Role of Corn Peptide Powder in Lipopolysaccharide-Induced Inflammatory Responses in 3T3-L1 Adipocytes.

Corn peptide (CP) is a short, naturally occurring, and physiologically active peptide generated from corn-protease-catalyzed hydrolysis. CP plays a role in preventing obesity-related disorders, but its impact on reducing inflammation is unknown. Hence, this study examined the possible protective effects of corn peptide powder (CPP) against the harmful effects of lipopolysaccharide (LPS), with a particular emphasis on reducing oxidative damage and inflammation in adipocytes. Hence, mature 3T3-L1 adipocytes underwent exposure to 10 ng/mL LPS, with or without CPP (10 and 20 µg/mL). LPS stimulation increased reactive oxygen species and superoxide anion generation. However, this effect was reduced in a dose-dependent manner by pretreatment with CPP. CPP treatment elevated the mRNA expressions of the antioxidant enzymes manganese superoxide dismutase (mnSOD) and glutathione peroxidase 1 (Gpx1) while reducing the mRNA expressions of the cytosolic reactive oxygen species indicators p40 and p67 (NADPH oxidase 2). In addition, CPP inhibited the monocyte chemoattractant protein-1, tumor necrosis factor-alpha, Toll-like receptor 4, and nuclear factor kappa B mRNA expressions induced by LPS. These findings demonstrate that CPP may ameliorate adipocyte dysfunction by suppressing oxidative damage and inflammatory responses through a new mechanism known as Toll-like receptor 4/nuclear factor kappa B-mediated signaling.

Momordica charantia Bioactive Components: Hypoglycemic and Hypolipidemic Benefits Through Gut Health Modulation.

Momordica charantia (MC), a member of the Cucurbitaceae family, is well known for its pharmacological activities that exhibit hypoglycemic and hypolipidemic properties. These properties are largely because of its abundant bioactive compounds and phytochemicals. Over the years, numerous studies have confirmed the regulatory effects of MC extract on glycolipid metabolism. However, there is a lack of comprehensive reviews on newly discovered MC-related components, such as insulin receptor-binding protein-19, adMc1, and MC protein-30 and triterpenoids 3ß,7ß,25-trihydroxycucurbita-5,23(E)-dien-19-al, and the role of MC in gut microbiota and bitter taste receptors. This review offers an up-to-date overview of the recently reported chemical compositions of MC, including polysaccharides, saponins, polyphenolics, peptides, and their beneficial effects. It also provides the latest updates on the role of MC in the regulation of gut microbiota and bitter taste receptor signaling pathways. As a result, this review will serve as a theoretical basis for potential applications in the creation or modification of MC-based nutrient supplements.

Piceatannol, a Dietary Polyphenol, Alleviates Adipose Tissue Loss in Pre-Clinical Model of Cancer-Associated Cachexia via Lipolysis Inhibition.

Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC in vivo. Piceatannol reduced cancer-associated lipolysis by at least 50% in both CCM and cytokine-induced lipolysis in vitro. Further gene and protein analysis confirmed that piceatannol modulated the stability of lipolytic proteins. Moreover, piceatannol protected tumor-bearing mice against weight-loss in early stages of CAC largely through preserving adipose tissue, with no effect on survival. This study demonstrates the use of a dietary compound to preserve adipose in models of early stage CAC and provides groundwork for further investigation of piceatannol or piceatannol-rich foods as alternative medicine in the preservation of body fat mass and future CAC therapy.

Oxidative Stress Protection by Canary Seed (Phalaris canariensis L.) Peptides in Caco-2 Cells and Caenorhabditis elegans.

