Increase In Number Of Adipocytes Research Articles

Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity

Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction; however, the effects on skeletal tissue and the underlying mechanisms are still unclear. Here, we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles, leading to a switch in skeletal stem/progenitor cell (SSPC) differentiation between osteoblasts and adipocytes and bone deterioration. Bone marrow macrophage (BMM)-secreted extracellular vesicles (BMM-EVs) from obese mice induced bone deterioration (decreased bone volume, bone microstructural deterioration, and increased adipocyte numbers) when administered to lean mice. Conversely, BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients. We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates, miR-140 (with the function of promoting adipogenesis) and miR-378a (with the function of enhancing osteogenesis) coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis. BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration, while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice. BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration. More importantly, we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system, and this approach rescued bone deterioration in obese mice. Thus, our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.

PPA1 promotes adipogenesis by regulating the stability of C/EBPs.

Adipogenesis significantly contributes to healthy adipose tissue expansion in obesity. Increasing adipocyte number or function to alleviate adipose tissue overload could serve as a therapeutic strategy for both lipodystrophy and obesity-related metabolic syndrome. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate (PPi) and is involved in many biochemical reactions, but its function in adipose tissue has not been studied previously. In this study, we demonstrated that adipose-specific PPA1 knockout (PPA1AKO) mice showed lipodystrophy and spontaneously developed hepatic steatosis and severe insulin resistance under normal chow diet feeding. PPA1 deficiency suppressed the differentiation of primary adipocyte precursors and 3T3-L1 cells. Notably, PPA1 overexpression can restore inhibited adipogenesis in preadipocytes isolated from db/db mice and type 2 diabetes patients. Mechanistic studies have revealed that PPA1 acts as a positive regulator of early adipocyte differentiation by promoting CCAAT/enhancer-binding proteinβ and δ (C/EBPβ and δ) protein stability. Moreover, the function of PPA1 in adipogenesis is independent of its PPi catalytic activity. Collectively, our in vivo and in vitro findings demonstrated that PPA1 is a novel critical upstream regulator of adipogenesis, controlling adipose tissue development and whole-body metabolic homeostasis.

Effect of Per and Poly-Fluoroalkyl Substances on Pregnancy and Child Development.

Childhood obesity is significantly influenced by maternal exposure to Per- and Poly-Fluoroalkyl Substances (PFAS) during pregnancy. PFAS exposure occurs through the Peroxisome Proliferator-Activated Receptor (PPAR-γ) receptor, leading to increased fat deposition and profound health effects in child growth and development. Despite ongoing investigations, the relationship between maternal serum PFAS concentration and child obesity requires further exploration. This study aimedto review the possible effects of Per and poly-fluoroalkyl substances exposure and their mechanism in overweight/obese children from pregnant ladies. A detailed literature survey was conducted using online databases, including Science Direct, Google Scholar, Scopus, Cochrane, and PubMed. The study focused on the diverse effects of PFAS on maternal and child health, with particular emphasis on neurological complications. Child growth development depends upon breastfeeding and placenta health, which is disrupted by PFAS exposure, ultimately destroying the body mass index of the child. Neurotoxicity testing utilized the SH-SY5Y human-derived cell line as an in vitro model, revealing PFAS-induced increases in adipocyte number, reduced cell size, altered lipid conglomeration, increased adiposity, and changes in liver function. in vivo studies in mice and human cell lines indicated PPAR-γ and ER-α activation, leading to adiposity and weight gain through Estrogen signaling and Lipid metabolism. PFAS concentrations positively correlated in maternal sera, analyzed by liquid chromatography/quadrupole mass spectrometry. PFAS, with a long half-life of 3.5-8.5 years, is commonly found in the serum of pregnant women, crossing the placenta barrier. This exposure disrupts placental homeostasis, negatively impacting mechanisms of action and potentially leading to deterioration in pregnancy and child health. Further research is needed to comprehensively understand the complex interplay between PFAS exposure and its implications for maternal and child well-being.

Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1β, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

Effects of Total Flavonoids of Epimedium on Bone Marrow Adipose Tissue in Ovariectomized Rats.

