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

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

10.1101/150003 ◽

2017 ◽

Author(s):

Cécile Milet ◽

Marianne Bléher ◽

Kassandra Allbright ◽

Mickael Orgeur ◽

Fanny Coulpier ◽

...

Keyword(s):

Extracellular Matrix ◽

Adipose Tissue ◽

Energy Expenditure ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Negative Regulator ◽

Molecular Signature ◽

Beige Adipocyte ◽

Matrix Gene

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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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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Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

The FASEB Journal ◽

10.1096/fj.201800577r ◽

2018 ◽

Vol 33 (1) ◽

pp. 844-856 ◽

Cited By ~ 8

Author(s):

Wenyan Fu ◽

Yang Liu ◽

Christina Sun ◽

Hang Yin

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Beige Adipocyte

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Aquaglyceroporins Are Differentially Expressed in Beige and White Adipocytes

International Journal of Molecular Sciences ◽

10.3390/ijms21020610 ◽

2020 ◽

Vol 21 (2) ◽

pp. 610

Author(s):

Inês Vieira da Silva ◽

Francisco Díaz-Sáez ◽

António Zorzano ◽

Anna Gumà ◽

Marta Camps ◽

...

Keyword(s):

Adipose Tissue ◽

Adipocyte Differentiation ◽

Expression Patterns ◽

Physiological Role ◽

Glycerol Metabolism ◽

Metabolic Complications ◽

Altered Expression ◽

Beige Adipocyte ◽

White Adipocyte ◽

White Adipocytes

Browning of white adipocytes has been proposed as a powerful strategy to overcome metabolic complications, since brown adipocytes are more catabolic, expending energy as a heat form. However, the biological pathways involved in the browning process are still unclear. Aquaglyceroporins are a sub-class of aquaporin water channels that also permeate glycerol and are involved in body energy homeostasis. In the adipose tissue, aquaporin-7 (AQP7) is the most representative isoform, being crucial for white adipocyte fully differentiation and glycerol metabolism. The altered expression of AQP7 is involved in the onset of obesity and metabolic disorders. Herein, we investigated if aquaglyceroporins are implicated in beige adipocyte differentiation, similar to white cells. Thus, we optimized a protocol of murine 3T3-L1 preadipocytes browning that displayed increased beige and decreased white adipose tissue features at both gene and protein levels and evaluated aquaporin expression patterns along the differentiation process together with cellular lipid content. Our results revealed that AQP7 and aquaporin-9 (AQP9) expression was downregulated throughout beige adipocyte differentiation compared to white differentiation, which may be related to the beige physiological role of heat production from oxidative metabolism, contrasting with the anabolic/catabolic lipid metabolism requiring glycerol gateways occurring in white adipose cells.

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Differential actions of PPAR-α and PPAR-β/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice

PLoS ONE ◽

10.1371/journal.pone.0191365 ◽

2018 ◽

Vol 13 (1) ◽

pp. e0191365 ◽

Cited By ~ 15

Author(s):

Tamiris Lima Rachid ◽

Flavia Maria Silva-Veiga ◽

Francielle Graus-Nunes ◽

Isabele Bringhenti ◽

Carlos Alberto Mandarim-de-Lacerda ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Male Mice ◽

Beige Adipocyte ◽

Subcutaneous White Adipose Tissue ◽

Obese Male

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Fatty Acids, White Adipose Tissue Development, and Adipocyte Differentiation

Nutrient–Gene Interactions in Health and Disease ◽

10.1201/9781420039108-4 ◽

2001 ◽

pp. 63-76

Author(s):

Gérard Ailhaud

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Tissue Development ◽

Adipose Tissue Development

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PPARγ-K107 SUMOylation regulates insulin sensitivity but not adiposity in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814522115 ◽

2018 ◽

Vol 115 (48) ◽

pp. 12102-12111 ◽

Cited By ~ 6

Author(s):

Takeshi Katafuchi ◽

William L. Holland ◽

Rahul K. Kollipara ◽

Ralf Kittler ◽

David J. Mangelsdorf ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Mutant Mice ◽

Covalent Attachment ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain.

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