scholarly journals Insulin/IGF-I Regulation of Necdin and Brown Adipocyte Differentiation Via CREB- and FoxO1-Associated Pathways

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3680-3689 ◽  
Author(s):  
Aaron M. Cypess ◽  
Hongbin Zhang ◽  
Tim J. Schulz ◽  
Tian Lian Huang ◽  
Daniel O. Espinoza ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Adipocyte Differentiation ◽  
Active Form ◽  
Proximal Region ◽  
Dominant Negative ◽  
Brown Adipocyte ◽  
Akt Pathway ◽  
Brown Adipose ◽  
Igf I ◽  
Phosphoinositide 3 Kinase

Brown adipose tissue plays an important role in obesity, insulin resistance, and diabetes. We have previously shown that the transition from brown preadipocytes to mature adipocytes is mediated in part by insulin receptor substrate (IRS)-1 and the cell cycle regulator protein necdin. In this study, we used pharmacological inhibitors and adenoviral dominant negative constructs to demonstrate that this transition involves IRS-1 activation of Ras and ERK1/2, resulting in phosphorylation of cAMP response element-binding protein (CREB) and suppression of necdin expression. This signaling did not include an elevation of intracellular calcium. A constitutively active form of CREB expressed in IRS-1 knockout cells decreased necdin promoter activity, necdin mRNA, and necdin protein levels, leading to a partial restoration of differentiation. By contrast, forkhead box protein (Fox)O1, which is regulated by the phosphoinositide 3 kinase-Akt pathway, increased necdin promoter activity. Based on reporter gene assays using truncations of the necdin promoter and chromatin immunoprecipitation studies, we demonstrated that CREB and FoxO1 are recruited to the necdin promoter, likely interacting with specific consensus sequences in the proximal region. Based on these results, we propose that insulin/IGF-I act through IRS-1 phosphorylation to stimulate differentiation of brown preadipocytes via two complementary pathways: 1) the Ras-ERK1/2 pathway to activate CREB and 2) the phosphoinositide 3 kinase-Akt pathway to deactivate FoxO1. These two pathways combine to decrease necdin levels and permit the clonal expansion and coordinated gene expression necessary to complete brown adipocyte differentiation.

scholarly journals Regulation of the RAP1/RAF-1/Extracellularly Regulated Kinase-1/2 Cascade and Prolactin Release by the Phosphoinositide 3-Kinase/AKT Pathway in Pituitary Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 6036-6045 ◽  
Author(s):  
David Romano ◽  
Morgane Pertuit ◽  
Ramahefarizo Rasolonjanahary ◽  
Jean-Vianney Barnier ◽  
Karine Magalon ◽  
...  
Keyword(s):  
Active Form ◽  
Dominant Negative ◽  
Akt Pathway ◽  
Dominant Negative Mutant ◽  
Pituitary Cells ◽  
Negative Effects ◽  
Igf I ◽  
Regulatory Effects ◽  
Phosphoinositide 3 Kinase ◽  
Rap1 Activation

In pituitary cells, prolactin (PRL) synthesis and release are controlled by multiple transduction pathways. In the GH4C1 somatolactotroph cell line, we previously reported that MAPK ERK-1/2 are a point of convergence between the pathways involved in the PRL gene regulation. In the present study, we focused on the involvement of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the MAPK ERK-1/2 regulation and PRL secretion in pituitary cells. Either specific pharmacological PI3K and Akt inhibitors (LY294002, Akt I, and phosphoinositide analog-6) or Akt dominant-negative mutant (K179M) enhanced ERK-1/2 phosphorylation in unstimulated GH4C1 cells. Under the same conditions, PI3K and Akt inhibition also both increased Raf-1 kinase activity and the levels of GTP-bound (active form) monomeric G protein Rap1, which suggests that a down-regulation of the ERK-1/2 cascade is induced by the PI3K/Akt signaling pathway in unstimulated cells. On the contrary, ERK-1/2 phosphorylation, Raf-1 activity, and Rap1 activation were almost completely blocked in IGF-I-stimulated cells previously subjected to PI3K or Akt inhibition. Although the PRL promoter was not affected by either PI3K/Akt inhibition or activation, PRL release increased in response to the pharmacological PI3K/Akt inhibitors in unstimulated GH4C1 and rat pituitary primary cells. The IGF-I-stimulated PRL secretion was diminished, on the contrary, by the pharmacological PI3K/Akt inhibitors. Taken together, these findings indicate that the PI3K/Akt pathway exerts dual regulatory effects on both the Rap1/Raf-1/ERK-1/2 cascade and PRL release in pituitary cells, i.e. negative effects in unstimulated cells and positive ones in IGF-I-stimulated cells.