Bone marrow adipose tissue has brown fat characteristics. Several studies have demonstrated that total flavonoids of Epimedium (TFE) could prevent bone loss and reduce the white adiposity in bone marrow induced by ovariectomy (OVX) in rats. However, the effects of TFE on marrow brown fat in OVX rats remain unclear. In this word, we addressed this question expected to provide a new target for preventing and treating osteoporosis. Thirty-six 3-month-old female Sprague-Dawley rats were equally divided into Sham controls, OVX controls, and OVX treated with TFE. Chemical shift coding magnetic resonance was performed to detect marrow fat fraction at the left femur at baseline, 6 and 12 weeks post-OVX. Bone mineral density at the lumbar spine and femur was measured by dual-energy x-ray absorptiometry. Serum bone biomarkers by ELISA, trabecular bone microarchitecture at the proximal tibia by micro-CT, quantitative parameters of marrow adipocyte by hematoxylin, and eosin staining were evaluated. The marrow adipocyte gene and protein expressions profile were determined by real-time quantitative PCR and immunostaining in whole tibiae. We found that TFE treatment could decrease bone turnover rate and improved bone mineral density and trabecular microarchitecture in OVX rats. OVX resulted in marrow adipogenesis as evidenced by increased marrow fat fraction, larger marrow adipocyte size, increased adipocyte number and percentage of adipocyte area, marrow white adipocyte gene, and protein expression, including PPARγ2 and FABP4. These pathological changes induced by estrogen deficiency were restored by TFE treatment. TFE also increased brown adipocyte expressions of the transcription factor Ucp1 and Prdm16 in whole tibiae. There was no detectible protein expression of brown adipocyte markers in the proximal tibia. Taken together, TFE regulation of bone marrow adiposity in OVX rats is mediated, at least in part, via maintaining the reciprocity of white and brown adipose tissue.

Long-Lasting Effects of Incubation Temperature During Fetal Development on Subcutaneous Adipose Tissue of Broilers.

Increasing evidence indicates that fetal programming may cause permanent effects on offspring adipose tissue and body composition. Previous study showed reduction in newly-hatched broiler chick adiposity by manipulating incubation temperature during fetal development. The present study examined whether incubation temperature during fetal development has long-term effects on post-hatching fat deposition in broilers. Broiler breeder eggs (Cobb-500®) were incubated under constant low (36°C, LT), control (37.5°C, CT) or high (39°C, HT) temperature from day 13 onward, giving to eggshell temperature of 37.3 ± 0.08°C, 37.8 ± 0.2°C, and 38.8 ± 0.3°C, respectively. Male chicks were reared under recommended temperatures until 42 days old. LT 21 days old broilers exhibited higher blood cholesterol than CT broilers, and higher triglycerids, VLDL, and LDL, and lower HDL than CT and HT broilers. LT broilers presented higher liver cholesterol than CT broilers and lower ether extract percentage than CT broilers. Adipocyte count was lower in the abdomen than in the thigh. Until day 21 of age, feed intake was higher in LT than in HT broilers. At day 42 of age, blood cholesterol and LDL were higher in HT broilers than in CT and LT broilers. Liver cholesterol was higher in LT than in HT broilers. LT treatment reduced neck and increased thigh adipocyte size compared to CT treatment, while the HT treatment reduced abdomen and neck adipocyte size compared to other two treatments and in the thigh compared to LT treatment. In CT broilers, thigh adipocytes were smaller than abdomen and neck adipocytes. HT treatment increased adipocyte number per area in the neck compared to LT and CT treatment, and LT and HT treatments reduced adipocyte count in the thigh compared to CT treatment. CT broilers presented higher adipocyte count in the thigh than the abdomen and neck, while HT broilers presented higher adipocyte count in the neck than the abdomen and thigh. Cell proliferation was lower in the abdomen than in the thigh. The results show incubation temperature manipulation during fetal development has long-term and distinct effects on regional adiposity, and can be used to modulate broiler fat deposition.

Inhibition of the Monocarboxylate Transporter 1 (MCT1) Promotes 3T3-L1 Adipocyte Proliferation and Enhances Insulin Sensitivity.

