Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity
Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences. Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences. Obesity is a major public health problem that contributes to the development of type 2 diabetes and cardiovascular disease (1Flegal , K. M. , M. D. Carroll , B. K. Kit , and C. L. Ogden . 2012. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA . 307 : 491–497 .Google Scholar). Excessive lipid accumulation in adipose tissue is a key pathological driver of obesity, and is manifested by an increase in the number (hyperplasia) and size (hypertrophy) of adipocytes. Differentiation of preadipocytes to mature adipocytes (adipogenesis) is an integral mediator of this process, and is under the control of a transcription factor network that regulates lipid biosynthesis and metabolism (2Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Transcriptional regulation of adipogenesis.Genes Dev. 2000; 14: 1293-1307Crossref PubMed Google Scholar). Most notably, PPAR-γ, CCAAT/enhancer-binding protein (C/EBP)α, and sterol regulatory-element-binding protein (SREBP)1c are central mediators of this process through the regulation of LPL, acetyl-CoA carboxylase 1 (ACC1), and FAS expression (2Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Transcriptional regulation of adipogenesis.Genes Dev. 2000; 14: 1293-1307Crossref PubMed Google Scholar, 3MacDougald O.A. Lane M.D. Transcriptional regulation of gene expression during adipocyte differentiation.Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (936) Google Scholar). Sustained activation of this process, however, is a key pathological driver of obesity that results in adipocyte dysfunction, glucose intolerance, and ultimately the development of insulin resistance and type 2 diabetes (4Odegaard J.I. Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis.Science. 2013; 339: 172-177Crossref PubMed Scopus (490) Google Scholar, 5Sun K. Kusminski C.M. Scherer P.E. Adipose tissue remodeling and obesity.J. Clin. Invest. 2011; 121: 2094-2101Crossref PubMed Scopus (1221) Google Scholar). Consequently, an improved understanding of the key pathways that regulate adipogenesis and adipocyte function offers enormous potential to facilitate the development of novel therapeutic strategies that mitigate the development and progression of obesity-associated metabolic diseases. In addition to a well-established role in xenobiotic metabolism, cytochromes P450 (CYPs) metabolize essential fatty acids to bioactive eicosanoids in various cell types. Most notably, arachidonic acid is metabolized by CYP2J and CYP2C epoxygenases to epoxyeicosatrienoic acids (EETs), which are rapidly hydrolyzed by soluble epoxide hydrolase (sEH, Ephx2) (6Zeldin D.C. Epoxygenase pathways of arachidonic acid metabolism.J. Biol. Chem. 2001; 276: 36059-36062Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar). CYP-derived EETs are key regulators of a myriad of biological processes in the cardiovascular system, including vascular tone and inflammation (7Imig J.D. Epoxides and soluble epoxide hydrolase in cardiovascular physiology.Physiol. Rev. 2012; 92: 101-130Crossref PubMed Scopus (267) Google Scholar, 8Deng Y. Theken K.N. Lee C.R. Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation.J. Mol. Cell. Cardiol. 2010; 48: 331-341Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). It also has been reported that EETs elicit protective effects in obesity-associated metabolic disease (9Sodhi K. Puri N. Inoue K. Falck J.R. Schwartzman M.L. Abraham N.G. EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels.Prostaglandins Other Lipid Mediat. 2012; 98: 133-142Crossref PubMed Scopus (52) Google Scholar, 10Bettaieb A. Nagata N. AbouBechara D. Chahed S. Morisseau C. Hammock B.D. Haj F.G. Soluble epoxide hydrolase deficiency or inhibition attenuates diet-induced endoplasmic reticulum stress in liver and adipose tissue.J. Biol. Chem. 2013; 288: 14189-14199Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar, 11Luria A. Bettaieb A. Xi Y. Shieh G.J. Liu H.C. Inoue H. Tsai H.J. Imig J.D. Haj F.G. Hammock B.D. