Key Adipogenic Transcription Factors Research Articles

Ketone bodies promote epididymal white adipose expansion to alleviate liver steatosis in response to a ketogenic diet

Liver can sense the nutrient status and send signals to other organs to regulate overall metabolic homoeostasis. Herein, we demonstrate that ketone bodies act as signals released from the liver that specifically determine the distribution of excess lipid in epididymal white adipose tissue (eWAT) when exposed to a ketogenic diet (KD). An acute KD can immediately result in excess lipid deposition in the liver. Subsequently, the liver sends the ketone body β-hydroxybutyrate (BHB) to regulate white adipose expansion, including adipogenesis and lipogenesis, to alleviate hepatic lipid accumulation. When ketone bodies are depleted by deleting 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) gene in liver, the enhanced lipid deposition in eWAT but not in inguinal white adipose tissue (iWAT) is preferentially blocked, while lipid accumulation in liver is not alleviated. Mechanistically, ketone body BHB can significantly decrease lysine acetylation of peroxisome proliferator-activated receptor gamma (PPARγ) in eWAT, causing enhanced activity of PPARγ, the key adipogenic transcription factor. These observations suggest that the liver senses metabolic stress first and sends a corresponding signal, that is, ketone body BHB, to specifically promote eWAT expansion to adapt to metabolic challenges.

Endoplasmic Reticulum Stress and Its Impact on Adipogenesis: Molecular Mechanisms Implicated.

Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress has the potential to disrupt the signaling of the unfolded protein response (UPR), thereby influencing adipogenesis. This comprehensive review illuminates the molecular mechanisms that underpin the interplay between ER stress and adipogenesis. We delve into the dysregulation of UPR pathways, namely, IRE1-XBP1, PERK and ATF6 in relation to adipocyte differentiation, lipid metabolism, and tissue inflammation. Moreover, we scrutinize how ER stress impacts key adipogenic transcription factors such as proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) along with their interaction with other signaling pathways. The cellular ramifications include alterations in lipid metabolism, dysregulation of adipokines, and aged adipose tissue inflammation. We also discuss the potential roles the molecular chaperones cyclophilin A and cyclophilin B play in adipogenesis. By shedding light on the intricate relationship between ER stress and adipogenesis, this review paves the way for devising innovative therapeutic interventions.

Sangyod rice extract inhibits adipocyte growth and differentiation via mTOR, Akt, and AMPK pathways

This study aimed to evaluate Sangyod rice extract (SRE) in two aspects: its effect on 3T3-L1 cell proliferation during early adipocyte differentiation and its anti-adipogenic properties. Initially, SRE reduced 3T3-L1 preadipocyte proliferation by downregulating mTOR and Akt expression. In later stages, it significantly inhibited adipogenesis, lowering lipid accumulation and triglyceride levels. SRE achieved these effects by suppressing key adipogenic transcription factors (PPAR-γ, C/EBPα, C/EBPβ, SREBP-1c, SREBP-2) and lipogenic genes (perilipin, aP2, ACC, FasN, LPL, HSL, ATGL), as well as adipokine genes (leptin, resistin, AdipoQ, AdipoQ-R1, AdipoQ-R2). AMPK activation played a crucial role in SRE's mechanism, hindering adipogenesis. Moreover, SRE was found to decrease glucose uptake by suppressing the gene expression of glucose transporter 4 (Glut4) and the insulin receptor (IsnR). This research highlights the potential of SRE as an anti-obesity agent, particularly in alleviating insulin resistance and obesity. This suggests that SRE could be formulated into a functional food product with these advantageous properties.

