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 Browning Effects of a Chronic Pterostilbene Supplementation in Mice Fed a High-Fat Diet

2019 ◽  
Vol 20 (21) ◽  
pp. 5377 ◽  
Author(s):  
Martina La Spina ◽  
Eva Galletta ◽  
Michele Azzolini ◽  
Saioa Gomez Zorita ◽  
Sofia Parrasia ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Uncoupling Protein ◽  
Protein A ◽  
Health Concern ◽  
Marker Genes ◽  
High Fat ◽  
Protein Levels

Obesity and related comorbidities are a major health concern. The drugs used to treat these conditions are largely inadequate or dangerous, and a well-researched approach based on nutraceuticals would be highly useful. Pterostilbene (Pt), i.e., 3,5-dimethylresveratrol, has been reported to be effective in animal models of obesity, acting on different metabolic pathways. We investigate here its ability to induce browning of white adipose tissue. Pt (5 µM) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 µmol/kg/day) to mice fed an obesogenic high-fat diet (HFD) for 30 weeks, starting at weaning. In the cultured adipocytes, the treatment elicited a significant increase of the levels of Uncoupling Protein 1 (UCP1) protein—a key component of thermogenic, energy-dissipating beige/brown adipocytes. In vivo administration antagonized weight increase, more so in males than in females. Analysis of inguinal White Adipose Tissue (WAT) revealed a trend towards browning, with significantly increased transcription of several marker genes (Cidea, Ebf2, Pgc1α, PPARγ, Sirt1, and Tbx1) and an increase in UCP1 protein levels, which, however, did not achieve significance. Given the lack of known side effects of Pt, this study strengthens the candidacy of this natural phenol as an anti-obesity nutraceutical.

scholarly journals Current Progress in Adipose Tissue Biology: Implications in Obesity and Its Comorbidities

2020 ◽  
Vol 12 (2) ◽  
pp. 85-101
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Common Factor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Brown Adipose ◽  
Key Factor ◽  
Beige Fat

BACKGROUND: Obesity has been decades become a highly interest study, accompanied by the realization that adipose tissue (AT) plays a major role in the regulation of metabolic function.CONTENT: In past few years, adipocytes classification, development, and differentiation has been significant changes. The white adipose tissue (WAT) can transform to a phenotype like brown adipose (BAT) type and function. Exercise and cold induction were the most common factor for fat browning; however batokines such as fibroblast growth factor (FGF)-21, interleukin (IL)-6, Slit homolog 2 protein (SLIT2)-C, and Meteorin-like protein (METRNL) perform a beneficial browning action by increasing peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α protein levels, a key factor to stimulate mitochondrial biogenesis and uncoupling Protein 1 (UCP1) transcription, thus change the WAT phenotype into beige.SUMMARY: AT recently known as a complex organ, not only bearing a storage function but as well as the master regulator of energy balance and nutritional homeostasis; brown and beige fat express constitutively high levels of thermogenic genes and raise our expectation on new strategies for fighting obesity and metabolic disorders.KEYWORDS: obesity, white adipose tissue, brown adipose tissue, beige adipose tissue, inflammation, IR, metabolic disease

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.

scholarly journals ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue

2019 ◽  
Vol 317 (6) ◽  
pp. E1140-E1149 ◽  
Author(s):  
Yasuhiro Kawabe ◽  
Jun Mori ◽  
Hidechika Morimoto ◽  
Mihoko Yamaguchi ◽  
Satoshi Miyagaki ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
White Adipose Tissue ◽  
Uncoupling Protein ◽  
Ang Ii ◽  
Angiotensin Converting Enzyme 2 ◽  
Histone Deacetylase 3 ◽  
Subcutaneous White Adipose Tissue ◽  
Protein Levels ◽  
Brown Adipose