Enlarged, hypertrophic adipocytes are less responsive to insulin and are a hallmark feature of obesity, contributing to many of the negative metabolic consequences of excess adipose tissue. Although the mechanisms remain unclear, the adipocyte size appears to be inversely correlated with insulin sensitivity and glucose tolerance, wherein smaller adipocytes are insulin-sensitive and larger adipocytes develop insulin resistance and exhibit an impaired glucose uptake. Thus, pharmacological strategies aimed at regulating adipocyte hypertrophy (increase in adipocyte size) in favor of promoting hyperplasia (increase in adipocyte number) have the potential to improve adipocyte insulin sensitivity and provide therapeutic benefits in the context of metabolic disorders. As white adipose tissue can metabolize large amounts of glucose to lactate, using transcriptomics and in vitro characterization we explore the functional consequences of inhibiting monocarboxylate transporter 1 (MCT1) activity in fully differentiated adipocytes. Our studies show that the pharmacological inhibition of MCT1, a key regulator of the cellular metabolism and proliferation, promotes the re-entry of mature adipocytes into the cell cycle. Furthermore, we demonstrate that inhibitor-treated adipocytes exhibit an enhanced insulin-stimulated glucose uptake as compared with untreated adipocytes, and that this outcome is dependent on the cyclin-dependent kinase 1 (CDK1) activity. In summary, we identify a mechanism though which MCT1 inhibition improves the insulin sensitivity of mature adipocytes by inducing cell cycle re-entry. These results provide the foundation for future studies investigating the role MCT1 plays in adipocyte hyperplasia, and its therapeutic potential as a drug target for obesity and metabolic disease.

Bone marrow adiposity during pathologic bone loss: molecular mechanisms underlying the cellular events.

Bone marrow (BM) is a heterogeneous niche where bone marrow stromal cells (BMSCs), osteoblasts, osteoclasts, adipocytes, hematopoietic cells, and immune cells coexist. The cellular composition of BM changes with various pathophysiological states. A reduction in osteoblast number and a concomitant increase in adipocyte number in aging and pathological conditions put bone marrow adipose tissue (BMAT) into spotlight. Accumulating evidence strongly supports that an overwhelming production of BMAT is a major contributor to bone loss disorders. Therefore, BMAT-targeted therapy can be an efficient and feasible intervention for osteoporosis. However, compared to blocking bone-destroying molecules produced by BMAT, suppressing BMAT formation is theoretically a more effective and fundamental approach in treating osteoporotic bone diseases. Thus, a deep insight into the molecular basis underlying increased BM adiposity during pathologic bone loss is critical to formulate strategies for therapeutically manipulating BMAT. In this review, we comprehensively summarize the molecular mechanisms involved in adipocyte differentiation of BMSCs as well as the interaction between bone marrow adipocytes and osteoclasts. More importantly, we further discuss the potential clinical implications of therapeutically targeting the upstream of BMAT formation in bone loss diseases.

Cadmium exposure induces osteoporosis through cellular senescence, associated with activation of NF-κB pathway and mitochondrial dysfunction

Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stromal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-κB signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16INK4a protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescence-associated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-κB inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.

Myonectin inhibits adipogenesis in 3T3-L1 preadipocytes by regulating p38 MAPK pathway

In current times, obesity is a major health problem closely associated with metabolic disease such as diabetes, dyslipidemia, and cardiovascular disease. The direct cause of obesity is known as an abnormal increase in fat cell size and the adipocyte pool. Hyperplasia, the increase in number of adipocytes, results from adipogenesis in which preadipocytes differentiate into mature adipocytes. Adipogenesis is regulated by local and systemic cues that alter transduction pathways and subsequent control of adipogenic transcription factors. Therefore, the regulation of adipogenesis is an important target for preventing obesity. Myonectin, a member of the CTRP family, is a type of myokine released by skeletal muscle cells. Although several studies have shown that myonectin is associated with lipid metabolism, the role of myonectin during adipogenesis is not known. Here, we demonstrate the role of myonectin during adipocyte differentiation of 3T3-L1 cells. We found that myonectin inhibits the adipogenesis of 3T3-L1 preadipocytes with a reduction in the expression of adipogenic transcription factors such as C/EBPα, β and PPARγ. Furthermore, we show that myonectin has an inhibitory effect on adipogenesis through the regulation of the p38 MAPK pathway and CHOP. These findings suggest that myonectin may be a novel therapeutic target for the prevention of obesity.

Nutmeg extract potentially alters characteristics of white adipose tissue in rats.

