scholarly journals Differential Effects of 17,18-EEQ and 19,20-EDP Combined with Soluble Epoxide Hydrolase Inhibitor t-TUCB on Diet-Induced Obesity in Mice

2021 ◽  
Vol 22 (15) ◽  
pp. 8267
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Haoying Wu ◽  
Jun Yang ◽  
Jiangang Chen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Expression ◽  
Epoxide Hydrolase ◽  
Metabolic Disorders ◽  
Soluble Epoxide Hydrolase ◽  
Acid Oxidation ◽  
Serum Triglycerides ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
Metabolic Protein

17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT.

scholarly journals Differential Effects of Combined Soluble Epoxide Hydrolase Inhibitor t-TUCB and n-3 Epoxides in Diet-Induced Obesity

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1260-1260
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Christophe Morisseau ◽  
Bruce Hammock ◽  
Ahmed Bettaieb ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Protein Expression ◽  
Cold Tolerance ◽  
High Fat Diet ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Brown Adipose

Abstract Objectives Brown adipose tissue (BAT) is a promising target for obesity prevention. N-3 epoxides are fatty acid epoxides produced from n-3 polyunsaturated fatty acids and shown to be beneficial for health. However, these epoxides are unstable and quickly metabolized by the cytosolic soluble epoxide hydrolase (sEH). Here, we investigated the effects of sEH inhibitor (t-TUCB) alone or combined with two different n-3 epoxides on BAT activation in the development of diet-induced obesity and associated metabolic disorders. Methods Male C57BL6/J mice were fed a high-fat diet and received either of the following treatment: the vehicle control, t-TUCB alone (T), or t-TUCB combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) via osmotic minipump delivery near the interscapular BAT for 6 weeks. Mice were examined for changes in body weight, food intake, glucose, insulin, and cold tolerance tests, and indirect calorimetry. Blood and tissue biochemical analyses were also performed to assess changes in metabolic homeostasis. Results Although no differences in food intake were observed, there were small but significant increases in body weight in both T and T + EDP groups. Mice in the T + EDP and T + EEQ groups showed significant decreases in fasting glucose and serum TG levels, higher core body temperature, and better cold tolerance compared to the controls. However, heat production was significantly increased only in the T + EEQ group. Thermogenic UCP1 protein expression showed a moderate, but not significant, increase in the T + EEQ group. On the other hand, PGC1 α protein expression was significantly increased in the T, T + EDP, and T + EEQ groups compared to the controls. Perilipin protein expression and phosphorylation were also significantly increased in the three treated groups. In contrast, protein expression of FABP4 and HSL was only increased in the T and T + EDP groups, and CD36 protein expression was only increased in the T + EEQ group. Conclusions Our results suggest that sEH pharmacological inhibition by t-TUCB combined with n-3 epoxides may prevent high-fat diet-induced glucose and lipid disorders, in part through increased thermogenesis and upregulating of protein expression of thermogenic and lipid metabolic genes. Funding Sources The work was supported by NIH grants to L.Z., A.B., and B.D.H.

scholarly journals Soluble Epoxide Hydrolase Inhibition by t-TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity

2020 ◽  
Vol 21 (19) ◽  
pp. 7039
Author(s):  
Haley Overby ◽  
Yang Yang ◽  
Xinyun Xu ◽  
Katherine Graham ◽  
Kelsey Hildreth ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Protein Expression ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Obese Mice ◽  
Serum Triglycerides ◽  
Treatment And Prevention ◽  
Diet Induced Obesity ◽  
Brown Adipogenesis

Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH and sEHI in brown adipogenesis and BAT activity in treating diet-induced obesity (DIO) have not been reported. sEH expression was studied in in vitro models of brown adipogenesis and the fat tissues of DIO mice. The effects of the sEHI, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy-benzoic acid (t-TUCB), were studied in vitro and in the obese mice via mini osmotic pump delivery. sEH expression was increased in brown adipogenesis and the BAT of the DIO mice. t-TUCB promoted brown adipogenesis in vitro. Although t-TCUB did not change body weight, fat pad weight, or glucose and insulin tolerance in the obese mice, it decreased serum triglycerides and increased protein expression of genes important for lipid metabolism in the BAT. Our results suggest that sEH may play a critical role in brown adipogenesis, and sEHI may be beneficial in improving BAT protein expression involved in lipid metabolism. Further studies using the sEHI combined with EpFA generating diets for obesity treatment and prevention are warranted.