During oxidative stress, degenerative diseases such as atherosclerosis, Alzheimer's, and certain cancers are likely to develop. Recent research on canary seed (Phalaris canariensis) peptides has demonstrated the high in vitro antioxidant potential. Thus, this study aimed to assess the cellular and in vivo antioxidant capacity of a low-molecular-weight (<3 kDa) canary seed peptide fraction (CSPF) using Caco-2 cells and the Caenorhabditis elegans model. The results show that the CSPF had no cytotoxicity effect on Caco-2 cells at any tested concentration (0.3−2.5 mg/mL). Additionally, the cellular antioxidant activity (CAA) of the CSPF was concentration-dependent, and the highest activity achieved was 80% by the CSPF at 2.5 mg/mL. Similarly, incubation with the CSPF significantly mitigated the acute and chronic oxidative damage, extending the lifespan of the nematodes by 88 and 61%, respectively. Furthermore, it was demonstrated that the CSPF reduced the accumulation of reactive oxygen species (ROS) to safe levels after sub-lethal doses of pro-oxidant paraquat. Quantitative real-time PCR revealed that the CSPF increased the expression of oxidative-stress-response-related gene GST-4. Overall, these results show that the CSPFs relied on GST-4 upregulation and scavenging of free radicals to confer oxidative stress protection and suggest that a CSPF can be used as a natural antioxidant in foods for health applications.

Pharmacological inhibition of acyl-coenzyme A:cholesterol acyltransferase alleviates obesity and insulin resistance in diet-induced obese mice by regulating food intake.

BACKGROUND/OBJECTIVES: Acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyze the formation of cholesteryl ester (CE) from free cholesterol to regulate intracellular cholesterol homeostasis. Despite the well-documented role of ACATs in hypercholesterolemia and their emerging role in cancer and Alzheimer's disease, the role of ACATs in adipose lipid metabolism and obesity is poorly understood. Herein, we investigated the therapeutic potential of pharmacological inhibition of ACATs in obesity. METHODS: We administrated avasimibe, an ACAT inhibitor, or vehicle to high-fat diet-induced obese (DIO) mice via intraperitoneal injection and evaluated adiposity, food intake, energy expenditure, and glucose homeostasis. Moreover, we examined the effect of avasimibe on the expressions of the genes in adipogenesis, lipogenesis, inflammation and adipose pathology in adipose tissue by real-time PCR. We also performed a pair feeding study to determine the mechanism for body weight lowering effect of avasimibe. RESULTS: Avasimibe treatment markedly decreased body weight, body fat content and food intake with increased energy expenditure in DIO mice. Avasimibe treatment significantly lowered blood levels of glucose and insulin, and improved glucose tolerance in obese mice. The beneficial effects of avasimibe were associated with lower levels of adipocyte-specific genes in adipose tissue and the suppression of food intake. Using a pair-feeding study, we further demonstrated that avasimibe-promoted weight loss is attributed mainly to the reduction of food intake. CONCLUSIONS: These results indicate that avasimibe ameliorates obesity and its-related insulin resistance in DIO mice through, at least in part, suppression of food intake.

Piceatannol attenuates fat accumulation and oxidative stress in steatosis-induced HepG2 cells.

Non-alcoholic fatty liver disease (NAFLD), which affects over 20% of the adult population, is the most common liver disease worldwide and can progress to inflammatory hepatitis, cirrhosis and liver cancer. The need to alleviate NAFLD is imperative, but there are limited pharmacological therapies available. Based on previous reports that piceatannol, a stilbenoid metabolite of resveratrol, exhibits anti-obesity, antioxidant and anti-inflammatory effects, the goal of this study was to determine the efficacy of piceatannol on prevention and/or treatment of NAFLD. The results showed that piceatannol significantly decreased fat accumulation and suppressed lipogenesis and fatty acids (FAs) uptake by decreasing sterol regulatory element-binding protein 1 (SREBP1) and cluster of differentiation 36 (CD36) in steatosis-induced HepG2 hepatocytes. Piceatannol treatment also promoted FAs ß-oxidation by increasing farnesoid X receptor (FXR), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyltransferase 1α (CPT1α) under steatosis conditions. Moreover, piceatannol significantly suppressed FA-induced oxidative stress and inhibited phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases 1/2 (ERK1/2). Overall, it is suggested that piceatannol reduced fat accumulation in steatosis-induced HepG2 cells by suppressing lipogenesis (SREBP1 and ACC) and FA uptake (CD36), and promoting FAs oxidation (FXR, PPARα and CPT1α).

Butein inhibits lipogenesis in Caenorhabditis elegans.

