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Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes.

ABSTRACT: The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.

SUBMITTER: Kavalakatt S

PROVIDER: S-EPMC8329193 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Role of heat shock protein 70 in regulation of anti-inflammatory response to curcumin in 3T3-L1 adipocytes

Project description:BACKGROUND/OBJECTIVES Curcumin is a well-known phytochemical with anti-inflammatory effects. Heat shock protein (HSP) 70, an intracellular chaperone, inhibits proinflammatory signaling activation. Although curcumin has been shown to induce HSP70 expression in various cell types, whether HSP70 mediates the anti-inflammatory effects of curcumin in mature adipocytes remains unclear. MATERIALS/METHODS To assess the role of HSP70 in regulating the anti-inflammatory response to curcumin in adipocytes, fully differentiated 3T3-L1 adipocytes were treated with curcumin, lipopolysaccharide (LPS), and/or the HSP70 inhibitor pifithrin-μ (PFT-μ). The expression levels of HSP70 and proinflammatory cytokines were then measured. RESULTS Curcumin upregulated HSP70 expression at both protein and mRNA levels and attenuated LPS-induced Il6, Ptx3, and Ccl2 mRNA upregulation. PFT-μ tended to exacerbate the LPS-induced upregulation of Il6, Ptx3, Ccl2, and Tnfa mRNA expression. However, on curcumin pretreatment, the tendency of PFT-μ to upregulate LPS-induced proinflammatory cytokine expression decreased or disappeared. CONCLUSION These results indicate that HSP70 is involved in the regulation of inflammatory responses but may not be crucial for the anti-inflammatory effects of curcumin in 3T3-L1 adipocytes.

| S-EPMC10232195 | biostudies-literature

Heat shock response relieves ER stress.

Project description:Accumulation of misfolded protein in the endoplasmic reticulum (ER) causes stress. The unfolded protein response (UPR), a transcriptional induction pathway, is activated to relieve ER stress. Although UPR is not essential for viability, UPR-deficient cells are more sensitive to ER stress; ire1Delta cells cannot grow when challenged with tunicamycin or by overexpression of misfolded CPY(*). In these cells, multiple functions are defective, including translocation, ER-associated degradation (ERAD), and ER-to-Golgi transport. We tested whether heat shock response (HSR) can relieve ER stress. Using a constitutively active Hsf1 transcription factor to induce HSR without temperature shift, we find that HSR rescues growth of stressed ire1Delta cells, and partially relieves defects in translocation and ERAD. Cargo-specific effects of constitutively active Hsf1 on ER-to-Golgi transport are correlated with enhanced protein levels of the respective cargo receptors. In vivo, HSR is activated by ER stress, albeit to a lower level than that caused by heat. Genomic analysis of HSR targets reveals that >25% have function in common with UPR targets. We propose that HSR can relieve stress in UPR-deficient cells by affecting multiple ER activities.

| S-EPMC2323268 | biostudies-literature

Amber Extract Reduces Lipid Content in Mature 3T3-L1 Adipocytes by Activating the Lipolysis Pathway.

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Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes.

Project description:Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism's health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1β), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

| S-EPMC6266132 | biostudies-literature

Repression of GLUT4 expression by the endoplasmic reticulum stress response in 3T3-L1 adipocytes.

Project description:Expression of GLUT4 is decreased in adipocytes in obesity and type 2 diabetes, contributing to the insulin resistance of these states. Recent investigations suggest a role for activation of the ER stress response in the pathophysiology of type 2 diabetes. We investigated activation of the ER stress response in 3T3-L1 adipocytes. We show that activation of the ER stress response decreased GLUT4 expression at the level of gene transcription. Activation of the ER stress response also increased the expression of CHOP10, an inhibitor of the activity and expression of C/EBPalpha. As expected, activation of the ER stress response decreased expression of C/EBPalpha, an activator of GLUT4 expression, providing a mechanism to account for the repression of GLUT4 by ER stress activation. Our studies identify repression of GLUT4 expression as another potential mechanism for obesity-induced activation of the ER stress response to contribute to the insulin resistance of obesity.