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance.Proc. Natl. Acad. Sci. USA. 2011; 108: 9038-9043Crossref PubMed Scopus (119) Google Scholar, 12Xu X. Zhao C.X. Wang L. Tu L. Fang X. Zheng C. Edin M.L. Zeldin D.C. Wang D.W. Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice.Diabetes. 2010; 59: 997-1005Crossref PubMed Scopus (95) Google Scholar). However, the impact of adipogenesis and obesity on EET biosynthesis in adipose tissue and the functional role of EETs in the regulation of adipogenesis and the pathogenesis of obesity remains poorly understood. Consequently, using established in vitro (differentiated 3T3-L1 cells) and in vivo [high-fat diet (HFD)-fed mice] models, we investigated: a) the impact of adipogenesis and obesity on the bioavailability of adipose-derived EETs; and b) the functional effects of EETs on adipogenesis and obesity, and their downstream pathological consequences. Reagents were obtained from Sigma-Aldrich (St. Louis, MO) unless otherwise indicated. The stable EET analog 14,15-epoxyeicosa-8(Z)-enoic acid (14,15-EE-8(Z)-E) and CYP epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) were purchased from Cayman Chemical (Ann Arbor, MI). The stable EET analogs (S)-2-(11-(nonyloxy) undec-8(Z)-enamido)succinic acid (NUDSA) and (S)-2-(13-(3-butylureido) tridec-8(Z)-enamido)succinic acid (EET-A, sodium salt) were synthesized by Dr. John Falck (University of Texas Southwestern, TX) (13Imig J.D. Elmarakby A. Nithipatikom K. Wei S. Capdevila J.H. Tuniki V.R. Sangras B. Anjaiah S. Manthati V.L. Sudarshan Reddy D. et al.Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions.Front. 2010; PubMed Scopus Google Scholar, Liu Falck J.R. Imig J.D. epoxyeicosatrienoic acid analogs 2013; PubMed Scopus Google Scholar). that with and and and were by Dr. Zeldin of H. Zhao Y. Zeldin D.C. expression, and of cytochrome and of their fatty acid PubMed Scopus Google Scholar, G.J. M.D. Falck J.R. et P450 a arachidonic acid in Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). and were purchased from and 3T3-L1 preadipocytes were obtained from were to in with and with and differentiated mature adipocytes with and 1 with as X. X. M. Wang H. lipid metabolism by endoplasmic reticulum stress and in 2013; PubMed Scopus Google Scholar). In the were 2 and cells were on and In the cells were differentiated for and with and and and or and were and for and 3T3-L1 cells were in in for and in The cells were with in for and with as X. X. M. Wang H. lipid metabolism by endoplasmic reticulum stress and in 2013; PubMed Scopus Google Scholar). were obtained with a with an under a In to lipid the with for and by an of experiments were in mice on a mice were purchased from of mice with of and a for and by as C.J. M. M. Nagata K. J.R. of soluble epoxide hydrolase a role in Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Edin M.L. Theken K.N. et CYP epoxygenase and soluble epoxide hydrolase vascular in 2011; PubMed Scopus Google Scholar). mice to and and were in for and using a experiments were in with the US of for the and of and were by the and In mice a control diet a high-fat diet or a for diet is and is with arachidonic acid in In mice were fed the for and in the or control the of the In mice were fed the for 2 and or via the of the In and control mice were fed the diet for or In body weight and were were by and adipose tissue and of the tissue in and the in and in for were from 3T3-L1 and mice by and by as M.L. Wang et expression of cytochrome P450 epoxygenase to in 2011; PubMed Scopus Google Scholar). with and and with of acid in in with acid and for for and the were with of with of The were with 2 of and through the were and with of and 1 of with of in The were under and in of of with an were using a which and a of phase acid in phase acid in and the phase as from to to from to to from to to B. to the with a of to and for were in of and in for were on an with a to a of were in a as and The of were to for via to were to cell Adipose tissue were to tissue The of EETs and acids and and were as CYP epoxygenase metabolic function Y. Edin M.L. Theken K.N. et CYP epoxygenase and soluble epoxide hydrolase vascular in 2011; PubMed Scopus Google Scholar, K.N. Y. A. Lee C.R. high-fat diet-induced in cytochrome 2012; PubMed Scopus Google Scholar). 