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

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.

HDL promotes adiponectin gene expression via the CAMKK/CAMKIV pathway

2021 ◽  
Author(s):  
Toshihiro Kobayashi ◽  
Hitomi Imachi ◽  
Kensaku Fukunaga ◽  
Jingya Lyu ◽  
Seisuke Sato ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Promoter Activity ◽  
Active Form ◽  
Specific Inhibitor ◽  
Density Lipoprotein ◽  
Dominant Negative ◽  
Activation Mechanism ◽  
Dominant Negative Mutant ◽  
Type I

Adiponectin (APN) is an adipokine that protects against diabetes and atherosclerosis. High-density lipoprotein (HDL) mediates reverse cholesterol transport, which also protects against atherosclerosis. In this process, the human homolog of the B class type I scavenger receptor (SR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. The level of circulating adiponectin is positively correlated with the serum level of HDL-cholesterol. In this study, we investigated whether HDL stimulates the gene expression of adiponectin through the Ca²+/calmodulin (CaM)-dependent protein kinase IV (CaMKIV) cascade. Adiponectin expression was examined using real-time PCR and western blot analysis in 3T3-L1 cells incubated with HDL. CaMKIV activity was assessed by detection of activation loop phosphorylation (at Thr196 residue), and the effect of the constitutively active form, CaMKIVc, on adiponectin promoter activity was investigated. Our results showed that HDL stimulated APN gene expression via hSR-BI/CLA-1. Furthermore, we explored the signaling pathways by which HDL stimulated APN expression in 3T3-L1 cells. The stimulation of APN gene expression by HDL appears to be mediated by CaMKK, as STO-609, a specific inhibitor of CaMKK2, prevents this effect. We revealed that CaMKIVc increased APN gene transcriptional activity, and the CaMKIV dominant negative mutant blocked the effect of HDL on APN promoter activity. Finally, knockdown of hSR-BI/CLA-1 also cancelled the effect of HDL on APN gene expression. These results suggest that HDL has important role to improve the function of adipocytes by activating hSR-BI/CLA-1 and CaMKK/CaMKIV pathway is conceivable as one of the signaling pathways of this activation mechanism.

scholarly journals SUN-587 IDH1-Dependent Alpha-KG Regulates Brown Fat Differentiation and Function by Modulating Histone Methylation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Won Kon Kim ◽  
Baek-Soo Han
Keyword(s):  
Histone Methylation ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Uncoupling Protein ◽  
Ectopic Expression ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
And Function ◽  
Brown Adipogenesis

Abstract Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. These results suggested that the IDH1–α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.

scholarly journals CD90 Is Dispensable for White and Beige/Brown Adipocyte Differentiation

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.

scholarly journals Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling ofβ-Adrenergic Receptors to Phosphoinositide 3-Kinase

2009 ◽  
Vol 2009 ◽  
pp. 1-8
Author(s):  
Julie Simard ◽  
Matthieu Boucher ◽  
Rachel Massé ◽  
Terence E. Hébert ◽  
Guy Rousseau
Keyword(s):  
Pertussis Toxin ◽  
Transmembrane Domain ◽  
Dominant Negative ◽  
Akt Pathway ◽  
Hek 293 ◽  
Protein Receptor ◽  
293 Cells ◽  
Molecular Determinants ◽  
The Difference ◽  
Phosphoinositide 3 Kinase

An agonist-occupiedβ2-adrenergic receptor (β2-AR) recruits G protein receptor kinase-2 (GRK2) which is recruited to the membrane. Thus, the physical proximity of activatedβ2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that theβ1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the twoβ-AR subtypes. Using transiently transfected HEK 293 cells expressing eitherβ1- orβ2-AR, we also observed that in presence of an agonist,β2-AR, but notβ1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is,β1×β2-AR can activate the PI-3K/Akt pathway whereasβ2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K byβ2- orβ1×β2-AR stimulation. Ligand-mediated internalization of theβ2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further thatβ2-AR activates PI-3K via a pertussis toxin-sensitive mechanism.

scholarly journals Changes in the Balance of Phosphoinositide 3-Kinase/Protein Kinase B (Akt) and the Mitogen-activated Protein Kinases (ERK/p38MAPK) Determine a Phenotype of Visceral and Vascular Smooth Muscle Cells

