Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ

2012 ◽  
Vol 443 (3) ◽  
pp. 799-810 ◽  
Author(s):  
Jordi Armengol ◽  
Josep A. Villena ◽  
Elayne Hondares ◽  
María C. Carmona ◽  
Hei Sook Sul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Proximal Promoter ◽  
Brown Adipocyte ◽  
Specific Marker ◽  
Brown Adipose ◽  
Factor C

Pref-1 (pre-adipocyte factor-1) is known to play a central role in regulating white adipocyte differentiation, but the role of Pref-1 in BAT (brown adipose tissue) has not been analysed. In the present study we found that Pref-1 expression is high in fetal BAT and declines progressively after birth. However, Pref-1-null mice showed unaltered fetal development of BAT, but exhibited signs of over-activation of BAT thermogenesis in the post-natal period. In C/EBP (CCAAT/enhancer-binding protein) α-null mice, a rodent model of impaired fetal BAT differentiation, Pref-1 was dramatically overexpressed, in association with reduced expression of the Ucp1 (uncoupling protein 1) gene, a BAT-specific marker of thermogenic differentiation. In brown adipocyte cell culture models, Pref-1 was mostly expressed in pre-adipocytes and declined with brown adipocyte differentiation. The transcription factor C/EBPδ activated the Pref-1 gene transcription in brown adipocytes, through binding to the proximal promoter region. Accordingly, siRNA (small interfering RNA)-induced C/EBPδ knockdown led to reduced Pref-1 gene expression. This effect is consistent with the observed overexpression of C/EBPδ in C/EBPα-null BAT and high expression of C/EBPδ in brown pre-adipocytes. Dexamethasone treatment of brown pre-adipocytes suppressed Pref-1 down-regulation occurring throughout the brown adipocyte differentiation process, increased the expression of C/EBPδ and strongly impaired expression of the thermogenic markers UCP1 and PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-α]. However, it did not alter normal fat accumulation or expression of non-BAT-specific genes. Collectively, these results specifically implicate Pref-1 in controlling the thermogenic gene expression program in BAT, and identify C/EBPδ as a novel transcriptional regulator of Pref-1 gene expression that may be related to the specific role of glucocorticoids in BAT differentiation.

scholarly journals Role of Ubiquilins for Brown Adipocyte Proteostasis and Thermogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolin Muley ◽  
Stefan Kotschi ◽  
Alexander Bartelt
Keyword(s):  
Gene Expression ◽  
Quality Control ◽  
Adipose Tissue ◽  
Cold Exposure ◽  
Protein Quality ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Shivering Thermogenesis

The acclimatization of brown adipose tissue (BAT) to sustained cold exposure requires an adaptive increase in proteasomal protein quality control. Ubiquilins represent a recently identified family of shuttle proteins with versatile functions in protein degradation, such as facilitating substrate targeting and proteasomal degradation. However, whether ubiquilins participate in brown adipocyte function has not been investigated so far. Here, we determine the role of ubiquilins for proteostasis and non-shivering thermogenesis in brown adipocytes. We found that Ubqln1, 2 and 4 are highly expressed in BAT and their expression was induced by cold and proteasomal inhibition. Surprisingly, silencing of ubiquilin gene expression (one or multiple in combinations) did not lead to aggravated ER stress or inflammation. Moreover, ubiquitin level and proteasomal activity under basal conditions were not impacted by loss of ubiquilins. Also, non-shivering thermogenesis measured by norepinephrine-induced respiration remained intact after loss of ubiquilins. In conclusion, ubiquilin proteins are highly abundant in BAT and regulated by cold, but they are dispensable for brown adipocyte proteostasis and thermogenesis.

scholarly journals Physical Activity Attenuates the Obesity-Induced Dysregulated Expression of Brown Adipokines in Murine Interscapular Brown Adipose Tissue

2021 ◽  
Vol 22 (19) ◽  
pp. 10391
Author(s):  
Takuya Sakurai ◽  
Toshiyuki Fukutomi ◽  
Sachiko Yamamoto ◽  
Eriko Nozaki ◽  
Takako Kizaki
Keyword(s):  
Physical Activity ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Focal Point ◽  
Brown Adipocyte ◽  
Obese Mice ◽  
Gene Expressions ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose

In recent years, brown adipose tissue (BAT), which has a high heat-producing capacity, has been confirmed to exist even in adults, and it has become a focal point for the prevention and the improvement of obesity and lifestyle-related diseases. However, the influences of obesity and physical activity (PA) on the fluid factors secreted from BAT (brown adipokines) are not well understood. In this study, therefore, we focused on brown adipokines and investigated the effects of obesity and PA. The abnormal expressions of gene fluid factors such as galectin-3 (Lgals3) and Lgals3 binding protein (Lgals3bp), whose proteins are secreted from HB2 brown adipocytes, were observed in the interscapular BAT of obese mice fed a high-fat diet for 4 months. PA attenuated the abnormalities in the expressions of these genes. Furthermore, although the gene expressions of factors related to brown adipocyte differentiation such as peroxisome proliferator-activated receptor gamma coactivator 1-α were also down-regulated in the BAT of the obese mice, PA suppressed the down-regulation of these factors. On the other hand, lipogenesis was increased more in HB2 cells overexpressing Lgals3 compared with that in control cells, and the overexpression of Lgals3bp decreased the mitochondrial mass. These results indicate that PA attenuates the obesity-induced dysregulated expression of brown adipokines and suggests that Lgals3 and Lgals3bp are involved in brown adipocyte differentiation.

scholarly journals The Engrailed-1 Gene Stimulates Brown Adipogenesis

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Chuanhai Zhang ◽  
Yibing Weng ◽  
Fangxiong Shi ◽  
Wanzhu Jin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Lipid Accumulation ◽  
Brown Adipocyte ◽  
Specific Marker ◽  
Positive Regulator ◽  
Brown Adipose ◽  
Brown Adipogenesis

As a thermogenic organ, brown adipose tissue (BAT) has received a great attention in treating obesity and related diseases. It has been reported that brown adipocyte was derived from engrailed-1 (EN1) positive central dermomyotome. However, functions of EN1 in brown adipogenesis are largely unknown. Here we demonstrated that EN1 overexpression increased while EN1 knockdown decreased lipid accumulation and the expressions of key adipogenic genes including PPARγ2 and C/EBPαand mitochondrial OXPHOS as well as BAT specific marker UCP1. Taken together, our findings clearly indicate that EN1 is a positive regulator of brown adipogenesis.

scholarly journals Regulation of mitochondrial biogenesis in brown adipose tissue: nuclear respiratory factor-2/GA-binding protein is responsible for the transcriptional regulation of the gene for the mitochondrial ATP synthase β subunit

1998 ◽  
Vol 331 (1) ◽  
pp. 121-127 ◽  
Author(s):  
Josep A. VILLENA ◽  
Octavi VIÑAS ◽  
Teresa MAMPEL ◽  
Roser IGLESIAS ◽  
Marta GIRALT ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Adipocyte Differentiation ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Nuclear Respiratory Factor ◽  
Brown Adipose ◽  
Nuclear Respiratory Factor 2 ◽  
Ga Binding Protein

The regulation of transcription of the gene for the β subunit of the FoF1 ATP synthase (ATPsynβ) in brown adipose tissue has been studied as a model to determine the molecular mechanisms for mitochondrial biogenesis associated with brown adipocyte differentiation. The expression of the ATPsynβ mRNA is induced during the brown adipocyte differentiation that occurs during murine prenatal development or when brown adipocytes differentiate in culture. This induction occurs in parallel with enhanced gene expression for other nuclear and mitochondrially-encoded components of the respiratory chain/oxidative phosphorylation system (OXPHOS). Transient transfection assays indicated that the expression of the ATPsynβ gene promoter is higher in differentiated HIB-1B brown adipocytes than in non-differentiated HIB-1B cells. A major transcriptional regulatory site was identified between nt -306 and -266 in the ATPsynβ promoter. This element has a higher enhancer capacity in differentiated brown adipocyte HIB-1B cells than in non-differentiated cells. Electrophoretic shift analysis indicated that Sp1and nuclear respiratory factor-2/GA-binding protein (NRF2/GABP) were the main nuclear proteins present in brown adipose tissue that bind this site. Double-point mutant analysis indicated a major role for the NRF2/GABP site in the enhancer capacity of this element in brown fat cells. It is proposed that NRF2/GABP plays a pivotal role in the co-ordinated enhancement of OXPHOS gene expression associated with mitochondrial biogenesis in brown adipocyte differentiation.

