scholarly journals Induction of UCP1 and thermogenesis by a small molecule via AKAP1/PKA modulation

2020 ◽  
Vol 295 (44) ◽  
pp. 15054-15069
Author(s):  
Laurent Vergnes ◽  
Jason Y. Lin ◽  
Graeme R. Davies ◽  
Christopher D. Church ◽  
Karen Reue
Keyword(s):  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Mitochondrial Activity ◽  
Energy Regulation ◽  
Brown Adipocytes ◽  
Protein Levels ◽  
White Adipocytes ◽  
Increase Energy Expenditure ◽  
Beige Adipocytes ◽  
Anchoring Protein

Strategies to increase energy expenditure are an attractive approach to reduce excess fat storage and body weight to improve metabolic health. In mammals, uncoupling protein-1 (UCP1) in brown and beige adipocytes uncouples fatty acid oxidation from ATP generation in mitochondria and promotes energy dissipation as heat. We set out to identify small molecules that enhance UCP1 levels and activity using a high-throughput screen of nearly 12,000 compounds in mouse brown adipocytes. We identified a family of compounds that increase Ucp1 expression and mitochondrial activity (including un-coupled respiration) in mouse brown adipocytes and human brown and white adipocytes. The mechanism of action may be through compound binding to A kinase anchoring protein (AKAP) 1, modulating its localization to mitochondria and its interaction with protein kinase A (PKA), a known node in the β-adrenergic signaling pathway. In mice, the hit compound increased body temperature, UCP1 protein levels, and thermogenic gene expression. Some of the compound effects on mitochondrial function were UCP1- or AKAP1-independent, suggesting compound effects on multiple nodes of energy regulation. Overall, our results highlight a role for AKAP1 in thermogenesis, uncoupled respiration, and regulation energy balance.

scholarly journals Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels

2008 ◽  
Vol 199 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Andrea Anedda ◽  
Eduardo Rial ◽  
M Mar González-Barroso
Keyword(s):  
Oxidative Stress ◽  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
Protein Levels ◽  
White Adipocytes ◽  
Epididymal White Adipose Tissue ◽  
Amp Activated Protein Kinase

Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMP-activated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and β-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.

scholarly journals Regulation of human subcutaneous adipocyte differentiation by EID1

2015 ◽  
Vol 56 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Diana Vargas ◽  
Noriaki Shimokawa ◽  
Ryosuke Kaneko ◽  
Wendy Rosales ◽  
Adriana Parra ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Uncoupling Protein ◽  
Human Adipose Tissue ◽  
Mitochondrial Activity ◽  
Mitochondrial Uncoupling ◽  
Mitochondrial Uncoupling Protein ◽  
Triglyceride Accumulation ◽  
White Adipocytes ◽  
Beige Adipocytes

Increasing thermogenesis in white adipose tissues can be used to treat individuals at high risk for obesity and cardiovascular disease. The objective of this study was to determine the function of EP300-interacting inhibitor of differentiation (EID1), an inhibitor of muscle differentiation, in the induction of beige adipocytes from adipose mesenchymal stem cells (ADMSCs). Subcutaneous adipose tissue was obtained from healthy women undergoing abdominoplasty. ADMSCs were isolated in vitro, grown, and transfected with EID1 or EID1 siRNA, and differentiation was induced after 48 h by administering rosiglitazone. The effects of EID1 expression under the control of the aP2 promoter (aP2-EID1) were also evaluated in mature adipocytes that were differentiated from ADMSCs. Transfection of EID1 into ADMSCs reduced triglyceride accumulation while increasing levels of thermogenic proteins, such as PGC1α, TFAM, and mitochondrial uncoupling protein 1 (UCP1), all of which are markers of energy expenditure and mitochondrial activity. Furthermore, increased expression of the beige phenotype markers CITED1 and CD137 was observed. Transfection of aP2-EID1 transfection induced the conversion of mature white adipocytes to beige adipocytes, as evidenced by increased expression of PGC1α, UCP1, TFAM, and CITED1. These results indicate that EID1 can modulate ADMSCs, inducing a brown/beige lineage. EID1 may also activate beiging in white adipocytes obtained from subcutaneous human adipose tissue.