Butein, a flavonoid found in annatto seeds and lacquer trees, may be used for many health benefits, including the prevention of obesity. However, its anti-obesity effects are not completely understood; in particular, the effects of butein on the regulation of lipid metabolism have not been explained. Thus, the goal of the current study was to determine the effects of butein on lipid metabolism in Caenorhabditis elegans, which is a multi-organ nematode used as an animal model in obesity research. Butein at 70 µM reduced triglyceride content by 27% compared to the control without altering food intake and energy expenditure. The reduced triglyceride content by butein was associated with the downregulation of sbp-1, fasn-1, and fat-7, the lipogenesis-related homologs of sterol regulatory element-binding proteins, fatty acid synthase and stearoyl-CoA desaturase, respectively. Furthermore, fat-7 and skn-1, a homolog of nuclear respiratory factors, were identified as genetic requirements for butein's effects on triglyceride content in C. elegans. The effects of butein on sbp-1 and fasn-1 were dependent on skn-1, but the downregulation of fat-7 was independent of skn-1. These results suggest that the inhibitory effects of butein on lipogenesis are via SKN-1- and FAT-7-dependent pathways in C. elegans.

C. elegans ACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF-1 signaling.

Overly active acyl-coenzyme A: cholesterol acyltransferases (ACATs) are known to contribute to the development of atherosclerosis, cancer cell proliferation and de novo lipogenesis. However, the role of ACAT in systemic lipid metabolism and its consequence of aging is unknown. Using avasimibe, a clinically proven ACAT inhibitor, and mboa-1 mutant strain, a homologous to mammalian ACAT, herein, we found that Ava treatment and mboa-1 mutant exhibited a decreased fat accumulation during feeding and increased lipolysis with extended lifespan of C. elegans during fasting. Our study highlights the essential role of ACAT inhibitor and mboa-1 in fat mobilization and the survival of C. elegans in fasting through the modulation of the genes involved in lipolysis and insulin/IGF-1 signaling.

Antioxidant Capacity of Thistle (Cirsium japonicum) in Various Drying Methods and their Protection Effect on Neuronal PC12 Cells and Caenorhabditis elegans.

The aim of this study was, firstly, to evaluate the phenol profile of thistle (Cirsium japonicum, CJ) by High performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS), dried by different methods (90 °C hot-air, 70 °C hot-air, shade-, and freeze-drying). Secondly, we aimed to evaluate the relationship between phenolic compounds content and antioxidant properties. CJ contained chlorogenic acid, linarin, and pectolinarin. Total phenolic contents of CJ significantly decreased under hot-air-drying condition, especially chlorogenic acid contents in CJ have been reduced by 85% and 60% for 90 °C and 70 °C hot-air-drying, respectively. We evaluated the protective effect on adrenal pheochromocytoma (PC12) cells and Caenorhabditis elegans using shade-dried CJ, which has the largest phenolic contents and the strongest antioxidant property. CJ-treated PC 12 cells dose-dependently exhibited the protective effects against reactive oxygen species (ROS), while cell viability increases, lactate dehydrogenase release decreases, and ROS formation decreases. Furthermore, CJ has also shown protection against ROS in C. elegans. Consequently, CJ contributed to lifespan extension under ROS stress without influencing the physiological growth.

trans-Trismethoxy resveratrol decreased fat accumulation dependent on fat-6 and fat-7 in Caenorhabditis elegans.

trans-Trismethoxy resveratrol (TMR) is a methyl analog of resveratrol. It is found to exhibit enhanced biological effects compared to resveratrol, such as inhibition of cancer cell growth and pro-apoptotic activities. However, the role of TMR in lipid metabolism is not fully understood. In this study, we used Caenorhabditis elegans, an in vivo nematode model which has been widely applied in disease research, including research on obesity, to investigate the effect of TMR on lipid metabolism. Treatment with TMR (100 and 200 µM) for 4 days significantly reduced triglyceride accumulation (14% and 20% reduction over the control, respectively) of C. elegans, without affecting nematode growth, food intake and reproduction. Treatment with TMR significantly downregulated stearoyl-CoA desaturase genes, fat-6 and fat-7, accompanied by a decrease in the desaturation index of fatty acids, the ratio of oleic acid to stearic acid. These results suggest that TMR inhibits fat accumulation by downregulating stearoyl-CoA desaturase in C. elegans.