scholarly journals Allicin regulates energy homeostasis through brown adipose tissue

2019 ◽  
Author(s):  
Chuanhai Zhang ◽  
Xiaoyun He ◽  
Yao Sheng ◽  
Jia Xu ◽  
Cui Yang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Whole Body ◽  
Brown Adipocyte ◽  
Brown Adipose ◽  
Promising Therapeutic Approach ◽  
Treatment Of Obesity

AbstractBackground/objectives:Disorder of energy homeostasis can lead to a variety of metabolic diseases, especially obesity. Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a main bioactive ingredient in garlic, has multiple biology and pharmacological function. However, the role of Allicin, in the regulation of metabolic organ, especially the role of activation of BAT, has not been well studied. Here, we analyzed the role of Allicin in whole-body metabolism and the activation of BAT.Results:Allicin had a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in diet-introduced obesity (DIO) mice. Then we find that Allicin can strongly activate brown adipose tissue (BAT). The activation of brown adipocyte treated with Allicin was also confirmed in mouse primary brown adipocytes.Conclusion:Allicin can ameliorate obesity through activating brown adipose tissue. Our findings provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.

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

2016 ◽  
Vol 36 (15) ◽  
pp. 2027-2038 ◽  
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.

On the potential role of globins in brown adipose tissue: a novel conceptual model and studies in myoglobin knockout mice

2021 ◽  
Author(s):  
Michael L. Blackburn ◽  
Umesh D Wankhade ◽  
Kikumi D Ono-Moore ◽  
Sree V Chintapalli ◽  
Renee Fox ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Conceptual Model ◽  
Metabolic Regulation ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Sexually Dimorphic ◽  
Brown Adipose ◽  
No Signaling

Myoglobin (Mb) regulates O2 bioavailability in muscle and heart as partial pressure of O2 (pO2) drops with increased tissue workload. Globin proteins also modulate cellular NO pools, "scavenging" NO at higher pO2 and converting NO2- to NO as pO2 falls. Myoglobin binding of fatty acids may also signal a role in fat metabolism. Interestingly, Mb is expressed in brown adipose tissue (BAT), but its function is unknown. Herein, we present a new conceptual model that proposes links between BAT thermogenic activation, concurrently reduced pO2, and NO pools regulated by deoxy/oxy-globin toggling and xanthine oxidoreductase (XOR). We describe the effect of Mb knockout (Mb-/-) on BAT phenotype (lipid droplets, mitochondrial markers uncoupling protein 1 [UCP1] and cytochrome C oxidase 4 [Cox4], transcriptomics) in male and female mice fed a high fat diet (HFD, 45% of energy, ~13 wk), and examine Mb expression during brown adipocyte differentiation. Interscapular BAT weights did not differ by genotype, but there was a higher prevalence of mid-large sized droplets in Mb-/-. COX4 protein expression was significantly reduced in Mb-/- BAT, and a suite of metabolic/NO/stress/hypoxia transcripts were lower. All of these Mb-/--associated differences were most apparent in females. The new conceptual model, and results derived from Mb-/- mice, suggest a role for Mb in BAT metabolic regulation, in part through sexually dimorphic systems and NO signaling. This possibility requires further validation in light of significant mouse-to-mouse variability of BAT Mb mRNA and protein abundances in wildtype mice and lower expression relative to muscle and heart.

scholarly journals Identification of biomarkers of brown adipose tissue aging highlights the role of dysfunctional energy and nucleotide metabolism pathways

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carola Mancini ◽  
Sabrina Gohlke ◽  
Francisco Garcia-Carrizo ◽  
Vyacheslav Zagoriy ◽  
Heike Stephanowitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Nucleotide Metabolism ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Interscapular Brown Adipose Tissue ◽  
Potential Biomarker ◽  
Brown Adipose ◽  
Tissue Aging