The angiotensin II (ANG II)-ANG II type 1 receptor (AT1R) axis is a key player in the pathophysiology of obesity. Angiotensin-converting enzyme 2 (ACE2) counteracts the ANG II/AT1R axis via converting ANG II to angiotensin 1–7 (Ang 1–7), which is known to have an anti-obesity effect. In this study, we hypothesized that ACE2 exerts a strong anti-obesity effect by increasing Ang 1–7 levels. We injected intraperitoneally recombinant human ACE2 (rhACE2, 2.0 mg·kg−1·day−1) for 28 days to high-fat diet (HFD)-induced obesity mice. rhACE2 treatment decreased body weight and improved glucose metabolism. Furthermore, rhACE2 increased oxygen consumption and upregulated thermogenesis in HFD-fed mice. In the rhACE2 treatment group, brown adipose tissue (BAT) mass increased, accompanied with ameliorated insulin signaling and increased protein levels of uncoupling protein-1 (UCP-1) and PRD1-BF1-RIZ1 homologous domain containing 16. Importantly, subcutaneous white adipose tissue (sWAT) mass decreased, concomitant with browning, which was established by the increase of UCP-1 expression. The browning is the result of increased H3K27 acetylation via the downregulation of histone deacetylase 3 and increased H3K9 acetylation via upregulation of GCN5 and P300/CBP-associated factor. These results suggest that rhACE2 exerts anti-obesity effects by stimulating BAT and inducing browning in sWAT. ACE2 and the Ang 1–7 axis represent a potential therapeutic approach to prevent the development of obesity.

Regulation of the level of uncoupling protein in brown adipose tissue by insulin

1990 ◽  
Vol 258 (2) ◽  
pp. R418-R424 ◽  
Author(s):  
A. Geloen ◽  
P. Trayhurn
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Protein Content ◽  
White Adipose Tissue ◽  
Oxidase Activity ◽  
Uncoupling Protein ◽  
Mitochondrial Protein ◽  
Brown Adipose ◽  
Epididymal White Adipose Tissue

The role of insulin in the regulation of the thermogenic activity and capacity (uncoupling protein content) of brown adipose tissue (BAT) has been investigated using mice made diabetic with streptozotocin and then subsequently infused with different doses of insulin. After 12 days of diabetes, the animals received either 0, 8, 16, or 32 units of insulin.kg body wt-1.day-1 delivered by osmotic minipumps implanted subcutaneously for 12 days. After 12 days of diabetes, body weight, interscapular BAT, and epididymal white adipose tissue weights were each reduced. In BAT, significant decreases (P less than 0.05) in the mitochondrial protein content (63%), cytochrome oxidase activity (79%), mitochondrial GDP binding (51%), and the specific mitochondrial concentration and total tissue content of uncoupling protein (71 and 89%, respectively) were obtained, indicating that the thermogenic activity and capacity of the tissue were reduced in diabetes. The infusion of insulin at a dose of 8 units.kg-1.day-1 normalized mitochondrial GDP binding and doubled the concentration of uncoupling protein. Body weight, epididymal white adipose tissue weight, and the mitochondrial protein content of BAT were restored with 16 units of insulin.kg-1.day-1. Higher doses of insulin did not further increase the specific mitochondrial concentration of uncoupling protein, but the mitochondrial content (and thereby the total uncoupling protein content) of BAT was increased and blood glucose normalized. There was a significant correlation between the dose of insulin replacement and several of the parameters measured in BAT: mitochondrial protein content (r = 0.68, P less than 0.001), cytochrome oxidase activity (r = 0.54, P less than 0.001), and total uncoupling protein content (r = 0.68, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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 D-Mannitol Induces a Brown Fat-like Phenotype via a β3-Adrenergic Receptor-Dependent Mechanism

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 768
Author(s):  
Hui-Jeon Jeon ◽  
Dong Kyu Choi ◽  
JaeHeon Choi ◽  
Seul Lee ◽  
Heejin Lee ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Protein Kinase ◽  
White Adipose Tissue ◽  
Adrenergic Receptor ◽  
Uncoupling Protein ◽  
The Body ◽  
Brown Fat ◽  
White Adipocytes