3,3'-Diindolylmethane suppresses high-fat diet-induced obesity through inhibiting adipogenesis of pre-adipocytes by targeting USP2 activity.

SCOPE: Indole-3-carbinol (I3C), a derivative abundant in cruciferous vegetables such as cabbage, is well known for its various health benefits such as chemo-preventive and anti-obesity effects. I3C is easily metabolized to 3,3'-diindolylmethane (DIM), a more stable form, in acidic conditions of the stomach. However, the anti-obesity effect of DIM has not been investigated clearly. We sought to investigate the effect of DIM on diet-induced obesity and to elucidate its underlying mechanisms. METHODS AND RESULTS: High-fat diet (HFD)-fed obese mouse and MDI-induced 3T3-L1 adipogenesis models were used to study the effect of DIM. We observed that the administration of DIM (50 mg/kg BW) significantly suppressed HFD-induced obesity, associated with a decrease in adipose tissue. Additionally, we observed that DIM treatment (40 and 60 µM), but not I3C treatment, significantly inhibited MDI-induced adipogenesis by reducing the levels of several adipogenic proteins such as PPAR-γ and C/EBPα. DIM, but not I3C, suppressed cell cycle progression in the G1 phase, which occurred in the early stage of adipogenesis, inducing post-translational degradation of cyclin D1 by inhibiting ubiquitin specific peptidase 2 (USP2) activities. CONCLUSION: Our findings indicate that cruciferous vegetables, which can produce DIM as a metabolite, have the potential to prevent or treat chronic obesity.

The Therapeutic Potential of Piceatannol, a Natural Stilbene, in Metabolic Diseases: A Review.

Metabolic disease comprises a set of risk factors highly associated with obesity and insulin resistance and is a consequence of central adiposity, hyperglycemia, and dyslipidemia. Furthermore, obesity increases the risk of the development of metabolic disease due to ectopic fat deposition, low-grade inflammation, and systemic energy disorders caused by dysregulated adipose tissue function. Piceatannol is a naturally occurring polyphenolic stilbene found in various fruits and vegetables and has been reported to exhibit anticancer and anti-inflammatory properties. In addition, recently reported beneficial effects of piceatannol on hypercholesterolemia, atherosclerosis, and angiogenesis underscore its therapeutic potential in cardiovascular disease. However, investigation of its role in metabolic disease is still in its infancy. This review intensively summarizes in vitro and in vivo studies supporting the potential therapeutic effects of piceatannol in metabolic disease, including inhibition of adipogenesis and lipid metabolism in adipocytes, and regulation of hyperlipidemia, hyperglycemia, insulin resistance, and fatty acid-induced inflammation and oxidative stress.

Overexpression of Pref-1 in pancreatic islet ß-cells in mice causes hyperinsulinemia with increased islet mass and insulin secretion.

Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet ß-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets in vivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet ß-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet ß-cells and insulin production.

Caffeic acid phenethyl ester, a major component of propolis, suppresses high fat diet-induced obesity through inhibiting adipogenesis at the mitotic clonal expansion stage.

In the present study, we aimed to investigate the antiobesity effect of CAPE in vivo, and the mechanism by which CAPE regulates body weight in vitro. To confirm the antiobesity effect of CAPE in vivo, mice were fed with a high fat diet (HFD) with different concentrations of CAPE for 5 weeks. CAPE significantly reduced body weight gain and epididymal fat mass in obese mice fed a HFD. In accordance with in vivo results, Oil red O staining results showed that CAPE significantly suppressed MDI-induced adipogenesis of 3T3-L1 preadipocytes. FACS analysis results showed that CAPE delayed MDI-stimulated cell cycle progression, thereby contributing to inhibit mitotic clonal expansion (MCE), which is a prerequisite step for adipogenesis. Also, CAPE regulated the expression of cyclin D1 and the phosphorylation of ERK and Akt, which are upstream of cyclin D1. These results suggest that CAPE exerts an antiobesity effect in vivo, presumably through inhibiting adipogenesis at an early stage of adipogenesis.

Reversine increases the plasticity of lineage-committed preadipocytes to osteogenesis by inhibiting adipogenesis through induction of TGF-ß pathway in vitro.