scholarly journals Liraglutide suppresses obesity and promotes browning of white fat via miR-27b in vivo and in vitro

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110550
Author(s):  
Xing Wang ◽  
Shuchun Chen ◽  
Dan Lv ◽  
Zelin Li ◽  
Luping Ren ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
White Adipocytes ◽  
White Fat

Objective To investigate the effect of liraglutide on the browning of white fat and the suppression of obesity via regulating microRNA (miR)-27b in vivo and in vitro. Methods Sprague-Dawley rats were fed a high-fat (HF) diet and 3T3-L1 pre-adipocytes were differentiated into mature white adipocytes. Rats and mature adipocytes were then treated with different doses of liraglutide. The mRNA and protein levels of browning-associated proteins, including uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), CCAAT enhancer binding protein β (CEBPβ), cell death-inducing DFFA-like effector A (CIDEA) and peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α), were detected using quantitative real-time polymerase chain reaction and Western blotting. Results Liraglutide decreased body weight and reduced the levels of blood glucose, triglyceride and low-density lipoprotein cholesterol in HF diet-fed rats. Liraglutide increased the levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α in vivo and vitro. The levels of miR-27b were upregulated in HF diet-fed rats, whereas liraglutide reduced the levels of miR-27b. In vitro, overexpression of miR-27b decreased the mRNA and protein levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α. Transfection with the miR-27b mimics attenuated the effect of liraglutide on the browning of white adipocytes. Conclusion Liraglutide induced browning of white adipose through regulation of miR-27b.

scholarly journals Comparison of triacylglycerol synthesis in rat brown and white adipocytes. Effects of hypothyroidism and streptozotocin-diabetes on enzyme activities and metabolic fluxes

1988 ◽  
Vol 250 (2) ◽  
pp. 325-333 ◽  
Author(s):  
H S Baht ◽  
E D Saggerson
Keyword(s):  
Fatty Acid ◽  
Enzyme Activities ◽  
Metabolic Flux ◽  
Streptozotocin Diabetes ◽  
Fatty Acyl ◽  
Brown Adipocyte ◽  
Acid Oxidation ◽  
Brown Adipocytes ◽  
Triacylglycerol Synthesis ◽  
White Adipocytes

1. Adipocytes were isolated from the interscapular brown fat and the epididymal white fat of normal, streptozotocin-diabetic and hypothyroid rats. 2. Measurements were made of the maximum rate of triacylglycerol synthesis by monitoring the incorporation of [U-14C]glucose into acylglycerol glycerol in the presence of palmitate (1 mM) and insulin (4 nM) and of the activities of the following triacylglycerol-synthesizing enzymes: fatty acyl-CoA synthetase (FAS), mitochondrial and microsomal forms of glycerolphosphate acyltransferase (GPAT), dihydroxyacetonephosphate acyltransferase (DHAPAT), monoacylglycerol phosphate acyltransferase (MGPAT), Mg2+-dependent phosphatidate phosphohydrolase (PPH) and diacylglycerol acyltransferase (DGAT). 3. FAS activity in brown adipocytes was predominantly localized in the mitochondrial fraction, whereas a microsomal localization of this enzyme predominated in white adipocytes. Subcellular distributions of the other enzyme activities in brown adipocytes were similar to those shown previously with white adipocytes [Saggerson, Carpenter, Cheng & Sooranna (1980) Biochem. J. 190, 183-189]. 4. Relative to cell DNA, brown adipocytes had lower activities of triacylglycerol-synthesizing enzymes and showed lower rates of metabolic flux into acylglycerols than did white adipocytes isolated from the same animals. 5. Diabetes decreased both metabolic flux into acylglycerols and the activities of triacylglycerol-synthesizing enzymes in white adipocytes. By contrast, although diabetes decreased metabolic flux into brown-adipocyte acylglycerols by 80%, there were no decreases in the activities of triacylglycerol-synthesizing enzymes, and the activity of PPH was significantly increased. 6. Hypothyroidism increased metabolic flux into acylglycerols in both cell types, and increased activities of all triacylglycerol-synthesizing enzymes in brown adipocytes. By contrast, in white adipocytes, although hypothyroidism increased the activities of FAS, microsomal GPAT and DGAT, this condition decreased the activities of mitochondrial GPAT and PPH. 7. It was calculated that the maximum capabilities for fatty acid oxidation and esterification are approximately equal in brown adipocytes. In white adipocytes esterification is predominant by approx. 100-fold. 8. Diabetes almost abolished incorporation of [U-14C]glucose into fatty acids in both adipocyte types. Hypothyroidism increased fatty acid synthesis in white and brown adipocytes by 50% and 1000% respectively.

