scholarly journals Glucocorticoid/Adiponectin Axis Mediates Full Activation of Cold-Induced Beige Fat Thermogenesis

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1573
Author(s):  
Liping Luo ◽  
Lu Wang ◽  
Yan Luo ◽  
Estevan Romero ◽  
Xin Yang ◽  
...  
Keyword(s):  
Cold Stress ◽  
Mrna Levels ◽  
Stress Hormone ◽  
Adaptive Thermogenesis ◽  
White Adipocytes ◽  
Beige Fat ◽  
Response To Stress ◽  
Circulating Levels ◽  
Full Activation

Glucocorticoids (GCs), a class of corticosteroids produced by the adrenal cortex in response to stress, exert obesity-promoting effects. Although adaptive thermogenesis has been considered an effective approach to counteract obesity, whether GCs play a role in regulating cold stress-induced thermogenesis remains incompletely understood. Here, we show that the circulating levels of stress hormone corticosterone (GC in rodents) were significantly elevated, whereas the levels of adiponectin, an adipokine that was linked to cold-induced adaptive thermogenesis, were decreased 48 h post cold exposure. The administration of a glucocorticoid hydrocortisone downregulated adiponectin protein and mRNA levels in both WAT and white adipocytes, and upregulated thermogenic gene expression in inguinal fat. In contrast, mifepristone, a glucocorticoid receptor antagonist, enhanced adiponectin expression and suppressed energy expenditure in vivo. Mechanistically, hydrocortisone suppressed adiponectin expression by antagonizing PPARγ in differentiated 3T3-L1 adipocytes. Ultimately, adiponectin deficiency restored mifepristone-decreased oxygen consumption and suppressed the expression of thermogenic genes in inguinal fat. Taken together, our study reveals that the GCs/adiponectin axis is a key regulator of beige fat thermogenesis in response to acute cold stress.

scholarly journals Betatrophin knockdown induces beiging and mitochondria biogenesis of white adipocytes

2020 ◽  
Vol 245 (1) ◽  
pp. 93-100 ◽  
Author(s):  
Zhe-Zhen Liao ◽  
Xiao-Yan Qi ◽  
Ya-Di Wang ◽  
Jiao-Yang Li ◽  
Qian-Qian Gu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ampk Signaling ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Mitochondria Biogenesis ◽  
Paracrine Actions ◽  
White Fat

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

scholarly journals Lsd1 prevents age-programed loss of beige adipocytes

2017 ◽  
Vol 114 (20) ◽  
pp. 5265-5270 ◽  
Author(s):  
Delphine Duteil ◽  
Milica Tosic ◽  
Dominica Willmann ◽  
Anastasia Georgiadi ◽  
Toufike Kanouni ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Fat Cell ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Age Related ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
And Function

Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Accordingly, adipocyte-specific increase of Lsd1 expression is sufficient to rescue the age-related transition of beige adipocytes to white adipocytes in vivo, whereas loss of Lsd1 precipitates it. Lsd1 maintains beige adipocytes by controlling the expression of peroxisome proliferator-activated receptor α (Ppara), and treatment with a Ppara agonist is sufficient to rescue the loss of beige adipocytes caused by Lsd1 ablation. In summary, our data provide insights into the mechanism controlling the age-related beige-to-white adipocyte transition and identify Lsd1 as a regulator of beige fat cell maintenance.

scholarly journals Rac-dependent signaling from keratinocytes promotes differentiation of intradermal white adipocytes

2018 ◽  
Author(s):  
Takehiko Ueyama ◽  
Megumi Sakuma ◽  
Mio Nakatsuji ◽  
Tatsuya Uebi ◽  
Takeshi Hamada ◽  
...  
Keyword(s):  
Culture Medium ◽  
Culture Media ◽  
Brown Adipocyte ◽  
Mrna Levels ◽  
Primary Keratinocytes ◽  
White Adipocytes ◽  
Combinational Treatment ◽  
Single Knockout ◽  
Brown Adipogenesis

AbstractRac signaling affects numerous downstream targets; however, few studies have established in vivo levels. We generated mice with a single knockout (KO) of Rac1 (Keratin5 (K5)-Cre;Rac1flox/flox, Rac1-KO) and double KO of Rac1 and Rac3 (K5-Cre;Rac1flox/flox;Rac3−/−, Rac1/Rac3-DKO) in keratinocytes. Strikingly, Rac1-KO mice exhibited thinner dermal white adipose tissue, which was considerably further reduced in Rac1/Rac3-DKO mice. DNA microarray using primary keratinocytes from Rac1/Rac3-DKO mice exhibited decreased mRNA levels of Bmp2, Bmp5, Fgf20, Fgf21, Fgfbp1, and Pdgfα. Combinational treatment with BMP2 and FGF21 or BMP2 and FGF20 in culture medium, but not individual purified recombinant proteins, could differentiate 3T3-L1 fibroblasts into adipocytes, as could culture media obtained from primary keratinocytes. Conversely, addition of anti-BMP2 or anti-FGF21 antibodies into the culture medium inhibited fibroblast differentiation. Furthermore, combinational treatment with BMP2 and FGF21 promoted adipocyte differentiation only of rat primary white, but not brown, adipocyte precursors. Notably, brown adipogenesis by FGF21 was inhibited by BMP2. Thus, we proposed novel paracrine pathways from keratinocytes to intradermal pre-adipocytes, which function as Rac-dependent modulators of white adipogenesis, but also brown adipogenesis.