Reversine has been reported to reverse differentiation of lineage-committed cells to mesenchymal stem cells (MSCs), which then enables them to be differentiated into other various lineages. Both adipocytes and osteoblasts are known to originate from common MSCs, and the balance between adipogenesis and osteogenesis in MSCs is reported to modulate the progression of various human diseases, such as obesity and osteoporosis. However, the role of reversine in modulating the adipogenic potential of lineage-committed preadipocytes and their plasticity to osteogenesis is unclear. Here we report that reversine has an anti-adipogenic function in 3T3-L1 preadipocytes in vitro and alters cell morphology and viability. The transforming growth factor-ß (TGF-ß) pathway appears to be required for the anti-adipogenic effect of reversine, due to reversine-induced expression of genes involved in TGF-ß pathway and reversal of reversine-inhibited adipogenesis by inhibition of TGF-ß pathway. We show that treatment with reversine transformed 3T3-L1 preadipocytes into MSC-like cells, as evidenced by the expression of MSCs marker genes. This, in turn, allowed differentiation of lineage-committed 3T3-L1 preadipocytes to osteoblasts under the osteogenic condition in vitro. Collectively, these findings reveal a new function of reversine in reversing lineage-committed preadipocytes to osteogenesis in vitro, and provide new insights into adipose tissue-based regeneration of osteoblasts.

Curcumin prevents leptin-induced tight junction dysfunction in intestinal Caco-2 BBe cells.

Maintaining tight junction (TJ) integrity in the intestine is critical for nutrient absorption, host defense, and host immunity. While leptin secreted from adipose tissue is associated with obesity and obesity-related intestinal inflammation, the role of luminal leptin in intestinal TJ function is elusive. Here, we examined the role of leptin in intestinal TJ function in Caco-2 BBe cells and further explored the function of curcumin (CCM) in leptin-induced TJ dysfunction. Apical leptin, but not basolateral leptin, treatment at a concentration of 100 ng/ml deteriorated TJ function in Caco-2 BBe cells. Leptin-impaired TJ alteration was resulted from induction of leptin receptor-dependent JAK2/STAT3 signaling pathway and its-related PI3K/Akt/ERK1/2 signaling pathways. Apical leptin also lowered the expression levels of genes encoding TJ-associated proteins such as zonula occludens-3, claudin-5, and occludin, and elevated expression of pro-inflammatory genes such as IL-6 and TNF-α. Leptin-impaired TJ junction in Caco-2 BBe cells was blunted by a 30-min CCM pretreatment through inhibition of leptin receptor-dependent signaling pathway, and its-associated induction of expression of genes encoding TJ-associated proteins and pro-inflammatory cytokines. Our results elucidate a novel function of luminal leptin in intestinal TJ dysfunction, and further identify CCM as an effective dietary compound that prevents leptin-impaired TJ function in intestinal cells.

A metabolite of daidzein, 6,7,4'-trihydroxyisoflavone, suppresses adipogenesis in 3T3-L1 preadipocytes via ATP-competitive inhibition of PI3K.

SCOPE: Daidzein is one of the major soy isoflavones. Following ingestion, daidzein is readily metabolized in the liver and converted into hydroxylated metabolites. One such metabolite is 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), which has been the focus of recent studies due to its various health benefits, however, its anti-adipogenic activity has not been investigated. Our objective was to determine the effects of 6,7,4'-THIF on adipogenesis in 3T3-L1 preadipocytes and elucidate the mechanisms of action involved. METHODS AND RESULTS: Adipogenesis was stimulated in 3T3-L1 preadipocytes. Both 6,7,4'-THIF and daidzein were treated in the presence and absence of mixture of isobutylmethylxanthine, dexamethasone, and insulin (MDI). We observed that 6,7,4'-THIF, but not daidzein, inhibited MDI-induced adipogenesis significantly at 40 and 80 µM, associated with decreased peroxisome proliferator-activated receptor-γ and C/EBP-α protein expression. 6,7,4'-THIF significantly suppressed MDI-induced lipid accumulation in the early stage of adipogenesis, attributable to a suppression of cell proliferation and the induction of cell cycle arrest. We also determined that 6,7,4'-THIF, but not daidzein, attenuated phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. 6,7,4'-THIF was found to inhibit PI3K activity via direct binding in an ATP-competitive manner. CONCLUSION: Our results suggest that 6,7,4'-THIF suppresses adipogenesis in 3T3-L1 preadipocytes by directly targeting PI3K. Soy isoflavones like 6,7,4'-THIF may have potential for development into novel treatment strategies for chronic obesity.