Chrysin inhibits adipogenesis by modulating PPARγ: in silico and in vitro studies

Adipose tissue is the major storage site of lipids and plays a vital role in energy homeostasis. Adipogenesis is a well-regulated process wherein preadipocytes differentiate into adipocytes. It requires the sequential activation of numerous transcription factors, including peroxisome proliferator activated receptor-γ (PPAR-γ). Phytochemicals have been reported to regulate adipogenesis and flavonoids represent the most researched groups of phytochemicals with regard to their effect on adipogenesis. Chrysin is a naturally occurring flavone and is reported to have anti-inflammatory effects in obese conditions. The present study was aimed to examine the effect of chrysin on adipogenesis. In silico Molecular docking, dynamic simulation studies and in vitro cell-based assays showed that chrysin inhibited adipogenesis by modulating key adipogenic transcription factor PPARγ. Enhanced adipogenesis leads to obesity and targeting adipogenesis is potential in regulating adipose tissue development. So, these investigations may provide important information for designing therapeutic interventions to control adiposity. Communicated by Ramaswamy H. Sarma

Standardized pectolinarin rich-Cirsium setidens Nakai extract attenuates bisphenol A-induced the 3T3-L1 adipocytes differentiation and obese C57BL/6J mice via the suppression of adipogenesis-related transcription factors

Endocrine-disrupting chemicals (EDCs), called obesogens, play an important role in obesity by mimicking or disrupting bioidentical hormones. In this study, we determined the obesogenic effect of bisphenol A (BPA) and evaluated the anti-obesogenic effects of a standardized Cirsium setidens Nakai ethanolic extract (CNE) as a functional food ingredient on the lipid accumulation and expression of key adipogenic transcription factors (ATFs) in 3 T3-L1 adipocytes and C57BL/6J mice. The underlying mechanism of the obesogenic effect of BPA was confirmed using the peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662. In addition, the anti-obesogenic effects of CNE were confirmed by measuring the lipid accumulation, reactive oxygen species (ROS) production, body and adipose tissue weights, and the adipogenesis- and lipogenesis-related proteins in BPA-induced 3T3-L1 adipocytes and obese mice. These findings indicate that CNE could potentially be used as a promising natural means to prevent BPA-induced obesity and obesity-related metabolic diseases.

1,3,5,8-Tetrahydroxyxanthone suppressed adipogenesis via activating Hedgehog signaling in 3T3-L1 adipocytes.

In this study, we investigated the effect of 1,3,5,8-tetrahydroxyxanthone (THX) on the adipogenesis of 3T3-L1 adipocytes. THX, a xanthone isolated from Gentianella acuta, inhibited lipid accumulation in 3T3-L1 adipocytes and reduced the protein levels of the key adipogenic transcriptional factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in a dose-dependent manner. In addition, THX enhanced the transcriptional activity of Gli1 known as the key indicator of Hedgehog (Hh) signaling activity and increased the expression of Gli1 and its upstream regulator Smo. The Smo activator SAG exerted the similar effect with THX on regulating Gli1, Smo, PPARγ and C/EBPα expression, which led to the suppression of fat formation in 3T3-L1 adipocytes. Furthermore, we found that the inhibitory effect of THX on adipogenesis was derived from regulation of the early stage of adipogenesis. These results suggest that THX suppresses the differentiation of adipocyte through Hh signaling and may be considered as a potent agent for the prevention of obesity.

Derhamnosylmaysin Inhibits Adipogenesis via Inhibiting Expression of PPARγ and C/EBPα in 3T3-L1 Cells.

We investigated the effects of derhamnosylmaysin (DM) on adipogenesis and lipid accumulation in 3T3-L1 adipocytes. Our data showed that DM inhibited lipid accumulation and adipocyte differentiation in 3T3-L1 cells. Treatment of 3T3-L1 adipocytes with DM decreased the expression of major transcription factors, such as sterol regulatory element-binding protein-1c (SREBP-1c), the CCAAT-enhancer-binding protein (CEBP) family, and peroxisome proliferator-activated receptor gamma (PPARγ), in the regulation of adipocyte differentiation. Moreover, the expression of their downstream target genes related to adipogenesis and lipogenesis, including adipocyte fatty acid-binding protein (aP2), lipoprotein lipase (LPL), stearyl-CoA-desaturase-1 (SCD-1), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS), was also decreased by treatment with DM during adipogenesis. Additionally, DM attenuated insulin-stimulated phosphorylation of Akt. These results first demonstrated that DM inhibited adipogenesis and lipogenesis through downregulation of the key adipogenic transcription factors SREBP-1c, the CEBP family, and PPARγ and inactivation of the major adipogenesis signaling factor Akt, which is intermediated in insulin. These studies demonstrated that DM is a new bioactive compound for antiadipogenic reagents for controlling overweight and obesity.