3T3-L1 and adipose tissue were using the to as Y. Edin M.L. Theken K.N. et CYP epoxygenase and soluble epoxide hydrolase vascular in 2011; PubMed Scopus Google Scholar). of fatty acid protein FAS protein 1 and were using on The of for the metabolism a of and for K.N. Y. Lee C.R. of the alters cytochrome expression and 2011; PubMed Scopus Google Scholar). expression to or and to control using the of gene expression using and the 2001; PubMed Scopus Google Scholar). 3T3-L1 cell were and the protein as Wang X. H. by stress pathways in 2010; PubMed Scopus Google Scholar). protein and by and to were in in for 2 with or and with the were by using the The of the using In to CYP epoxygenase metabolic 3T3-L1 preadipocytes and mature adipocytes were in with 1 of arachidonic acid for and EET and in the were by and EET were and to cell In to metabolic with 1 cell from 3T3-L1 preadipocytes or mature adipocytes in a of for as of soluble epoxide hydrolase Scholar). The were with 1 of with and to under The in and EET and were by The as a of metabolic K.N. Edin M.L. B. K. A. et of cytochrome eicosanoids in with stable cardiovascular 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). tissue and were with and and The adipocyte size using and the adipocyte as C.J. J.R. S. K. novel for adipocyte 2013; PubMed Google Scholar). for in mice by using an body as D.W. D. of in of the 2011; PubMed Scopus Google Scholar). and mass were 2 and and as a of body and were by in mice using a which also and D.W. D. of in of the 2011; PubMed Scopus Google Scholar). were obtained in to body and The and metabolic were were and with by 2 body 1 body glucose were and and using the as G.J. S. C.M. for and metabolic of glucose homeostasis in 2010; PubMed Scopus Google Scholar). to glucose and the of of the a glucose The under the glucose using the of were by in the 3T3-L1 cell in the D. for 2012; PubMed Scopus Google to in the during adipocyte The results were as to and to the The impact of adipocyte on metabolic pathways by which is on the and a model to a for were significantly and the in 3T3-L1 preadipocytes and differentiated pathways were significantly the and pathways were significantly the and arachidonic acid acid arachidonic acid acid arachidonic acid arachidonic acid acid acid The pathways were significantly the and in a were as to the by a to to the control for that were in the glucose were using model and a were using the indicated. using or and the of adipocyte on the in 3T3-L1 adipocytes. and the of preadipocytes mature adipocytes. The demonstrated a of the preadipocytes and differentiated adipocytes the CYP arachidonic acid pathway the significantly during adipocyte The and were significantly in 3T3-L1 mature adipocytes with preadipocytes 2 and the expression of key CYP epoxygenases and and epoxide and and protein were and protein in mature adipocytes with preadipocytes with the expression the to EETs and epoxygenase metabolic significantly and the to to metabolic significantly in mature adipocytes. findings that induction of adipogenesis the CYP epoxygenase pathway and the bioavailability of EETs in adipocytes. fed a increase in body weight and weight significantly EET and in in models, with Furthermore, EET with body weight adipose tissue weight key of adipogenesis and in and activation of the in these results are with in vitro experiments and that induction of adipose tissue expansion EET in In to the functional role of the CYP epoxygenase pathway in the regulation of we differentiated 3T3-L1 preadipocytes to mature adipocytes in the of the CYP epoxygenase of lipid accumulation in mature to the of experiments were using the stable EET and of and the of 3T3-L1 preadipocytes mature adipocytes. Furthermore, the induction of the adipocyte transcription and and the adipocyte LPL, and these findings the CYP epoxygenase pathway as a key functional of of the EET analog reduces gene expression in 3T3-L1 3T3-L1 cells were to with and or for FAS and were by and to results were the were to are