scholarly journals Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice

Diabetologia ◽  
2011 ◽  
Vol 55 (1) ◽  
pp. 183-193 ◽  
Author(s):  
C. Zhang ◽  
C. McFarlane ◽  
S. Lokireddy ◽  
S. Masuda ◽  
X. Ge ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Diet Induced Obesity ◽  
Brown Adipose

scholarly journals A common East Asian-specific ALDH2 mutation causes obesity and insulin resistance: therapeutic effect of reducing toxic aldehydes by ALDH2 activation

2020 ◽  
Author(s):  
Yi-Cheng Chang ◽  
Hsiao-Lin Lee ◽  
Wenjin Yang ◽  
Meng-Lun Hsieh ◽  
Cai-Cin Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Electron Transport ◽  
Energy Expenditure ◽  
Fatty Liver ◽  
Fatty Acid Oxidation ◽  
Water Soluble ◽  
Acid Oxidation ◽  
Diet Induced Obesity ◽  
Brown Adipose

Abstract Obesity and type 2 diabetes have reached pandemic proportion. In particular, the population with diabetes is expected to rise rapidly in East and South Asia. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal (4-HNE). A missense mutation, Glu504Lys of ALDH2 (denoted as the ALDH2*2 allele) is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We found that Aldh2*2/*2 homozygous knock-in (KI) mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver on a high-fat high-sucrose diet compared with controls. The Aldh2 KI mice demonstrated reduced energy expenditure and thermogenesis. Proteomic analyses of the brown adipose tissue (BAT) of the Aldh2 KI mice identified increased 4-HNE-adducted proteins involved in fatty acid oxidation and electron transport chain. Fatty acid oxidation rate and mitochondrial electron transport activity were reduced in the BAT of the Aldh2 KI mice, which explained the decrease in thermogenesis and energy expenditure. AD-9308 is a water-soluble prodrug of a potent and highly selective ALDH2 activator AD-5591. In vitro, AD-5591 enhanced both WT and mutant ALDH2 enzymatic activities. AD-9308 allosterically activates ALDH2 mainly by partially blocking the substrate exit tunnel, thereby accelerating the substrate-enzyme collision. In vivo, AD-9308 treatment reduced serum 4-HNE levels, ameliorated diet-induced obesity and fatty liver, and improved glucose homeostasis in both Aldh2 WT and KI mice dose-dependently. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for treating metabolic diseases.

scholarly journals Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue

iScience ◽  
2021 ◽  
pp. 102434
Author(s):  
Winifred W. Yau ◽  
Kiraely Adam Wong ◽  
Jin Zhou ◽  
Nivetha Kanakaram Thimmukonda ◽  
Yajun Wu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
Fatty Acid Oxidation ◽  
Cold Exposure ◽  
Acid Oxidation ◽  
Brown Adipose ◽  
Mitochondrial Turnover

scholarly journals Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors

ACS Omega ◽  
2018 ◽  
Vol 3 (10) ◽  
pp. 14076-14086 ◽  
Author(s):  
Sean D. Kodani ◽  
Debin Wan ◽  
Karen M. Wagner ◽  
Sung Hee Hwang ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epoxide Hydrolase ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Soluble Epoxide Hydrolase ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

scholarly journals Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity

2015 ◽  
Vol 35 (12) ◽  
pp. 2536-2543 ◽  
Author(s):  
Denuja Karunakaran ◽  
Laura Richards ◽  
Michele Geoffrion ◽  
Danyk Barrette ◽  
Ryan J. Gotfrit ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Metabolic Dysfunction ◽  
Diet Induced Obesity
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