Bio-Waste Products of Mangifera indica L. Reduce Adipogenesis and Exert Antioxidant Effects on 3T3-L1 Cells.

Several studies highlighted the beneficial value of natural compounds in the prevention and treatment of obesity. Here, we investigated the anti-obesity effects of extracts of peel and seed of mango (Mangifera indica L.) cultivated in Sicily (Italy) in 3T3-L1 cells. Mango Peel (MPE) and Mango Seed (MSE) extracts at a 100 µg/mL concentration significantly reduced lipid accumulation and triacylglycerol contents during 3T3-L1 adipocyte differentiation without toxicity. HPLC-ESI-MS analysis showed that both the extracts contain some polyphenolic compounds that can account for the observed biological effects. The anti-adipogenic effect of MPE and MSE was the result of down-regulation of the key adipogenic transcription factor PPARγ and its downstream targets FABP4/aP2, GLUT4 and Adipsin, as well SREBP-1c, a transcription factor which promotes lipogenesis. In addition, both MPE and MSE significantly activated AMPK with the consequent inhibition of Acetyl-CoA-carboxylase (ACC) and up-regulated PPARα. The addition of compound C, a specific AMPK inhibitor, reduced the effects of MPE and MSE on AMPK and ACC phosphorylation, suggesting a role of AMPK in mediating MPE and MSE anti-lipogenic effects. Notably, MPE and MSE possess an elevated radical scavenging activity, as demonstrated by DPPH radical scavenging assay, and reduced ROS content produced during adipocyte differentiation. This last effect could be a consequence of the increase in the antioxidant factors Nrf2, MnSOD and HO-1. In conclusion, MPE and MSE possesses both anti-adipogenic and antioxidant potential, thus suggesting that the bio-waste products of mango are promising anti-obesity natural compounds.

Disulfiram Exerts Antiadipogenic, Anti-Inflammatory, and Antifibrotic Therapeutic Effects in anIn VitroModel of Graves' Orbitopathy

Background: Adipogenesis, glycosaminoglycan hyaluronan (HA) production, inflammation, and fibrosis are the main pathogenic mechanisms responsible for Graves' orbitopathy (GO). We hypothesized that disulfiram (DSF), an aldehyde dehydrogenase (ALDH) inhibitor used to treat alcoholism, would have therapeutic effects on orbital fibroblasts (OFs) in GO. This study aimed at determining the therapeutic effects and underlying mechanisms of DSF on these parameters. Methods: Primary cultures of OFs from six GO patients and six control subjects were established. The OFs were allowed to differentiate into adipocytes and treated with various concentrations of DSF. Lipid accumulation within the cells was evaluated by Oil Red O staining. Real-time polymerase chain reaction (RT-PCR) and Western blotting were used to measure the expression of key adipogenic transcription factors, ALDH1A1, ALDH2, and mitogen-activated protein kinase (MAPK) signaling proteins. Apoptosis assays and reactive oxygen species levels were evaluated by flow cytometry. HA production was measured by using an enzyme-linked immunosorbent assay (ELISA) kit. The mRNA levels of proinflammatory molecules were measured by using RT-PCR after interleukin (IL)-1β stimulation with or without DSF. The mRNA expression of markers associated with fibrosis was examined by using RT-PCR after transforming growth factor (TGF)-β1 stimulation with or without DSF. The wound-healing assay was assessed by phase-contrast microscopy. Results: Under identical adipogenesis conditions, GO OFs effectively differentiated, while normal control (NC) OFs did not. DSF dose dependently suppressed lipid accumulation during adipogenesis in GO OFs. The expression of key adipogenic transcription factors, such as perilipin-1 (PLIN1), PPARγ (PPARG), FABP4, and c/EBPα (CEBPA), was downregulated. Further, DSF inhibited the phosphorylation of ERK by inhibiting ALDH1A1. In addition, DSF attenuated HA production and suppressed inflammatory molecule expression induced by IL-1β in GO OFs and NC OFs. The antifibrotic effects of DSF on TGF-β1 were also observed in GO OFs. Conclusions: In the current study, we provide evidence of the inhibitory effect of DSF on GO OFs adipogenesis, HA production, inflammation, and fibrosis in vitro. The results of this study are noteworthy and indicate the potential use of DSF as a therapeutic agent for the treatment of GO.