to the control to the marked of EET during the early of adipocyte we to the early phase adipocyte to the anti-adipogenic effects of EET analog with during the 2 or adipocyte to a as the However, initiation of of on or to on adipocyte Furthermore, with during and the induction of and 2 early and with cells with the lipid accumulation however, initiation of with the early phase or to findings that EET analogs significantly adipocyte via inhibition of the early phase of adipogenesis. of an EET analog to administration in the Liu Falck J.R. Imig J.D. epoxyeicosatrienoic acid analogs 2013; PubMed Scopus Google significantly body weight and adipose tissue expansion with effects were with a in of metabolic that administration the suppression of with the increase in and metabolic also significantly expression of in Furthermore, significantly the induction of glucose Although significantly or fed glucose high-fat significantly increase or fed glucose with the control the obesity and glucose of an EET analog to in vivo (13Imig J.D. Elmarakby A. Nithipatikom K. Wei S. Capdevila J.H. Tuniki V.R. Sangras B. Anjaiah S. Manthati V.L. Sudarshan Reddy D. et al.Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions.Front. 2010; PubMed Scopus Google also significantly weight with Furthermore, and with the effects by the induction of mass adipocyte and expression of the and in were significantly and expression of in significantly by In a of mice with of and significantly EETs in for Although a decrease in body weight mice a significantly induction of and in and glucose with and these results that therapeutic of EETs elicits metabolic protective effects in diet-induced obesity in mice activation and glucose and mice were fed a or control diet for or body weight from and and in and were by to and to the control diet glucose were and an glucose and The is The and in or fed glucose and mice were Adipogenesis plays a key role in the initiation and progression of obesity and obesity-associated metabolic diseases. Although CYP EETs potent protective effects in the cardiovascular (7Imig J.D. Epoxides and soluble epoxide hydrolase in cardiovascular physiology.Physiol. Rev. 2012; 92: 101-130Crossref PubMed Scopus (267) Google Scholar, 8Deng Y. Theken K.N. Lee C.R. Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation.J. Mol. Cell. Cardiol. 2010; 48: 331-341Abstract Full Text Full Text PDF PubMed Scopus (131) Google the functional role of EETs in the regulation of adipogenesis and the pathogenesis of obesity remains poorly understood. In the we demonstrated a) adipogenesis and obesity-associated adipose expansion significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of EET in adipose and b) the effects of EETs elicits potent anti-adipogenic and effects in vitro and in Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence in the early of obesity, and strategies that promote the protective effects of EETs in adipose tissue offers enormous therapeutic potential for obesity-associated metabolic diseases. reported that obesity with significantly EET in with established cardiovascular disease K.N. Edin M.L. B. K. A. et of cytochrome eicosanoids in with stable cardiovascular 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). Although studies have demonstrated that induction of obesity reduces EETs in and K.N. Y. A. Lee C.R. high-fat diet-induced in cytochrome 2012; PubMed Scopus Google Scholar, X. A. D.W. Wang Y. L. Imig J.D. epoxygenase and epoxide hydrolase expression in the of 288: PubMed Scopus Google as as alters biosynthesis and biosynthesis in adipose tissue C. H. C. A. et contribution to obesity-associated inflammation and insulin resistance in mice.Diabetes. 2012; PubMed Scopus Google Scholar, S. deficiency attenuates adipose tissue and inflammation in Biol. Chem. 2011; Full Text Full Text PDF PubMed Scopus Google the impact of obesity on EET bioavailability in adipose tissue has been Consequently, we a to the during adipocyte in 3T3-L1 significantly the however, the CYP EETs and were and the significantly with and expression were and expression in mature with in cells and adipocytes L. K. Falck J.R. Schwartzman M.L. Abraham N.G. EET and HO-1 and expression in cell Other Lipid Mediat. 