BackgroundBrowning of white adipose tissue (WAT) is a promising approach to obesity treatment. During browning, WAT transforms into beige adipose tissue through stimulation of the peroxisome proliferator activated receptor γ (PPARγ). Nutmeg, one of the Indonesian herbs, reportedly has dual roles as a PPARα/γ partial agonist. Even though nutmeg has been traditionally used in body weight reduction, there is limited information regarding the potential role of nutmeg in browning of WAT.ObjectivesIn this study, we explored the effect of nutmeg seed extract (NuSE) as a potential inductor of WAT browning.MethodsTwelve male Wistar rats, 5–6 weeks old, were divided into control and nutmeg groups. The rats in nutmeg group were given NuSE for 12 weeks by oral gavage. After 12 weeks, the rat's inguinal WAT and brown adipose tissue (BAT) were collected, weighed and stored at − 80°C until use.ResultsWe observed that even though NuSE did not reduce the final body weight, it significantly reduced body weight gain. NuSE also increased protein levels of peroxisome proliferator activated receptor γ coactivator 1α (PGC‐1α) and uncoupling protein 3 (UCP3) significantly and tended to increase UCP2 and UCP1 levels. Furthermore, NuSE induced macroscopic and microscopic morphological changes of inguinal WAT, marked by significantly increased adipocyte numbers and decreased adipocyte size.ConclusionsEven though NuSE did not increase UCP1 significantly, it potentially alters inguinal WAT characteristics and leads to browning through PGC‐1α and UCP3 induction. However, UCP3’s specific mechanism in WAT browning remains unclear. Our findings could contribute to obesity treatment in the future.

Development of a Novel Anti-Obesity Compound with Inhibiting Properties on the Lipid Accumulation in 3T3-L1 Adipocytes

Background:Obesity as a developing global challenge can be characterized by increase in adipocyte number and size arising from adipogenesis. Control of adipogenesis, as a potential strategy, can prevent and manage obesity. So far, the effectiveness of herbal medicine and active ingredients therapies for obesity and metabolic syndrome treatment has been investigated. In this study, a novel combination of berberine, catechin, and capsaicin was developed, and their effect on 3T3-L1 adipocytes was investigated. Methods:The effect of active ingredient on the cell viability was assessed by MTT assay. Adipocytes were treated with various concentrations of berberine (3 and 6.25 μM), catechin (6.25 and 12.5 μM), and capsaicin (6.25 and 12.5 μM) alone and in combination. Results:All active ingredients did not affect the cell viability by MTT assay at different concentrations. The dual and triple combinations of three active ingredients showed excellent potential as anti-obese without any toxicity. The inhibitory effect of berberine, catechin, and capsaicin on the differentiation of 3T3-L1 preadipocytes was found to be dose-dependent. These results indicate that catechin in both doses may have a stronger effect than the two other active ingredients on the intracellular lipid accumulation. Also, the triple combination of the aforementioned ingredients showed better responses than their dual combination. Conclusion:This work is the first report to simultaneously investigate these three active ingredients in a single, dual, and triple formats. The berberine, catechin, and capsaicin co-treatment inhibits the adipogenesis during the differentiation process. This compound can be a prospective therapy for obesity and relevant diseases such as dyslipidemia.

The Role of Autophagy in White Adipose Tissue Function: Implications for Metabolic Health.

White adipose tissue (WAT) is a highly adaptive endocrine organ that continuously remodels in response to nutritional cues. WAT expands to store excess energy by increasing adipocyte number and/or size. Failure in WAT expansion has serious consequences on metabolic health resulting in altered lipid, glucose, and inflammatory profiles. Besides an impaired adipogenesis, fibrosis and low-grade inflammation also characterize dysfunctional WAT. Nevertheless, the precise mechanisms leading to impaired WAT expansibility are yet unresolved. Autophagy is a conserved and essential process for cellular homeostasis, which constitutively allows the recycling of damaged or long-lived proteins and organelles, but is also highly induced under stress conditions to provide nutrients and remove pathogens. By modulating protein and organelle content, autophagy is also essential for cell remodeling, maintenance, and survival. In this line, autophagy has been involved in many processes affected during WAT maladaptation, including adipogenesis, adipocyte, and macrophage function, inflammatory response, and fibrosis. WAT autophagy dysregulation is related to obesity and diabetes. However, it remains unclear whether WAT autophagy alteration in obese and diabetic patients are the cause or the consequence of WAT malfunction. In this review, current data regarding these issues are discussed, focusing on evidence from human studies.

Decreased PEDF Expression Promotes Adipogenic Differentiation through the Up-Regulation of CD36.