β-Carotene stimulates browning of 3T3-L1 white adipocytes by enhancing thermogenesis via the β3-AR/p38 MAPK/SIRT signaling pathway

BackgroundNatural compounds with medicinal properties are part of a strategic trend in the treatment of obesity. The vitamin A agent, β-carotene, is a well-known carotenoid, and its numerous functions in metabolism have been widely studied. The activation of thermogenesis by stimulating white fat browning (beiging) has been identified as a treatment for obese individuals. PurposeThe current study was undertaken to unveil the browning activity of β-carotene in 3T3-L1 white adipocytes. MethodsThe effects of β-carotene were evaluated in 3T3-L1 white adipocytes, and gene/protein expressions were determined by performing quantitative real-time PCR, immunoblot analysis, immunofluorescence assessment, and molecular docking techniques. Resultsβ-carotene strikingly increased the expression levels of brown-fat-specific marker proteins (UCP1, PRDM16, and PGC-1α) and beige-fat-specific genes (Cd137, Cidea, Cited1, andTbx1) in 3T3-L1 cells. Exposure to β-carotene also elevated the expressions of key adipogenic transcription factors C/EBPα and PPARγ in white adipocytes but decreased the expressions of lipogenic marker proteins ACC and FAS. Moreover, lipolysis and fat oxidation were regulated by β-carotene via upregulation of ATGL, pHSL, ACOX, and CPT1. In addition, molecular docking studies revealed β-carotene activation of the adenosine A2A receptor and β3-AR. β-Carotene increased the expressions of mitochondrial biogenic markers, stimulated the β3-AR and p38 MAPK signaling pathways and its downstream signaling molecules (SIRTs and ATF2), thereby inducing browning. ConclusionsTaken together, our results indicate the potential of β-carotene as a natural-source therapeutic anti-obesity agent.

Myostatin suppresses adipogenic differentiation and lipid accumulation by activating crosstalk between ERK1/2 and PKA signaling pathways in porcine subcutaneous preadipocytes.

The current study was undertaken to determine the effect of myostatin (MSTN) on lipid accumulation in porcine subcutaneous preadipocytes (PSPAs) and to further explore the potential molecular mechanisms. PSPAs isolated from Meishan weaned piglets were added with various concentrations of MSTN recombinant protein during the entire period of adipogenic differentiation process. Results showed that MSTN treatment significantly reduced the lipid accumulation, intracellular triglyceride (TG) content, glucose consumption, and glycerol phosphate dehydrogenase activity, while increased glycerol and free fatty acid release. Consistent with above results, the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway was obviously activated and thus key adipogenic transcription factors peroxisome proliferator-activated receptor-gamma (PPAR-γ), CCAAT/enhancer-binding protein-alpha (C/EBP-α), and their downstream enzymes fatty acid synthase and acetyl-CoA carboxylase were all inhibited. However, chemical inhibition of ERK1/2 signaling pathway by PD98059 markedly reversed the decreased TG content by increasing PPAR-γ expression. In addition, MSTN activated the cyclic AMP/protein kinase A (cAMP/PKA) pathway and stimulated lipolysis by reducing the expression of antilipolytic gene perilipin, thus elevated key lipolytic enzymes adipose triglyceride lipase and hormone-sensitive lipase (HSL) expression and enzyme activity. On the contrary, pretreatment with PKA inhibitor H89 significantly reversed TG accumulation by increasing PPAR-γ expression and thus inhibiting ERK1/2, perilipin, and HSL phosphorylation, supporting the crosstalk between PKA and ERK1/2 pathways in both the anti-adipogenic and pro-lipolytic effects. In summary, our results suggested that MSTN suppressed adipogenesis and stimulated lipolysis, which was mainly mediated by activating crosstalk of ERK1/2 and PKA signaling pathways, and consequently decreased lipid accumulation in PSPAs, our findings may provide novel insights for further exploring MSTN as a potent inhibitor of porcine subcutaneous lipid accumulation.

