RANKL induces beige adipocyte differentiation in preadipocytes

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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Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function

Molecular and Cellular Biology ◽

10.1128/mcb.01120-15 ◽

2016 ◽

Vol 36 (15) ◽

pp. 2027-2038 ◽

Cited By ~ 12

Author(s):

Hongyi Zhou ◽

Stephen M. Black ◽

Tyler W. Benson ◽

Neal L. Weintraub ◽

Weiqin Chen

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Adipocyte Differentiation ◽

Whole Body ◽

Brown Adipocyte ◽

Endoplasmic Reticulum Membrane ◽

Brown Adipocytes ◽

White Adipocyte ◽

Brown Adipose ◽

And Function

Brown adipose tissue (BAT) plays a unique role in regulating whole-body energy homeostasis by dissipating energy through thermogenic uncoupling. Berardinelli-Seip congenital lipodystrophy (BSCL) type 2 (BSCL2; also known as seipin) is a lipodystrophy-associated endoplasmic reticulum membrane protein essential for white adipocyte differentiation. Whether BSCL2 directly participates in brown adipocyte differentiation, development, and function, however, is unknown. We show that BSCL2 expression is increased during brown adipocyte differentiation. Its deletion does not impair the classic brown adipogenic program but rather induces premature activation of differentiating brown adipocytes through cyclic AMP (cAMP)/protein kinase A (PKA)-mediated lipolysis and fatty acid and glucose oxidation, as well as uncoupling. cAMP/PKA signaling is physiologically activated during neonatal BAT development in wild-type mice and greatly potentiated in mice with genetic deletion ofBscl2in brown progenitor cells, leading to reduced BAT mass and lipid content during neonatal brown fat formation. However, prolonged overactivation of cAMP/PKA signaling during BAT development ultimately causes apoptosis of brown adipocytes through inflammation, resulting in BAT atrophy and increased overall adiposity in adult mice. These findings reveal a key cell-autonomous role for BSCL2 in controlling BAT mass/activity and provide novel insights into therapeutic strategies targeting cAMP/PKA signaling to regulate brown adipocyte function, viability, and metabolic homeostasis.

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Abstract 339: Impaired Periaortic Adipocyte Differentiation in Angiotensin AT1 Receptor-Deficient Mice: Possible Role in Proinflammatory Phenotypic Modulation of Perivascular Adipose Tissue

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a339 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Daisuke Irie ◽

Hiroyuki Yamada ◽

Taku Kato ◽

Hiroyuki Kawahito ◽

Kouji Ikeda ◽

...

Keyword(s):

Adipose Tissue ◽

Adipocyte Differentiation ◽

At1 Receptor ◽

Brown Adipocyte ◽

Marker Genes ◽

Interscapular Brown Adipose Tissue ◽

Perivascular Adipose Tissue ◽

Expression Levels ◽

Brown Adipose ◽

Differentiation Marker

[BACKGROUND] The angiotensin II type 1 (AT1) receptor in visceral white adipose tissue (WAT) is closely implicated in lipid metabolism and energy homeostasis. Recently, perivascular adipose tissue (PVAT) has been shown to play a crucial role in the development of atherosclerosis; however, the effects of AT1 on PVAT properties and their functional relevance in atherogenesis remain undefined. [METHOD AND RESULT] We examined the fat depot-specific difference of adipose tissue among epididymal WAT, PVAT surrounding thoracic aorta, and interscapular brown adipose tissue (BAT) in 8-week-old apoE deficient (apoE-/-) mice. The expression levels of brown adipocyte marker genes (UCP-1, PGC-1α, Elovl3, PPARα, and Cidea) were significantly higher in BAT and PVAT compared with WAT (P<0.01). White adipocyte marker genes (Igfbp3, DPT, Tcf21, and Hoxc9), which were hardly expressed in BAT, showed a moderate expression levels in PVAT, suggesting that PVAT has a strikingly different phenotype from the classical WAT and BAT. We next examined the properties of PVAT in 8-week-old apoE-/-/AT1 receptor deficient (Agtr1-/-) mice. After 4 weeks of western diet, the expression levels of adipocyte differentiation maker genes (PPARγ, FABP4, c/EBPα) were markedly increased in apoE -/- PVAT (P<0.05), which was completely diminished in apoE-/-/Agtr1 -/- PVAT (P<0.01). To investigate the effect of AT1 on the periaortic adipocyte differentiation, we performed primary culture of preadipocyte from stromal vascular fraction in Agtr1 -/- and Agtr1+/+ PVAT. The mRNA expressions of adipocyte differentiation marker genes (PPARγ, FABP4, and c/EBPα) were time-dependently increased in Agtr1+/+ adipocyte. In contrast, FABP4 and c/EBPα mRNA expressions were markedly inhibited in Agtr1 -/- adipocyte, whereas PPARγ did not differ between the two groups during differentiation, suggesting that AT1 is essentially implicated in the terminal differentiation of periaortic adipocyte. [CONCLUSION] Our findings demonstrate that AT1 regulates the expression levels of late stage of adipocyte-differentiation marker genes in PVAT, suggesting that AT1-mediated modulation of periaortic adipocyte differentiation could be a novel therapeutic target for the prevention of atherosclerosis.

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CD90 Is Dispensable for White and Beige/Brown Adipocyte Differentiation

International Journal of Molecular Sciences ◽

10.3390/ijms21217907 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7907

Author(s):

Meike Dahlhaus ◽

Julian Roos ◽

Daniel Engel ◽

Daniel Tews ◽

Daniel Halbgebauer ◽

...