The presence of brown adipocytes within white adipose tissue is associated with phenotypes that exhibit improved metabolism and proper body weight maintenance. Therefore, a variety of dietary agents that facilitate the browning of white adipocytes have been investigated. In this study, we screened a natural product library comprising 133 compounds with the potential to promote the browning of white adipocytes, and found that D-mannitol induces the browning of 3T3-L1 adipocytes by enhancing the expression of brown fat-specific genes and proteins, and upregulating lipid metabolism markers. D-mannitol also increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase 1 (ACC), suggesting a possible role in lipolysis and fat oxidation. Moreover, an increase in the expression of genes associated with D-mannitol-induced browning was strongly correlated with the activation of the β3-adrenergic receptor as well as AMPK, protein kinase A (PKA), and PPARγ coactivator 1α (PGC1α). D-mannitol effectively reduced the body weight of mice fed a high-fat diet, and increased the expression of β1-oxidation and energy expenditure markers, such as Cidea, carnitine palmityl transferase 1 (CPT1), uncoupling protein 1 (UCP1), PGC1α, and acyl-coenzyme A oxidase (ACOX1) in the inguinal white adipose tissue. Our findings suggest that D-mannitol plays a dual regulatory role by inducing the generation of a brown fat-like phenotype and enhancing lipid metabolism. These results indicate that D-mannitol can function as an anti-obesity supplement.

scholarly journals Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Aung Than ◽  
Shaohai Xu ◽  
Ru Li ◽  
MelvinKhee-Shing Leow ◽  
Lei Sun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Receptor Activation ◽  
White Adipocytes ◽  
Brown Adipose ◽  
Beige Adipocytes ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type ◽  
Brown Adipogenesis

Abstract Brown adipose tissue dissipates energy in the form of heat. Recent studies have shown that adult humans possess both classical brown and beige adipocytes (brown-like adipocytes in white adipose tissue, WAT), and stimulating brown and beige adipocyte formation can be a new avenue to treat obesity. Angiotensin II (AngII) is a peptide hormone that plays important roles in energy metabolism via its angiotensin type 1 or type 2 receptors (AT1R and AT2R). Adipose tissue is a major source of AngII and expresses both types of its receptors, implying the autocrine and paracrine role of AngII in regulating adipose functions and self-remodeling. Here, based on the in vitro studies on primary cultures of mouse white adipocytes, we report that, AT2R activation, either by AngII or AT2R agonist (C21), induces white adipocyte browning, by increasing PPARγ expression, at least in part, via ERK1/2, PI3kinase/Akt and AMPK signaling pathways. It is also found that AngII–AT2R enhances brown adipogenesis. In the in vivo studies on mice, administration of AT1R antagonist (ZD7155) or AT2R agonist (C21) leads to the increase of WAT browning, body temperature and serum adiponectin, as well as the decrease of WAT mass and the serum levels of TNFα, triglycerides and free fatty acids. In addition, AT2R-induced browning effect is also observed in human white adipocytes, as evidenced by the increased UCP1 expression and oxygen consumption. Finally, we provide evidence that AT2R plays important roles in hormone T3-induced white adipose browning. This study, for the first time, reveals the browning and brown adipogenic effects of AT2R and suggests a potential therapeutic target to combat obesity and related metabolic disorders.

scholarly journals Dietary Silk Peptide Prevents High-Fat Diet-Induced Obesity and Promotes Adipose Browning by Activating AMP-Activated Protein Kinase in Mice

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 201 ◽  
Author(s):  
Kippeum Lee ◽  
Heegu Jin ◽  
Sungwoo Chei ◽  
Jeong-Yong Lee ◽  
Hyun-Ji Oh ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Uncoupling Protein ◽  
Acid Oxidation ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Silk Peptide ◽  
Amp Activated Protein Kinase

Obesity is associated with metabolic syndrome and other chronic diseases, and is caused when the energy intake is greater than the energy expenditure. We aimed to determine the mechanism whereby acid-hydrolyzed silk peptide (SP) prevents high-fat diet-induced obesity, and whether it induces browning and fatty acid oxidation (FAO) in white adipose tissue (WAT), using in vivo and ex vivo approaches. We determined the effects of dietary SP in high-fat diet-fed obese mice. The expression of adipose tissue-specific genes was quantified by western blotting, qRT-PCR, and immunofluorescence analysis. We also investigated whether SP directly induces browning in primarily subcutaneous WAT-derived adipocytes. Our findings demonstrate that SP has a browning effect in WAT by upregulating AMP-activated Protein Kinase (AMPK) phosphorylation and uncoupling protein 1 (UCP1) expression. SP also suppresses adipogenesis and promotes FAO, implying that it may have potential as an anti-obesity drug.

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