1999 ◽  
Vol 145 (4) ◽  
pp. 727-740 ◽  
Author(s):  
Ken'ichiro Hayashi ◽  
Masanori Takahashi ◽  
Kazuhiro Kimura ◽  
Wataru Nishida ◽  
Hiroshi Saga ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Signaling Pathways ◽  
Protein Kinase B ◽  
Muscle Cells ◽  
Akt Pathway ◽  
Vascular Smcs ◽  
Igf I ◽  
Phosphoinositide 3 Kinase

The molecular mechanisms behind phenotypic modulation of smooth muscle cells (SMCs) remain unclear. In our recent paper, we reported the establishment of novel culture system of gizzard SMCs (Hayashi, K., H. Saga, Y. Chimori, K. Kimura, Y. Yamanaka, and K. Sobue. 1998. J. Biol. Chem. 273: 28860–28867), in which insulin-like growth factor-I (IGF-I) was the most potent for maintaining the differentiated SMC phenotype, and IGF-I triggered the phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB(Akt)) pathway. Here, we investigated the signaling pathways involved in de-differentiation of gizzard SMCs induced by PDGF-BB, bFGF, and EGF. In contrast to the IGF-I–triggered pathway, PDGF-BB, bFGF, and EGF coordinately activated ERK and p38MAPK pathways. Further, the forced expression of active forms of MEK1 and MKK6, which are the upstream kinases of ERK and p38MAPK, respectively, induced de-differentiation even when SMCs were stimulated with IGF-I. Among three growth factors, PDGF-BB only triggered the PI3-K/PKB(Akt) pathway in addition to the ERK and p38MAPK pathways. When the ERK and p38MAPK pathways were simultaneously blocked by their specific inhibitors or an active form of either PI3-K or PKB(Akt) was transfected, PDGF-BB in turn initiated to maintain the differentiated SMC phenotype. We applied these findings to vascular SMCs, and demonstrated the possibility that the same signaling pathways might be involved in regulating the vascular SMC phenotype. These results suggest that changes in the balance between the PI3-K/PKB(Akt) pathway and the ERK and p38MAPK pathways would determine phenotypes of visceral and vascular SMCs. We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which induced de-differentiation of surrounding normal SMCs.

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 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 Soluble Epoxide Hydrolase Inhibitor t-AUCB Promotes Murine Brown Adipogenesis: Role of PPAR Gamma and PPAR Alpha (P21-069-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Kelsey Hildreth ◽  
Haley Overby ◽  
Sean Kodani ◽  
Christophe Morisseau ◽  
Bruce Hammock ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Adipocyte Differentiation ◽  
Uncoupling Protein ◽  
Soluble Epoxide Hydrolase ◽  
Ppar Gamma ◽  
Brown Adipocyte ◽  
Marker Genes ◽  
Ppar Alpha ◽  
Brown Adipose ◽  
Brown Adipogenesis

Abstract Objectives Brown adipose tissue has recently emerged as a novel target for obesity treatment and prevention. In contrast to the lipid storing function of white adipocytes, brown adipocytes are responsible for dissipating energy as heat, a process involving uncoupling protein 1 (UCP1). Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that converts epoxy fatty acids (EpFAs) into less active diols. By stabilizing endogenous EpFAs, potent small molecule sEH inhibitors have been shown to be beneficial for many chronic diseases. Several recent papers have reported that sEH inhibitors are able to reduce diet-induced obesity, possibly by upregulating UCP1 expression. In the current study, we sought to study the mechanisms by which sEH inhibitor acts on brown preadipocytes. Methods The effects of a potent sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), on murine brown adipocyte differentiation were evaluated by lipid accumulation and expression of brown adipocyte marker genes. PPAR alpha and PPAR gamma activation by t-AUCB was measured by their respective transactivation assays. The roles of PPARs were further studied by pharmacological antagonism and knockdown experiments by small RNA interference. Results We report that sEH expression was increased during murine brown adipocyte differentiation. t-AUCB dose-dependently promoted brown adipocyte differentiation. Moreover, we demonstrate that t-AUCB activated PPAR alpha, but not PPAR gamma. t-AUCB-induced upregulation of thermogenic gene Ucp1 and Pgc1 alpha and the general differentiation marker Fabp4 were significantly attenuated by the antagonist of PPAR alpha, GW6471. In contrast, they were only partially attenuated by the antagonist of PPAR gamma, GW9662, and specific knockdown of PPAR gamma. Conclusions Our findings suggest that sEH may regulate brown adipogenesis and sEH pharmacological inhibition by t-AUCB promotes brown adipogenesis, possibly through activation of PPAR alpha. Funding Sources The work is supported by NIH 1R15DK114790-01A1 (to LZ), R00DK100736 (to AB) and R01ES002710 (to BDH).

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