj/2110 ◽

2021 ◽

Vol 14 (1) ◽

pp. 153-161

Author(s):

Deepika Sharma ◽

Swati Sharma ◽

Preeti Chauhan

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

White Adipose Tissue ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Inner Mitochondrial Membrane ◽

Adipose Tissues ◽

Peroxisome Proliferator Activated Receptor ◽

Main Site ◽

Brown Adipose

Obesity is due to imbalance between energy intake and energy expenditure. Adipose tissues are the main site for the fat storage as well as for dissipation. There are two types of adipose tissues: white adipose tissue, which store fat as triglyceride, brown adipose tissue, which burns the fat into energy through the thermogenesis due to uncoupling protein1 present in inner mitochondrial membrane. Histone acylation causes changes in the chromatin structure without causing any change in the deoxyribonucleic acidsequence and thus regulate gene expression.Histonedeacetylase causes the deacylation of histone and interfere with function of histone. Thus histonedeacetylase inhibitors alter the expression of thermogenic gene encoding uncoupling protein 1, peroxisome proliferator activated receptor γ and also causes browning or beiging of white adipose tissue and increases the energy expenditure.

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A compendium of G-protein–coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure

Clinical Science ◽

10.1042/cs20190579 ◽

2020 ◽

Vol 134 (5) ◽

pp. 473-512 ◽

Cited By ~ 5

Author(s):

Ryan P. Ceddia ◽

Sheila Collins

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Signaling Pathways ◽

G Protein ◽

Uncoupling Protein ◽

Beige Adipocytes ◽

Nucleotide Regulation ◽

Ucp1 Expression ◽

Thermogenic Adipocytes ◽

G Protein Coupled

Abstract With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand–receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein–coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.

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