Ziziphus jujuba Mill. leaf extract restrains adipogenesis by targeting PI3K/AKT signaling pathway

The escalation in the global prevalence of obesity has focused attention on finding novel approaches for its management. Ziziphus jujuba Mill. (ZJL) leaf extract is reported as a traditional remedy for diverse pathological conditions, including obesity. The present study investigated whether ZJL affects adipogenic differentiation in human adipocytes. Additionally, following metabolite profiling of the extract, apigenin (APG), betulinic acid (BA) and maslinic acid (MA) were selected for biological activity evaluation. The possible interactions between APG, BA, MA and target proteins with a central role in adipogenesis were assessed through molecular docking. The potential mechanisms of ZJL, APG, BA and MA were identified using transcriptional analysis through real-time quantitative PCR and protein abundance evaluation by Western blotting. The obtained results revealed a concentration-dependent reduction of accumulated lipids after ZJL, BA and MA application. The key adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα) were strongly decreased at a protein level by all treatments. Moreover, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was found to be involved in the anti-adipogenic effect of ZJL, APG and BA. Collectively, our findings indicate that ZJL and its pure compounds hampered adipocyte differentiation through PI3K/AKT inhibition. Among the selected compounds, BA exhibits the most promising anti-adipogenic activity. Furthermore, being a complex mixture of phytochemicals, the ZJL extract could be utilized as source of yet unknown bioactive leads with potential implementation in obesity management.

DDB1 binds histone reader BRWD3 to activate the transcriptional cascade in adipogenesis and promote onset of obesity.

Obesity has become a global pandemic. Identification of key factors in adipogenesis helps to tackle obesity and related metabolic diseases. Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity. Although typically recognized as a component of the CUL4-RING E3 ubiquitin ligase complex, DDB1 stimulates adipogenesis independently of CUL4. A DDB1 mutant that does not bind CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient cells. Ddb1+/- mice show delayed postnatal development of white adipose tissues and are protected from diet-induced obesity. Mechanistically, by interacting with BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of ELK1 downstream immediate early response genes and facilitates the release of paused RNA polymerase II, thereby activating the transcriptional cascade in adipogenesis. Our findings have uncovered a CUL4-independent function of DDB1 in promoting the transcriptional cascade of adipogenesis, development of adipose tissues, and onset of obesity.

Mechanism of Formononetin-induced Stimulation of Adipocyte Fatty Acid Oxidation and Preadipocyte Differentiation

Decreased adipocyte fatty acid oxidation (FAO) and impaired preadipocyte differentiation characterize hypertrophic expansion of adipose tissue (AT) from obese and insulin resistant humans and are recognized as potential mechanisms for obesity-mediated dyslipidemia. Supplementation of formononetin (FMN), one of the principal isoflavones extracted from red clover or Huangqi (Astragalus roots), has been shown to have beneficial effects on obesity-related hyperlipidemia, a well-established cardiovascular risk factor. However, a target tissue and underlying mechanism(s) through which FMN acts have been under-investigated. Thus, we investigated whether FMN promotes adipocyte FAO and preadipocyte differentiation using 3T3-L1 preadipocytes to provide potential mechanisms of FMN action. We further extended this to the culture of 10T1/2 mesenchymal stem cells (MSCs) as well as mouse AT explants to reflect in vivo effects of FMN. In fully differentiated 3T3-L1 adipocytes, FMN-treatment significantly increased the expression levels of FAO-related proteins such as pAMPK, pACC, and CPT1, all of which were consistently upregulated in AT explant cultures treated with 10 μM FMN. In addition, FMN significantly enhanced the degree of differentiation of both 3T3-L1 preadipocytes and 10T1/2 MSCs into adipocytes as evidenced by Oil Red O staining of cellular lipids. This observation correlated with increased expression levels of key adipogenic transcription factors (PPARγ and C/EBPα) and their down-stream target proteins (FABP4, Glut4 and adiponectin). Moreover, FMN failed to exert its stimulatory effects on preadipocyte differentiation in both cell types in the presence of a PPARγ antagonist, suggesting a PPARγ-dependent effect of FMN. Collectively, these data provide possible mechanisms of action of FMN on lipid metabolism and further support the favorable in vivo effects of FMN in diet and obesity-induced dyslipidemia.

