Abstract 425: Brown Fat Activation Enhances the Lipid-lowering and Anti-atherogenic Effect of Statin Treatment

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Geerte Hoeke ◽  
Andrea D van Dam ◽  
Mariëtte R Boon ◽  
Jimmy F Berbée ◽  
Patrick C Rensen
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Plasma Cholesterol ◽  
Ldl Receptor ◽  
Hepatic Clearance ◽  
Cholesteryl Oleate ◽  
Statin Treatment ◽  
Hepatic Uptake ◽  
Lipid Lowering ◽  
Brown Adipose

Introduction: Brown adipose tissue (BAT) produces heat by burning triglyceride (TG)-derived fatty acids. As a result, BAT accelerates the formation and hepatic clearance of cholesterol-enriched lipoprotein remnants via the apoE-LDL receptor (LDLR) pathway, thereby alleviating hypercholesterolemia. Since statins upregulate hepatic LDLR expression, the aim of this study was to investigate whether BAT activation and statin treatment cooperate in lowering hyperlipidemia and atherosclerosis. Methods and Results: APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the selective β3-AR agonist CL316243 that activates BAT (CL, 20 μg/day; s.c.), atorvastatin (statin, 0.0036% w/w, in diet) or both. BAT activation alone and combined with statin treatment increased energy expenditure (+15%) as a result of increased fat oxidation (+50%). Furthermore, BAT activation decreased the lipid droplet content within BAT (-50%) and induced browning of subcutaneous white adipose tissue. BAT activation alone and combined with statin treatment also lowered plasma TG levels (-60%). In addition, plasma cholesterol was lowered by both BAT activation (-29%) and statin (-31%), but even further by the combination (-44%). The uptake of TG-derived fatty acids from glycerol tri[3H]oleate and [14C]cholesteryl oleate-labeled VLDL-mimicking particles into BAT was enhanced by BAT activation (+234%) and on top of statin (+220%), but not by statin alone. The hepatic uptake of the cholesterol-enriched remnants tended to be increased by BAT activation (+18%) or statin (+22%), and was markedly increased by the combination of BAT activation and statin treatment (+70%). Hepatic cholesterol levels were reduced by statin alone and the combination (-41%). Importantly, atherosclerosis development was decreased by BAT activation (-42%) and statin (-50%) alone and further decreased by the combination (-70%). Conclusions: BAT activation enhances the lipid-lowering and anti-atherogenic effect of statin treatment. We postulate that combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular diseases.

scholarly journals Lowering apolipoprotein CIII protects against high-fat diet–induced metabolic derangements

2021 ◽  
Vol 7 (11) ◽  
pp. eabc2931
Author(s):  
Ismael Valladolid-Acebes ◽  
Karin Åvall ◽  
Patricia Recio-López ◽  
Noah Moruzzi ◽  
Galyna Bryzgalova ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Hepatic Uptake ◽  
Metabolic Phenotype ◽  
High Fat ◽  
Apolipoprotein Ciii ◽  
Brown Adipose ◽  
Metabolically Healthy ◽  
And Function

Increased levels of apolipoprotein CIII (apoCIII), a key regulator of lipid metabolism, result in obesity-related metabolic derangements. We investigated mechanistically whether lowering or preventing high-fat diet (HFD)–induced increase in apoCIII protects against the detrimental metabolic consequences. Mice, first fed HFD for 10 weeks and thereafter also given an antisense (ASO) to lower apoCIII, already showed reduced levels of apoCIII and metabolic improvements after 4 weeks, despite maintained obesity. Prolonged ASO treatment reversed the metabolic phenotype due to increased lipase activity and receptor-mediated hepatic uptake of lipids. Fatty acids were transferred to the ketogenic pathway, and ketones were used in brown adipose tissue (BAT). This resulted in no fat accumulation and preserved morphology and function of liver and BAT. If ASO treatment started simultaneously with the HFD, mice remained lean and metabolically healthy. Thus, lowering apoCIII protects against and reverses the HFD-induced metabolic phenotype by promoting physiological insulin sensitivity.

Effect of sucrose-induced overfeeding on brown adipose tissue—With special reference to in vitro thermogenesis and fatty acids compositions

1995 ◽  
Vol 20 (6) ◽  
pp. 477-484 ◽  
Author(s):  
Akihiro Kuroshima ◽  
Tomie Ohno ◽  
Mitsuru Moriya ◽  
Hiroshi Ohinata ◽  
Takehiro Yahata ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Special Reference ◽  
Brown Adipose

Relationship between Fatty Acids of Adipose Tissue and Plasma Cholesterol

1975 ◽  
Vol 17 (4) ◽  
pp. 204-209
Author(s):  
A. Bucalossi ◽  
F. Bellini
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Plasma Cholesterol

Plasma Lipid-lowering and Lipogenesis-stimulating Actions of Ginseng Saponins in Tumor-bearing Rats

1983 ◽  
Vol 11 (01n04) ◽  
pp. 88-95 ◽  
Author(s):  
Masahiro Yamamoto ◽  
Akira Kumagai ◽  
Yuichi Yamamura
Keyword(s):  
Adipose Tissue ◽  
Oral Administration ◽  
Plasma Cholesterol ◽  
Lipid Fraction ◽  
Plasma Lipid ◽  
Male Rats ◽  
Lipid Lowering ◽  
Tumor Bearing ◽  
Saponin Content