AbstractBrown adipose tissue function declines during aging and may contribute to the onset of metabolic disorders such as diabetes and obesity. Only limited understanding of the mechanisms leading to the metabolic impairment of brown adipocytes during aging exists. To this end, interscapular brown adipose tissue samples were collected from young and aged mice for quantification of differential gene expression and metabolite levels. To identify potential processes involved in brown adipocyte dysfunction, metabolite concentrations were correlated to aging and significantly changed candidates were subsequently integrated with a non-targeted proteomic dataset and gene expression analyses. Our results include novel age-dependent correlations of polar intermediates in brown adipose tissue. Identified metabolites clustered around three biochemical processes, specifically energy metabolism, nucleotide metabolism and vitamin metabolism. One mechanism of brown adipose tissue dysfunction may be linked to mast cell activity, and we identify increased histamine levels in aged brown fat as a potential biomarker. In addition, alterations of genes involved in synthesis and degradation of many metabolites were mainly observed in the mature brown adipocyte fraction as opposed to the stromal vascular fraction. These findings may provide novel insights on the molecular mechanisms contributing to the impaired thermogenesis of brown adipocytes during aging.

scholarly journals Senescent T Cell Induces Brown Adipose Tissue “Whitening” Via Secreting IFN-γ

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiao-Xi Pan ◽  
Kang-Li Yao ◽  
Yong-Feng Yang ◽  
Qian Ge ◽  
Run Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Adipose Tissue ◽  
T Cell ◽  
Brown Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Critical Role ◽  
Brown Adipocyte ◽  
Brown Adipose ◽  
Ifn Γ ◽  
Old Mice

Aging-associated chronic inflammation is a key contributing factor to a cluster of chronic metabolic disorders, such as cardiovascular disease, obesity, and type 2 diabetes. Immune cells particularly T cells accumulate in adipose tissue with advancing age, and there exists a cross talk between T cell and preadipocyte, contributing to age-related adipose tissue remodeling. Here, we compared the difference in morphology and function of adipose tissue between young (3-month-old) and old (18-month-old) mice and showed the phenomenon of brown adipose tissue (BAT) “whitening” in old mice. Flow cytometry analysis suggested an increased proportion of T cells in BAT of old mice comparing with the young and exhibited senescent characteristics. We take advantage of coculture system to demonstrate directly that senescent T cells inhibited brown adipocyte differentiation of preadipocytes in adipose tissue. Mechanistically, both in vitro and in vivo studies suggested that senescent T cells produced and released a higher level of IFN-γ, which plays a critical role in inhibition of preadipocyte-to-brown adipocyte differentiation. Taken together, the data indicate that senescent T cell-derived IFN-γ is a key regulator in brown adipocyte differentiation.

scholarly journals New insights into the secretory functions of brown adipose tissue

2019 ◽  
Vol 243 (2) ◽  
pp. R19-R27 ◽  
Author(s):  
Joan Villarroya ◽  
Rubén Cereijo ◽  
Aleix Gavaldà-Navarro ◽  
Marion Peyrou ◽  
Marta Giralt ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Metabolic Diseases ◽  
Brown Adipocyte ◽  
Fibroblast Growth Factor 21 ◽  
Tissue Remodelling ◽  
Brown Adipocytes ◽  
Signalling Molecules ◽  
Brown Adipose

In recent years, an important secretory role of brown adipose tissue (BAT) has emerged, which is consistent, to some extent, with the earlier recognition of the important secretory role of white fat. The so-called brown adipokines or ‘batokines’ may play an autocrine role, which may either be positive or negative, in the thermogenic function of brown adipocytes. Additionally, there is a growing recognition of the signalling molecules released by brown adipocytes that target sympathetic nerve endings (such as neuregulin-4 and S100b protein), vascular cells (e.g., bone morphogenetic protein-8b), and immune cells (e.g., C-X-C motif chemokine ligand-14) to promote the tissue remodelling associated with the adaptive BAT recruitment in response to thermogenic stimuli. Moreover, existing indications of an endocrine role of BAT are being confirmed through the release of brown adipokines acting on other distant tissues and organs; a recent example is the recognition that BAT-secreted fibroblast growth factor-21 and myostatin target the heart and skeletal muscle, respectively. The application of proteomics technologies is aiding the identification of new members of the brown adipocyte secretome, such as the extracellular matrix or complement system components. In summary, BAT can no longer be considered a mere producer of heat in response to environment or dietary challenges; it is also an active secretory tissue releasing brown adipokines with a relevant local and systemic action. The identification of the major brown adipokines and their roles is highly important for the discovery of novel candidates useful in formulating intervention strategies for metabolic diseases.

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