Matrigel® enhances 3T3-L1 cell differentiation

ABSTRACT Culturing cells on bio-gels are believed to provide a more in vivo-like extracellular matrix. 3T3-L1 cells cultured on Matrigel® significantly alteregd their proliferation and differentiation as compared to growth on tissue culture-coated polystyrene surfaces. Growth on a 250-μm thick layer of Matrigel® facilitated the formation of cellular aggregates of 3T3-L1 cells. Differentiation of 3T3-L1 cells cultured on Matrigel® demonstrated increased levels of mRNA levels for key adipogenic transcription factors (PPARγ, C/EBPα, SREBP1), lipogenic markers (FAS, FABP4, LPL, PLIN1) and markers of adipocyte maturity (LEP), compared to cells cultured directly on a polystyrene tissue culture surface. The gene expression of extracellular matrix proteins (FN1, COL1A1, COL4A1, COL6, LAM) was decreased in 3T3-L1 cells cultured on Matrigel®. Furthermore, growth on Matrigel® increased lipid accumulation in 3T3-L1 cells in the presence and absence of rosiglitazone, a thiazolidinedione routinely used to optimize differentiation in these cells. These changes in adipocyte gene expression and lipid accumulation patterns may be a result of the increased cell–cell and cell–ECM interactions occurring on the Matrigel®, a scenario that is more reflective of an in vivo model. Taken together, our data advance the understanding of the value of culturing 3T3-L1 cells on Matrigel®.

Caffeic and Chlorogenic Acids Synergistically Activate Browning Program in Human Adipocytes: Implications of AMPK- and PPAR-Mediated Pathways.

Caffeic acid (CA) and chlorogenic acid (CGA) are phenolic compounds claimed to be responsible for the metabolic effects of coffee and tea consumption. Along with their structural similarities, they share common mechanisms such as activation of the AMP-activated protein kinase (AMPK) signaling. The present study aimed to investigate the anti-obesity potential of CA and CGA as co-treatment in human adipocytes. The molecular interactions of CA and CGA with key adipogenic transcription factors were simulated through an in silico molecular docking approach. The expression levels of white and brown adipocyte markers, as well as genes related to lipid metabolism, were analyzed by real-time quantitative PCR and Western blot analyses. Mechanistically, the CA/CGA combination induced lipolysis, upregulated AMPK and browning gene expression and downregulated peroxisome proliferator-activated receptor γ (PPARγ) at both transcriptional and protein levels. The gene expression profiles of the CA/CGA-co-treated adipocytes strongly resembled brown-like signatures. Major pathways identified included the AMPK- and PPAR-related signaling pathways. Collectively, these findings indicated that CA/CGA co-stimulation exerted a browning-inducing potential superior to that of either compound used alone which merits implementation in obesity management. Further, the obtained data provide additional insights on how CA and CGA modify adipocyte function, differentiation and lipid metabolism.

Phosphate restriction impairs mTORC1 signaling leading to increased bone marrow adipose tissue and decreased bone in growing mice.

Bone marrow stromal cells (BMSCs) are multipotent cells that differentiate into cells of the osteogenic and adipogenic lineage. A striking inverse relationship between bone marrow adipose tissue (BMAT) and bone volume is seen in several conditions, suggesting that differentiation of BMSCs into bone marrow adipocytes diverts cells from the osteogenic lineage, thereby compromising the structural and mechanical properties of bone. Phosphate restriction of growing mice acutely decreases bone formation, blocks osteoblast differentiation and increases BMAT. Studies performed to evaluate the cellular and molecular basis for the effects of acute phosphate restriction demonstrate that it acutely increases 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling in osteoblasts. This is accompanied by decreased expression of Wnt10b in BMSCs. Phosphate restriction also promotes expression of the key adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer binding protein α (CEBPα), in CXCL12 abundant reticular (CAR) cells, which represent undifferentiated BMSCs and are the main source of BMAT and osteoblasts in the adult murine skeleton. Consistent with this, lineage tracing studies reveal that the BMAT observed in phosphate-restricted mice is of CAR cell origin. To determine whether circumventing the decrease in mTORC1 signaling in maturing osteoblasts attenuates the osteoblast and BMAT phenotype, phosphate-restricted mice with OSX-CreERT2 -mediated haploinsufficiency of the mTORC1 inhibitor, TSC2, were generated. TSC2 haploinsufficiency in preosteoblasts/osteoblasts normalized bone volume and osteoblast number in phosphate-restricted mice and attenuated the increase in BMAT observed. Thus, acute phosphate restriction leads to decreased bone and increases BMAT by impairing mTORC1 signaling in osterix-expressing cells. © 2021 American Society for Bone and Mineral Research (ASBMR).