| S-EPMC2018654 | biostudies-literature

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Project description:Alkylglycerol monooxygenase (AGMO) is a tetrahydrobiopterin (BH4)-dependent enzyme with major expression in the liver and white adipose tissue that cleaves alkyl ether glycerolipids. The present study describes the disclosure and biological characterization of a candidate compound (Cp6), which inhibits AGMO with an IC50 of 30-100 µM and 5-20-fold preference of AGMO relative to other BH4-dependent enzymes, i.e., phenylalanine-hydroxylase and nitric oxide synthase. The viability and metabolic activity of mouse 3T3-L1 fibroblasts, HepG2 human hepatocytes and mouse RAW264.7 macrophages were not affected up to 10-fold of the IC50. However, Cp6 reversibly inhibited the differentiation of 3T3-L1 cells towards adipocytes, in which AGMO expression was upregulated upon differentiation. Cp6 reduced the accumulation of lipid droplets in adipocytes upon differentiation and in HepG2 cells exposed to free fatty acids. Cp6 also inhibited IL-4-driven differentiation of RAW264.7 macrophages towards M2-like macrophages, which serve as adipocyte progenitors in adipose tissue. Collectively, the data suggest that pharmacologic AGMO inhibition may affect lipid storage.

| S-EPMC8147360 | biostudies-literature

Perfluorobutanesulfonic acid (PFBS) potentiates adipogenesis of 3T3-L1 adipocytes.

Project description:Perfluorobutanesulfonic acid (PFBS) is used as the replacement of perfluorooctanesulfonic acid (PFOS) since 2000 because of the concern on PFOS' persistence in the environment and the bioaccumulation in animals. Accumulating evidence has shown the correlation between the exposure to perfluorinated compounds and enhanced adipogenesis. There is no report, however, of the effect of PFBS on adipogenesis. Therefore, the present work aimed to investigate the role of PFBS in adipogenesis using 3T3-L1 adipocytes. PFBS treatment for 6 days extensively promoted the differentiation of 3T3-L1 preadipocytes to adipocytes, resulting in significantly increased triglyceride levels. In particular, the treatments of PFBS at the early adipogenic differentiation period (day 0-2) were positively correlated with increased the triglyceride accumulation on day 6. PFBS treatments significantly increased the protein and mRNA levels of the master transcription factors in adipocyte differentiation; CCAAT/enhancer-binding protein ? (C/EBP?) and peroxisome proliferator-activated receptor gamma (PPAR?), along with acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the key proteins in lipogenesis. PFBS significantly activated the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) after 4-h treatment, and PFBS' effect on triglyceride was abolished by U0126, a specific MAPK/ERK kinase (MEK) inhibitor. In conclusion, PFBS increased the adipogenesis of 3T3-L1 adipocytes, in part, via MEK/ERK-dependent pathway.

| S-EPMC6169790 | biostudies-literature

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Project description:In recent years, obesity has been considered a pathological stage of early lifestyle-related diseases, and adipose tissue and adipocyte research has been active. Glycosphingolipids are involved in the pathogenesis of type 2 diabetes induced by insulin resistance, but the details of the glycosphingolipid molecular species composition of adipocytes have yet to be elucidated. We used 3T3-L1 adipocytes and the 1,2-dichloroethane-wash method to remove triacylglycerols, which are abundant in adipocytes, and analyzed the structures of glycosphingolipids, particularly neutral glycosphingolipids, using liquid chromatography-mass spectrometry.

| S-EPMC4541715 | biostudies-literature

Effect of Cucumis sativus on Dysfunctional 3T3-L1 Adipocytes.

Project description:Obesity is caused by lipid accumulation in adipose tissues inducing adipocyte dysfunction, characterized by insulin resistance, increased lipolysis, oxidative stress, and inflammation, leading to increased levels of adipokines. Herein the capacity of the subfractions (SFs) SF1, SF2, and SF3 from the Cucumis sativus aqueous fraction and their combinations (M) to control adipocyte dysfunction in vitro, in 3T3-L1 adipocytes was studied. Adipocytes, previously treated with dexamethasone or IL-1 to induce dysfunction, were incubated with different concentrations of the subfractions for 24 h. 2-deoxyglucose consumption and glycerol release were evaluated, and a surface model was constructed to determine the most effective SF concentrations to improve both parameters. Effective SF combinations were assessed in their capacity to control metabolic, pro-oxidative, and pro-inflammatory conditions. SF1, SF2 (40 μg/ml each) and SF3 (20 μg/ml) improved 2-deoxyglucose consumption by 87%, 57%, and 87%, respectively. SF1 and SF2 (5 μg/ml each) and SF3 (40 μg/mL) increased glycerol secretion by 10.6%, 18.9%, and 11.8%, respectively. Among five combinations tested, only M4 (SF1 40 μg/ml:SF2 60 μg/ml:SF3 30 μg/ml) and M5 (SF1 40 μg/ml:SF2 60 μg/mL:SF3 10 μg/ml) controlled effectively the metabolic, pro-oxidative, and proinflammatory conditions studied. Glycine, asparagine, and arginine were the main components in these SFs.

| S-EPMC6746747 | biostudies-literature

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