An advanced glycation end product (AGE)-receptor for AGEs (RAGE) axis restores adipogenic potential of senescent preadipocytes through modulation of p53 protein function.

The impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. Although advanced glycation end products (AGEs) derived from both foods and endogenous nonenzymatic glycation and AGE-associated signaling pathways are known to play a key role in aging and its related diseases, the role of AGEs in adipose aging remains elusive. We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes and mouse embryonic fibroblasts, as well as primary preadipocytes isolated from aged mice. Using glycated bovine serum albumin (BSA) as a model protein of AGEs, we found that glycated BSA restores the impaired adipogenic potential of senescent preadipocytes in vitro and ex vivo. However, glycated BSA showed no effect on adipogenesis in nonsenescent preadipocytes. The AGE-induced receptor for AGE (RAGE) expression is required for the pro-adipogenic function of AGEs in senescent preadipocytes. RAGE is required for impairment of p53 expression and p53 function in regulating p21 expression in senescent preadipocytes. We also observed a direct binding between RAGE and p53 in senescent preadipocytes. Taken together, our findings reveal a novel pro-adipogenic function of the AGE-RAGE axis in p53-regulated adipogenesis of senescent preadipocytes, providing new insights into aging-dependent adiposity by diet-driven and/or endogenous glycated proteins.

An inhibitory effect of resveratrol in the mitotic clonal expansion and insulin signaling pathway in the early phase of adipogenesis.

Resveratrol is known as a potent antiobesity compound that acts partly through inhibition of adipogenesis. However, the direct targets responsible for its antiadipogenic action are unclear. Our hypothesis is that resveratrol inhibits adipogenesis through modulation of mitotic clonal expansion (MCE) and cell signaling pathways in the early phase of differentiation. To test this, we examined the effects of resveratrol on MCE and insulin signaling pathway in the early phase of adipogenesis in murine preadipocytes. We observed that the antiadipogenic action of resveratrol is largely limited to the early phase of adipogenesis. Specifically, the presence of resveratrol in the first 24 hours of adipogenesis was required for its antiadipogenic effect. During the first 24 hours of adipogenesis, resveratrol impaired the progression of MCE by suppressing the cell cycle entry of preadipocytes to G2/M phase, and expression of cell cycle regulators cyclin A and cyclin-dependent kinase 2. Concomitantly, resveratrol inhibited insulin signaling pathway in the early phase of adipogenesis. Furthermore, we revealed an inhibitory effect of resveratrol on insulin receptor (IR) activity, and this is likely through a direct physical interaction between resveratrol and IR. The antiadipogenic effect of resveratrol is through inhibition of the MCE and IR-dependent insulin signaling pathway in the early phase of adipogenesis.

Selenate inhibits adipogenesis through induction of transforming growth factor-ß1 (TGF-ß1) signaling.

Selenium is essential for many aspects of human health. While selenium is known to protect against cancer and cardiovascular diseases, the role of selenium in adipose development is unknown. Here we show that selenate at non-toxic concentration exhibits an anti-adipogenic function in vitro and ex vivo. In addition, selenate induced a morphological change of these cells from fibroblast-like to spindle cell shape. However, other forms of selenium, including selenite and methylseleninic acid, showed either toxic or no effect on adipogenesis and morphology change of preadipocytes. The effects of selenate on adipogenesis and cell morphology change were blunted by the treatment with SB431542, a specific inhibitor of transforming growth factor-ß1 (TGF-ß1) receptor, neutralization TGF-ß1 by its antibody, and knockdown of TGF-ß1 in preadipocytes, suggesting a requirement of TGF-ß signaling for the anti-adipogenic function of selenate. Among tested forms of selenium, selenate appears to be an effective activator of TGF-ß1 expression in preadipocytes. These results indicate that selenate is a novel dietary micromineral that activates TGF-ß1 signaling in preadipocytes and modulates adipogenesis.