2011; PubMed Scopus Google Scholar, B.M. Morisseau C. A. Hammock and regulation of soluble epoxide hydrolase in adipose 2010; PubMed Scopus Google Scholar). Our studies also a functional suppression of CYP epoxygenase and induction of epoxide hydrolase metabolic in mature that the suppression of EET is to biosynthesis and with experiments in 3T3-L1 adipocytes and a in rats (9Sodhi K. Puri N. Inoue K. Falck J.R. Schwartzman M.L. Abraham N.G. EET agonist prevents adiposity and vascular dysfunction in rats fed a high fat diet via a decrease in Bach 1 and an increase in HO-1 levels.Prostaglandins Other Lipid Mediat. 2012; 98: 133-142Crossref PubMed Scopus (52) Google induction of obesity and adipose tissue expansion in mice with high fat significantly EET in we a marked suppression of EET and in which were with body weight gain, and transcription factor also a expression and EET in Our studies have demonstrated that activation of the EET biosynthesis K.N. Y. Lee C.R. of the alters cytochrome expression and 2011; PubMed Scopus Google Scholar). the integral contribution of inflammation in adipose tissue to the pathogenesis of obesity (4Odegaard J.I. Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis.Science. 2013; 339: 172-177Crossref PubMed Scopus (490) Google activation of obesity-associated also the suppression of EET bioavailability in adipose However, studies are to these effects and the It is to that we EET in adipose tissue which is a of the impact of obesity on EET adipose tissue as as remains an for this of In addition to the suppression of EET bioavailability during adipocyte inhibition of EET biosynthesis via administration of a CYP epoxygenase inhibitor significantly adipogenesis. Collectively, these suggest that CYP-derived EETs an integral functional role in the regulation of adipogenesis. Furthermore, EET analogs and lipid accumulation and adipocyte gene expression, that of EETs elicits potent anti-adipogenic Other EET analogs have been reported to adipogenesis in adipocytes L. K. Falck J.R. Schwartzman M.L. Abraham N.G. EET and HO-1 and expression in cell Other Lipid Mediat. 2011; PubMed Scopus Google Scholar, L. Inoue K. A. K. Manthati V.L. Zeldin D.C. Falck J.R. Schwartzman M.L. et acid agonist regulates adipocytes through activation of and a decrease in Dev. 2010; PubMed Scopus Google Scholar, L. L. K. Falck J.R. Abraham N.G. Schwartzman M.L. A. of adipocyte dysfunction in mice via of epoxyeicosatrienoic acids (EETs) and Biochem. 2012; PubMed Scopus Google Scholar). these studies and experiments the potent anti-adipogenic effects of EET analogs in cell Furthermore, experiments for the that EET analog elicits its anti-adipogenic effects through the and in the early phase of which are for adipocyte L. C. P. L. P. et of preadipocytes is on during the of the PubMed Scopus Google Scholar). by the marked and early suppression of and that were the initiation of EET analog during the phase of to the induction of transcription factor expression or lipid It is well-established that activation of and are central mediators of adipogenesis through their regulation of lipid biosynthesis and metabolism (2Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Transcriptional regulation of adipogenesis.Genes Dev. 2000; 14: 1293-1307Crossref PubMed Google Scholar, 3MacDougald O.A. Lane M.D. Transcriptional regulation of gene expression during adipocyte differentiation.Annu. Rev. Biochem. 1995; 64: 345-373Crossref PubMed Scopus (936) Google are to regulate this factor the early of inhibition of and activation of the protein and pathways and activation and adipocyte M. Wang K. X. factor adipogenesis via inhibition of the pathway in PubMed Scopus Google Scholar, Wang D. Y. B. Y. H. the of PubMed Scopus Google Scholar, Y. Y. activation regulates and by in PubMed Scopus Google Scholar). studies have demonstrated that the effects of EETs attenuates in in and the pathway in the vascular X. Zhao C.X. Wang L. Tu L. Fang X. Zheng C. Edin M.L. Zeldin D.C. Wang D.W. Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice.Diabetes. 