Sulfated polysaccharides from green seaweed Caulerpa prolifera suppress fat accumulation

Obesity and its related disorders are a global problem and new approaches to prevention and treatment are needed. In this study we demonstrate that a sample containing sulfated polysaccharides (SP) from the green alga Caulerpa prolifera has an antiadipogenic effect on 3T3-L1 cells and inhibits fat accumulation in the nematode Caenorhabditis elegans. Treatment with the SP-containing sample, in concentrations of 200 μg mL−1, decreases lipid accumulation and inhibits the expression of key adipogenic and lipogenic transcription factors. In addition, in vivo studies in C. elegans confirm that SP-containing samples decrease fat accumulation in both low and high glucose diets. Taken together, our results demonstrate the value of seaweed products as a dietary component, with possible benefits in the management of body weight and obesity, and support the need for further study of the potential of these molecules in the formulation of nutraceuticals and new approaches to treatment.

Cynandione A induces adipogenesis and beige adipocyte-related phenotype in 3T3-L1 cells

Abstract Cynandione A (CA) is a major ingredient of Cynanchum wilfordii. Here, we report a new function of CA in adipogenesis in 3T3-L1 cells, a preadipocyte cell line. During adipogenic differentiation in 3T3-L1 cells, CA boosted the process by enhancing the expression of key adipogenic transcription factors (Pparg and C/ebpa), brown adipocyte-related genes (Prdm16, Pgc-1a, Cidea, and Ucp1), and beige adipocyte-related genes (Tbx1 and Cited1). Additionally, CA increased mitochondrial mass and expression levels of mitochondria-related genes (Sirt3 and Tfam) in the cells. These results suggest that CA induces adipogenesis and beige adipocyte-related phenotype in adipocyte lineage cells.

Positive metabolic effects of selected probiotic bacteria on diet-induced obesity in mice are associated with improvement of dysbiotic gut microbiota.

Given the rising evidence that gut malfunction including changes in the gut microbiota composition, plays a major role in the development of obesity and associated metabolic diseases, the exploring of novel probiotic bacteria with potential health benefits has attracted great attention. Recently Lactobacillus spp., exert potent anti-obesity effects by regulating key transcriptional and translational factors in adipose tissues. However, the molecular mechanism behind the anti-obesity effect of probiotics is not yet fully understood. Therefore, we investigated the effect of Lactobacillus plantarum A29 on the expression of adipogenic and lipogenic genes in 3T3-L1 adipocytes and high-fat diet (HFD)-fed mice. We observed that the treatment of 3T3-L1 adipocytes with the cell-free metabolites of L plantarum inhibited their differentiation and fat depositions via downregulating the key adipogenic transcriptional factors (PPAR-γ, C/EBP-α, and C/EBP-β) and their downstream targets (FAS, aP2, ACC, and SREBP-1). Interestingly, supplementation with L plantarum reduced the fat mass and serum lipid profile concurrently with downregulation of lipogenic gene expression in the adipocytes, resulting in reductions in the bodyweight of HFD-fed obese mice. L plantarum treatment attenuated the development of obesity in HFD-fed mice via the activation of p38MAPK, p44/42, and AMPK-α by increasing their phosphorylation. Further analysis revealed that A29 modulated gut-associated microbiota composition. Thus, A 29 potential probiotic strain may alleviate the obesity development and its associated metabolic disorders via inhibiting PPARγ through activating the p38MAPK and p44/42 signaling pathways.