scholarly journals Sesamol promotes browning of white adipocytes to ameliorate obesity by inducing mitochondrial biogenesis and inhibition mitophagy via β3-AR/PKA signaling pathway

2021 ◽  
Author(s):  
Cui Lin ◽  
Jihua Chen ◽  
Minmin Hu ◽  
Wenya Zheng ◽  
Ziyu Song ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Total Cholesterol ◽  
Protein Kinase A ◽  
Mitochondrial Biogenesis ◽  
Uncoupling Protein ◽  
Obese Mice ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Kinase A

Background: Obesity is defined as an imbalance between energy intake and expenditure, and it is a serious risk factor of non-communicable diseases. Recently many studies have shown that promoting browning of white adipose tissue (WAT) to increase energy consumption has a great therapeutic potential for obesity. Sesamol, a lignan from sesame oil, had shown potential beneficial functions on obesity treatment. Objective: In this study, we used C57BL/6J mice and 3T3-L1 adipocytes to investigate the effects and the fundamental mechanisms of sesamol in enhancing the browning of white adipocytes to ameliorate obesity. Methods: Sixteen-week-old C57BL/6J male mice were fed high-fat diet (HFD) for 8 weeks to establish the obesity models. Half of the obese mice were administered with sesamol (100 mg/kg body weight [b.w.]/day [d] by gavage for another 8 weeks. Triacylglycerol (TG) and total cholesterol assay kits were used to quantify serum TG and total cholesterol (TC). Oil red O staining was used to detect lipid droplet in vitro. Mito-Tracker Green was used to detect the mitochondrial content. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the levels of beige-specific genes. Immunoblotting was used to detect the proteins involved in beige adipocytes formation. Results: Sesamol decreased the content of body fat and suppressed lipid accumulation in HFD-induced obese mice. In addition, sesamol significantly upregulated uncoupling protein-1 (UCP1) protein in adipose tissue. Further research found that sesamol also significantly activated the browning program in mature 3T3-L1 adipocytes, manifested by the increase in beige-specific genes and proteins. Moreover, sesamol greatly increased mitochondrial biogenesis, as proved by the upregulated protein levels of mitochondrial biogenesis, and the inhibition of the proteins associated with mitophagy. Furthermore, β3-adrenergic receptor (β3-AR), protein kinase A-C (PKA-C) and Phospho-protein kinase A (p-PKA) substrate were elevated by sesamol, and these effects were abolished by the pretreatment of antagonists β3-AR. Conclusion: Sesamol promoted browning of white adipocytes by inducing mitochondrial biogenesis and inhibiting mitophagy through the β3-AR/PKA pathway. This preclinical data promised the potential to consider sesamol as a metabolic modulator of HFD-induced obesity.

scholarly journals Fruit of Gardenia jasminoides Induces Mitochondrial Activation and Non-Shivering Thermogenesis through Regulation of PPARγ

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1418
Author(s):  
Woo Yong Park ◽  
Gahee Song ◽  
Ja Yeon Park ◽  
Kwan-Il Kim ◽  
Kwang Seok Ahn ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Exposure Model ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Gardenia Jasminoides ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Underlying Mechanisms ◽  
Induced Changes