2010; 59: 997-1005Crossref PubMed Scopus (95) Google Scholar, S. L. Lee C.R. Wang Y. Wang H. et epoxygenases cells from by via and PubMed Scopus Google Scholar, Falck J.R. of is by EETs that the PubMed Scopus Google that a CYP-derived EETs and pathways also in the early phase of adipogenesis. studies are to the key pathways that the effects of EETs on adipocyte the effects of EETs also potent metabolic protective effects in Most notably, EET analog administration significantly mitigated HFD-induced weight gain, adipose tissue expansion, and adipocyte gene Although the of weight by EET analog by a in in of in to the weight this is a However, EET analog administration the suppression of and expression of the protein which is in and in the in the of via fatty acid is a critical of in adipose tissue and of this process is a key driver of the pathogenesis of obesity B. adipose function and Rev. PubMed Scopus Google Scholar, B.M. of for metabolic 2013; PubMed Scopus (119) Google Scholar). these suggest that the effects of EETs attenuates adipose expansion and weight by metabolic in adipose The effects in mice and the anti-adipogenic effects in differentiated 3T3-L1 cells are to adipocyte and has been as the driver of adipose tissue expansion in obesity K. Kusminski C.M. Scherer P.E. Adipose tissue remodeling and obesity.J. Clin. Invest. 2011; 121: 2094-2101Crossref PubMed Scopus (1221) Google Scholar). It is to however, studies have demonstrated that adipogenesis also is an to HFD-induced obesity C. Scherer P.E. adipogenesis during adipose tissue expansion and 2013; PubMed Scopus Google the contribution of adipogenesis to obesity. Consequently, studies are to the contribution of adipocyte and and the to the effects of EET analogs in The development of glucose is a critical pathological consequence of obesity, which the development of type 2 diabetes (4Odegaard J.I. Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis.Science. 2013; 339: 172-177Crossref PubMed Scopus (490) Google Scholar). of the EET significantly the induction of glucose in mice with of and EET an induction of glucose and of high-fat In to EET analog weight in are with a improved glucose in mice in weight gain, with of A. Bettaieb A. Xi Y. Shieh G.J. Liu H.C. Inoue H. Tsai H.J. Imig J.D. Haj F.G. Hammock B.D. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance.Proc. Natl. Acad. Sci. USA. 2011; 108: 9038-9043Crossref PubMed Scopus (119) Google Scholar). The these including the potential for to gene remain and of adipocyte transcription factor and gene expression high fat however, significantly in studies have demonstrated that inhibition of factor activation HFD-induced glucose H. K. K. K. H. N. Y. A. et of and diet-induced obesity and type 2 Clin. Invest. 2001; 108: PubMed Scopus Google Scholar, L. P. B. with and PubMed Scopus Google Scholar). glucose during high-fat is by lipid P. M. J.I. M. S. A. et is for high-fat diet-induced insulin 2011; PubMed Scopus Google as to including pancreatic dysfunction, and insulin that are in the of obesity. experiments suggest that the effects of EETs in adipose tissue to improved glucose during the early of obesity, in through the activation of pro-adipogenic gene however, studies remain to these effects and the and to the metabolic protective effects of EET analog during the of obesity. In studies that CYP EETs an integral functional role in the regulation of adipogenesis and the pathogenesis of obesity, and suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity. strategies that promote the protective effects of EETs in adipose tissue offer enormous potential to mitigate obesity-associated metabolic disease and its downstream pathological consequences. The the of and for their to this acetyl-CoA carboxylase 1 protein under the adipose tissue CCAAT/enhancer-binding protein cytochrome P450 acid epoxyeicosatrienoic acid (S)-2-(13-(3-butylureido) tridec-8(Z)-enamido)succinic acid adipose tissue fatty acid protein and high-fat diet of (S)-2-(11-(nonyloxy) undec-8(Z)-enamido)succinic acid sterol regulatory-element-binding protein soluble epoxide hydrolase protein 1 high-fat diet