scholarly journals The Natural Osmolyte Trehalose Is a Positive Regulator of the Heat-Induced Activity of Yeast Heat Shock Transcription Factor

2006 ◽  
Vol 27 (4) ◽  
pp. 1505-1515 ◽  
Author(s):  
Laura K. Conlin ◽  
Hillary C. M. Nelson
Keyword(s):  
Heat Shock ◽  
Transcriptional Activity ◽  
Dynamic Range ◽  
Transcriptional Response ◽  
Mrna Levels ◽  
Adverse Conditions ◽  
Shock Response ◽  
Response To Stress ◽  
Low Levels

ABSTRACT In Saccharomyces cerevisiae, the intracellular concentration of trehalose increases rapidly in response to many environmental stresses, including heat shock. These high trehalose levels have been correlated with tolerance to adverse conditions and led to the model that trehalose functions as a chemical cochaperone. Here, we show that the transcriptional activity of Hsf1 during the heat shock response depends on trehalose. Strains with low levels of trehalose have a diminished transcriptional response to heat shock, while strains with high levels of trehalose have an enhanced transcriptional response to heat shock. The enhanced transcriptional response does not require the other heat-responsive transcription factors Msn2/4 but is dependent upon heat and Hsf1. In addition, the phosphorylation levels of Hsf1 correlate with both transcriptional activity and the presence of trehalose. These in vivo results support a new role for trehalose, where trehalose directly modifies the dynamic range of Hsf1 activity and therefore influences heat shock protein mRNA levels in response to stress.

scholarly journals Nesfatin-1 inhibits proliferation and enhances apoptosis of human adrenocortical H295R cells

2015 ◽  
Vol 226 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Manjunath Ramanjaneya ◽  
Bee K Tan ◽  
Marcin Rucinski ◽  
Mohamed Kawan ◽  
Jiamiao Hu ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Cell Model ◽  
Mrna Levels ◽  
Adrenocortical Cells ◽  
Peripheral Tissues ◽  
Paraventricular Nuclei ◽  
Response To Stress ◽  
H295r Cells

NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 are expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 genes as well as ERK1/2, p38 and JNK1/2 signalling cascades. This has implications for understanding the role of NUCB2/nesfatin in adrenal zonal development. NUCB2/nesfatin may also be a therapeutic target for adrenal cancer. However, further studies using in vivo models are needed to clarify these concepts.

Nanocurcumin: A Double-Edged Sword for Microcancers

2020 ◽  
Vol 26 (45) ◽  
pp. 5783-5792
Author(s):  
Kholood Abid Janjua ◽  
Adeeb Shehzad ◽  
Raheem Shahzad ◽  
Salman Ul Islam ◽  
Mazhar Ul Islam
Keyword(s):  
Intracellular Signaling ◽  
Dosage Forms ◽  
The Body ◽  
In Vivo Studies ◽  
Mrna Levels ◽  
Anticancer Activities ◽  
Road Map ◽  
Anticancer Effects

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

scholarly journals TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chengwu Xiao ◽  
Wei Zhang ◽  
Meimian Hua ◽  
Huan Chen ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

scholarly journals Glucolipotoxicity and GLP-1 secretion

2021 ◽  
Vol 9 (1) ◽  
pp. e001905
Author(s):  
Jung-Hee Hong ◽  
Dae-Hee Kim ◽  
Moon-Kyu Lee
Keyword(s):  
Glucose Transporter ◽  
Cell Function ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Simultaneous Treatment ◽  
L Cells ◽  
Triglyceride Accumulation

IntroductionThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and/or fatty acid levels.Research design and methodsTo investigate the effects of chronic glucolipotoxicity on glucagon-like peptide-1-(7-36) amide (GLP-1) secretion, we generated glucolipotoxic conditions in human NCI-H716 enteroendocrine cells using either 5 or 25 mM glucose with or without 500 µM palmitate for 72 hours. For in vivo study, we have established a chronic nutrient infusion model in the rat. Serial blood samples were collected for 2 hours after the consumption of a mixed meal to evaluate insulin sensitivity and β-cell function.ResultsChronic glucolipotoxic conditions decreased GLP-1 secretion and the expressions of pCREB, pGSK3β, β-catenin, and TCF7L2 in NCI-H716 cells. Glucolipotoxicity conditions reduced glucose transporter expression, glucose uptake, and nicotinamide-adenine dinucleotide phosphate (NADPH) levels in L-cells, and increased triglyceride accumulation. In contrast, PPARα and ATP levels were reduced, which correlated well with decreased levels of SUR1 and Kir6.2, cAMP contents and expressions of pCAMK2, EPAC and PKA. We also observed an increase in reactive oxygen species production, UCP2 expression and Complex I activity. Simultaneous treatment with insulin restored the GLP-1 secretion. Glucolipotoxic conditions decreased insulin secretion in a time-dependent manner in INS-1 cells, which was recovered with exendin-4 cotreatment. Glucose and SMOFlipid infusion for 6 hours decreased GLP-1 secretion and proglucagon mRNA levels as well as impaired the glucose tolerance, insulin and C-peptide secretion in rats.ConclusionThese results provide evidence for the first time that glucolipotoxicity could affect GLP-1 secretion through changes in glucose and lipid metabolism, gene expressions, and proglucagon biosynthesis and suggest the interrelationship between glucolipotoxicities of L-cells and β-cells which develops earlier than that of L-cells.

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