The extract of the Gardenia jasminoides fruit (GJFE) can been consumed as an herbal tea or used as a yellow dye. Recently, studies report that GFJE exerts inhibitory effects on lipid accumulation and adipogenesis in white adipocytes. We evaluated the thermogenic actions of GJFE by focusing on mitochondrial activation and studying the underlying mechanisms. To investigate the role of GJFE on thermogenesis in mice, we used an acute cold exposure model. After 2 weeks of feeding, the cold tolerance of GJFE-fed mice was notably increased compared to PBS-fed mice. This was due to an increase in thermogenic proteins in the inguinal white adipose tissue of the cold-exposed mice. Moreover, GJFE significantly increased thermogenic factors such as peroxisome proliferator-activated receptor gamma (PPARγ), uncoupling protein 1 (UCP1), and PPARγ coactivator 1 alpha (PGC1α) in vitro as well. Factors related to mitochondrial abundance and functions were also induced by GJFE in white and beige adipocytes. However, the treatment of PPARγ inhibitor abolished the GJFE-induced changes, indicating that activation of PPARγ is critical for the thermogenic effect of GJFE. In conclusion, GJFE induces thermogenic action by activating mitochondrial function via PPARγ activation. Through these findings, we suggest GJFE as a potential anti-obesity agent with a novel mechanism involving thermogenic action in white adipocytes.

scholarly journals Multifaceted Roles of Beige Fat in Energy Homeostasis Beyond UCP1

Endocrinology ◽  
2018 ◽  
Vol 159 (7) ◽  
pp. 2545-2553 ◽  
Author(s):  
Carlos Henrique Sponton ◽  
Shingo Kajimura
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Uncoupling Protein ◽  
Developmental Regulation ◽  
Brown Adipocytes ◽  
Adipose Tissue Depots ◽  
Brown Adipose ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Adipose Cells

Abstract Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1.

scholarly journals Withania somnifera Extract Enhances Energy Expenditure via Improving Mitochondrial Function in Adipose Tissue and Skeletal Muscle

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 431 ◽  
Author(s):  
Da-Hye Lee ◽  
Jiyun Ahn ◽  
Young-Jin Jang ◽  
Hyo-Deok Seo ◽  
Tae-Youl Ha ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Oxygen Consumption ◽  
Energy Expenditure ◽  
Mitochondrial Function ◽  
Withania Somnifera ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Mitochondrial Activity ◽  
Beige Adipocytes

Withania somnifera (WS), commonly known as ashwagandha, possesses diverse biological functions. WS root has mainly been used as an herbal medicine to treat anxiety and was recently reported to have an anti-obesity effect, however, the mechanisms underlying its action remain to be explored. We hypothesized that WS exerts its anti-obesity effect by enhancing energy expenditure through improving the mitochondrial function of brown/beige adipocytes and skeletal muscle. Male C57BL/6J mice were fed a high-fat diet (HFD) containing 0.25% or 0.5% WS 70% ethanol extract (WSE) for 10 weeks. WSE (0.5%) supplementation significantly suppressed the increases in body weight and serum lipids, and lipid accumulation in the liver and adipose tissue induced by HFD. WSE supplementation increased oxygen consumption and enhanced mitochondrial activity in brown fat and skeletal muscle in the HFD-fed mice. In addition, it promoted browning of subcutaneous fat by increasing mitochondrial uncoupling protein 1 (UCP1) expression. Withaferin A (WFA), a major compound of WS, enhanced the differentiation of pre-adipocytes into beige adipocytes and oxygen consumption in C2C12 murine myoblasts. These results suggest that WSE ameliorates diet-induced obesity by enhancing energy expenditure via promoting mitochondrial function in adipose tissue and skeletal muscle, and WFA is a key regulator in this function.