Ascited hepatoma (AH41C or AH130) was transplanted to male rats Donryu, strain. Plasma cholesterol, triglyceride (TG) and non-esterified fatty acid levels were reduced with oral administration of ginseng principle fraction 3 (saponin content, ca. 1/5). Incorporation of 1-[14C]-acetate into total lipids and fatty acids in adipose tissue was increased by fraction 3 administration in both normal and tumor-bearing rats. The incorporation increased in earlier stage of tumor growth and decreased in the later one. Incorporation of 1-[14C]-acetate into total lipid, free and esterified cholesterol, TG and phospholipid in the liver was also enhanced by fraction 3 administration in both normal and tumor-bearing animals. In vitro addition of ginseng principle fraction 4 (saponin content, ca. 1/2) increased incorporation of 1-[14C]-acetate into lipid fraction is adipose tissue and liver. Incorporation of 1-[14C]-acetate into lipid fractions in ascites hepatoma cells remained unchanged with both oral administration of fraction 3 and in vitro addition of fraction 4. DNA and protein synthesis in the tumor cells was not changed with in vitro addition of fraction 4.

scholarly journals Lack of activation of UCP1 in isolated brown adipose tissue mitochondria by glucose-O-ω-modified saturated fatty acids of various chain lengths

2013 ◽  
Vol 6 (3) ◽  
pp. 121-133 ◽  
Author(s):  
Eamon P. Breen ◽  
Wayne Pilgrim ◽  
Kieran J. Clarke ◽  
Cristy Yssel ◽  
Mark Farrell ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Saturated Fatty Acids ◽  
Brown Adipose ◽  
Chain Lengths

scholarly journals Pharmacological Inhibition of Soluble Epoxide Hydrolase by t-TUCB Improves Brown Adipose Tissue Activities in Diet-Induced Obesity

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1703-1703
Author(s):  
Yang Yang ◽  
Xinyun Xu ◽  
Katie Graham ◽  
Ahmed Bettaieb ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Food Intake ◽  
Brown Adipose Tissue ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Obese Mice ◽  
Treatment And Prevention ◽  
Insulin Tolerance ◽  
Brown Adipose

Abstract Objectives Brown adipose tissue (BAT), responsible for energy expenditure through nonshivering thermogenesis, has emerged as a novel target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH), encoded by Ephx2 gene, is a cytosolic enzyme that converts epoxy fatty acids (EpFAs) that are produced by cytochrome P-450 enzymes from polyunsaturated fatty acids into less active diols. Pharmacological inhibitors of sEH, such as trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido] cyclohexyloxy} benzoic acid (t-TUCB), have been shown to be beneficial for chronic diseases by inhibiting the degradation of EpFAs. We have previously shown that t-TUCB dose-dependently promotes brown adipogenesis in vitro. This study investigated the therapeutic effects of t-TUCB on BAT activation in diet-induced obese mice. Methods Male C57BL6/J mice were fed a high-fat diet (60% kcal from fat) for 8 weeks followed by random assignment into either the control or t-TUCB group (n = 10 per group) to receive either the vehicle control or t-TUCB (3 mg/kg/day) via osmotic minipump delivery at the subcutaneous area near the interscapular BAT for 6 weeks. Bodyweight and food intake, glucose and insulin tolerance tests, cold tolerance tests, and indirect calorimetry were measured before the mice were euthanized for further biochemical analysis. Results sEH inhibition by t-TUCB in the obese mice did not change body weight, fat pad weight, food intake, fasting blood glucose, glucose and insulin tolerance, or cold tolerance, but significantly decreased blood triglyceride levels and increased heat production during both day and night. Moreover, t-TUCB significantly increased protein expression of brown marker gene PGC-1alpha and lipid droplet-associated protein perilipin (PLIN), but not uncoupling protein 1 (UCP1), in the interscapular BAT of diet-induced obese mice. Conclusions Our results suggest that sEH pharmacological inhibition may be beneficial for BAT activation by increasing mitochondrial biogenesis and lipolysis in the BAT. Further studies using the sEH inhibitors and/or EpFA generating diets for obesity treatment and prevention are warranted. Funding Sources The work was supported by NIH 1R15DK114790–01A1 (to L.Z.), K99DK100736 and R00DK100736 (to A.B.), R15AT008733 (to S.W.), R35 ES030443 and P42ES004699 (to B.D.H).

Reduction of Insulin Signaling Upregulates Angiopoietin-like Protein 4 Through Elevated Free Fatty Acids in Diabetic Mice

2011 ◽  
Vol 120 (03) ◽  
pp. 139-144 ◽  
Author(s):  
N. Mizutani ◽  
N. Ozaki ◽  
Y. Seino ◽  
A. Fukami ◽  
E. Sakamoto ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
High Fat Diet ◽  
Serum Triglyceride ◽  
Diabetic Mice ◽  
Brown Adipose

AbstractAngiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved.Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks.The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells.These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.

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