Keyword(s):

Adipose Tissue ◽

Stromal Cells ◽

Adipocyte Differentiation ◽

Human Adipose Tissue ◽

Brown Adipocyte ◽

White Adipocyte ◽

White Adipocytes ◽

Brown Adipose ◽

Adipose Tissue Stromal Cells ◽

Flow Cytometric Sorting

Brown adipose tissue (BAT) is a thermogenic organ in rodents and humans. In mice, the transplantation of BAT has been successfully used to combat obesity and its comorbidities. While such beneficial properties of BAT are now evident, the developmental and cellular origins of brown, beige, and white adipocytes have remained only poorly understood, especially in humans. We recently discovered that CD90 is highly expressed in stromal cells isolated from human white adipose tissue (WAT) compared to BAT. Here, we studied whether CD90 interferes with brown or white adipogenesis or white adipocyte beiging. We applied flow cytometric sorting of human adipose tissue stromal cells (ASCs), a CRISPR/Cas9 knockout strategy in the human Simpson-Golabi-Behmel syndrome (SGBS) adipocyte model system, as well as a siRNA approach in human approaches supports the hypothesis that CD90 affects brown or white adipogenesis or white adipocyte beiging in humans. Taken together, our findings call the conclusions drawn from previous studies, which claimed a central role of CD90 in adipocyte differentiation, into question.

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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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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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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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Vibration Training Triggers Brown Adipocyte Relative Protein Expression in Rat White Adipose Tissue

BioMed Research International ◽

10.1155/2015/919401 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Chao Sun ◽

Ruixia Zeng ◽

Ge Cao ◽

Zhibang Song ◽

Yibo Zhang ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

White Adipose Tissue ◽

Protein Level ◽

The Body ◽

Whole Body ◽

Brown Adipocyte ◽

Brown Adipose ◽

Vibration Training ◽

Novel Strategy

Recently, vibration training is considered as a novel strategy of weight loss; however, its mechanisms are still unclear. In this study, normal or high-fat diet-induced rats were trained by whole body vibration for 8 weeks. We observed that the body weight and fat metabolism index, blood glucose, triglyceride, cholesterol, and free fatty acid in obesity rats decreased significantly compared with nonvibration group(n=6). Although intrascapular BAT weight did not change significantly, vibration enhanced ATP reduction and increased protein level of the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 in BAT. Interestingly, the adipocytes in retroperitoneal white adipose tissue (WAT) became smaller due to vibration exercise and had higher protein level of the key molecule of brown adipose tissue (BAT), PGC-1α, and UCP1 and inflammatory relative proteins, IL-6 and TNFα. Simultaneously, ATP content and PPARγprotein level in WAT became less in rats compared with nonvibration group. The results indicated that vibration training changed lipid metabolism in rats and promoted brown fat-like change in white adipose tissues through triggering BAT associated gene expression, inflammatory reflect, and reducing energy reserve.

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SIRT5 Regulates Brown Adipocyte Differentiation and Browning of Subcutaneous White Adipose Tissue

Diabetes ◽

10.2337/db18-1103 ◽

2019 ◽

Vol 68 (7) ◽

pp. 1449-1461 ◽

Cited By ~ 9

Author(s):

Lin Shuai ◽

Li-Na Zhang ◽

Bo-Han Li ◽

Chun-Lan Tang ◽

Ling-Yan Wu ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Adipocyte Differentiation ◽

Brown Adipocyte ◽

Subcutaneous White Adipose Tissue

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SIRT2 Suppresses Adipocyte Differentiation by Deacetylating FOXO1 and Enhancing FOXO1's Repressive Interaction with PPARγ

Molecular Biology of the Cell ◽

10.1091/mbc.e08-06-0647 ◽

2009 ◽

Vol 20 (3) ◽

pp. 801-808 ◽

Cited By ~ 156

Author(s):

Fei Wang ◽

Qiang Tong

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Energy Homeostasis ◽

Adipocyte Differentiation ◽

Critical Role ◽

Whole Body ◽

Nutrient Deprivation ◽

Metabolic Functions ◽

Brown Adipose ◽

Body Energy

Sirtuin family of proteins possesses NAD-dependent deacetylase and ADP ribosyltransferase activities. They are found to respond to nutrient deprivation and profoundly regulate metabolic functions. We have previously reported that caloric restriction increases the expression of one of the seven mammalian sirtuins, SIRT2, in tissues such as white adipose tissue. Because adipose tissue is a key metabolic organ playing a critical role in whole body energy homeostasis, we went on to explore the function of SIRT2 in adipose tissue. We found short-term food deprivation for 24 h, already induces SIRT2 expression in white and brown adipose tissues. Additionally, cold exposure elevates SIRT2 expression in brown adipose tissue but not in white adipose tissue. Intraperitoneal injection of a β-adrenergic agonist (isoproterenol) enhances SIRT2 expression in white adipose tissue. Retroviral expression of SIRT2 in 3T3-L1 adipocytes promotes lipolysis. SIRT2 inhibits 3T3-L1 adipocyte differentiation in low-glucose (1 g/l) or low-insulin (100 nM) condition. Mechanistically, SIRT2 suppresses adipogenesis by deacetylating FOXO1 to promote FOXO1's binding to PPARγ and subsequent repression on PPARγ transcriptional activity. Overall, our results indicate that SIRT2 responds to nutrient deprivation and energy expenditure to maintain energy homeostasis by promoting lipolysis and inhibiting adipocyte differentiation.

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