Functional assessment of white and brown adipocyte development and energy metabolism in cell culture. Dissociation of terminal differentiation and thermogenesis in brown adipocytes

1995 ◽  
Vol 108 (10) ◽  
pp. 3171-3180
Author(s):  
S. Klaus ◽  
M. Ely ◽  
D. Encke ◽  
G. Heldmaier
Keyword(s):  
Uncoupling Protein ◽  
Terminal Differentiation ◽  
Brown Adipocyte ◽  
Index Number ◽  
Brown Adipocytes ◽  
White Adipocytes ◽  
Dwarf Hamster ◽  
Microscopy Analysis ◽  
White Fat ◽  
Adipocyte Development

We investigated the effect of insulin, triiodothyronine (T3) and dexamethasone (a synthetic glucocorticoid) on differentiation, lipid metabolism and thermogenesis of preadipocytes isolated from white fat (WAT) and brown fat (BAT) from the Siberian dwarf hamster (Phodopus sungorus). Cell cultures from WAT and BAT were chronically treated with the above hormones alone or in any combination. After differentiation (day 8 or 9 of culture) we measured the following parameters: adipogenic index (number × size of adipocytes), protein content, lipolysis, cell respiration, and expression of the uncoupling protein UCP, which is unique to mitochondria of brown adipocytes. Insulin was the most important adipogenic factor for brown and white adipocytes and necessary for terminal differentiation, whereas dexamethasone alone completely inhibited differentiation. T3 had no effect on adipogenesis in WAT cultures, but further increased insulin stimulated adipogenesis in BAT cultures. Basal lipolysis was higher in WAT than in BAT cultures except when dexamethasone was present, which stimulated lipolysis in both culture types to the same extent. T3 had a pronounced dose dependent lipolytic effect on WAT cultures but very little effect on BAT cultures. Respiration rates were generally higher in differentiated adipocytes than in fibroblast like cells. T3 had no effect on thermogenesis in WAT cultures but increased thermogenesis in BAT cultures, and this was further elevated by insulin. UCP expression in BAT cultures could be detected by western blot in insulin treated, T3 treated and insulin+T3 treated cultures with highest expression in the latter. These results imply a possible dissociation of terminal differentiation and thermogenic function of brown adipocytes. In WAT cultures there was also a low level of UCP detectable in the insulin+T3 treated cultures. Immuno-fluorescence microscopy analysis revealed the presence of UCP in 10–15% of adipocytes from WAT cultures (in BAT cultures: 90%), indicating the presence of some brown preadipocytes in typical WAT deposits.

scholarly journals Gomisin N from Schisandra chinensis Ameliorates Lipid Accumulation and Induces a Brown Fat-Like Phenotype through AMP-Activated Protein Kinase in 3T3-L1 Adipocytes

2020 ◽  
Vol 21 (6) ◽  
pp. 2153
Author(s):  
Kippeum Lee ◽  
Yeon-Joo Lee ◽  
Kui-Jin Kim ◽  
Sungwoo Chei ◽  
Heegu Jin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lipid Accumulation ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Acid Oxidation ◽  
Schisandra Chinensis ◽  
White Adipocytes ◽  
Gomisin N ◽  
Amp Activated Protein Kinase

Obesity results from an imbalance between energy intake and energy expenditure, in which excess fat is stored as triglycerides (TGs) in white adipocytes. Recent studies have explored the anti-obesity effects of certain edible phytochemicals, which suppress TG accumulation and stimulate a brown adipocyte-like phenotype in white adipocytes. Gomisin N (GN) is an important bioactive component of Schisandra chinensis, a woody plant endemic to Asia. GN has antioxidant, anti-inflammatory and hepatoprotective effects in vivo and in vitro. However, the anti-obesity effects of GN in lipid metabolism and adipocyte browning have not yet been investigated. In the present study, we aimed to determine whether GN suppresses lipid accumulation and regulates energy metabolism, potentially via AMP-activated protein kinase (AMPK), in 3T3-L1 adipocytes. Our findings demonstrate that GN inhibited adipogenesis and lipogenesis in adipocyte differentiation. Also, GN not only increased the expression of thermogenic factors, including uncoupling protein 1 (UCP1), but also enhanced fatty acid oxidation (FAO) in 3T3-L1 cells. Therefore, GN may have a therapeutic benefit as a promising natural agent to combat obesity.

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