Adipogenesis is a tightly regulated cellular process that involves the action of multiple signaling pathways. Characterization of regulators that are associated with adipose development is crucial to understanding the mechanisms underlying obesity and other metabolic disorders. Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that was first described as a neurotrophic factor. The role of PEDF in lipid metabolism was established when adipose triglyceride lipase (ATGL), a major triglyceride hydrolase, was characterized as its binding partner. In this study, we investigated the downstream effects of PEDF on adipogenic differentiation using rat adipose-derived stem cells (AdSCs) and the mouse pre-adipocyte cell line 3T3-L1. Knocking down PEDF in differentiating cells resulted in elevated levels of ATGL and CD36, as well as other adipogenic markers, with a concomitant increase in adipocyte number. CD36, a scavenger receptor for a variety of ligands, regulated proliferation and lipogenic gene expression during adipogenesis. The CD36 increase due to PEDF down-regulation might be a result of elevated PPARγ. We further demonstrated that PEDF expression was regulated by dexamethasone, a synthetic glucocorticoid that is widely used for adipogenesis at the transcriptional level. Taken together, our findings highlight that PEDF negatively regulates adipogenesis through the regulation of various signaling intermediates, and it may play a crucial role in lipid metabolic disorders.

Pulsed electromagnetic fields prevented the decrease of bone formation in hindlimb-suspended rats by activating sAC/cAMP/PKA/CREB signaling pathway.

Microgravity is one of the main threats to the health of astronauts. Pulsed electromagnetic fields (PEMFs) have been considered as one of the potential countermeasures for bone loss induced by space flight. However, the optimal therapeutic parameters of PEMFs have not been obtained and the action mechanism is still largely unknown. In this study, a set of optimal therapeutic parameters for PEMFs (50 Hz, 0.6 mT 50% duty cycle and 90 min/day) selected based on high-throughput screening with cultured osteoblasts was used to prevent bone loss in rats induced by hindlimb suspension, a commonly accepted animal model to simulate the space environment. It was found that hindlimb suspension for 4 weeks led to significant decreases in femoral and vertebral bone mineral density (BMD) and their maximal loads, severe deterioration in bone micro-structure, and decreases in levels of bone formation markers and increases in bone resorption markers. PEMF treatment prevented about 50% of the decreased BMD and maximal loads, preserved the microstructure of cancellous bone and thickness of cortical bone, and inhibited decreases in bone formation markers. Histological analyses revealed that PEMFs significantly alleviated the reduction in osteoblast number and inhibited the increase in adipocyte number in the bone marrow. PEMFs also blocked decreases in serum levels of parathyroid hormone and its downstream signal molecule cAMP, and maintained the phosphorylation levels of protein kinase A (PKA) and cAMP response element-binding protein (CREB). The expression level of soluble adenylyl cyclases (sAC) was also maintained. It therefore can be concluded that PEMFs partially prevented the bone loss induced by weightless environment by maintaining bone formation through signaling of the sAC/cAMP/PKA/CREB pathway. Bioelectromagnetics. 39:569-584, 2018. © 2018 Wiley Periodicals, Inc.

Tetrabromobisphenol-A Promotes Early Adipogenesis and Lipogenesis in 3T3-L1 Cells.

Tetrabromobisphenol A (TBBPA) is the most common flame retardant used in electrical housings, circuit boards, and automobiles. High-throughput screening and binding assays have identified TBBPA as an agonist for human peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipogenesis. TBBPA has been suggested to be an obesogen based on in vitro cellular assays and zebrafish data. We hypothesized that exposing preadipocytes to TBBPA could influence adipogenesis via genes other than those in the PPARγ pathway due to its structural similarity to bisphenol A, which demonstrates varied endocrine disrupting activities. Mouse-derived 3T3-L1 preadipocytes were induced to differentiate and continually treated with TBBPA for 8 days. High-content imaging of adipocytes displayed increased adipocyte number and lipid accumulation when treated with TBBPA. TBBPA exhibited weak induction of mPPARγ, with an AC50 of 397 µM. Quantitative PCR revealed that TBBPA exposure increased early expression of genes involved in glucocorticoid receptor (GR) signaling and PPARγ transcriptional activation, as well as upregulating downstream genes needed for adipocyte maintenance and nontraditional ER signaling, such as Gpr30. Additionally, Pref1 and Thy1, inhibitors of differentiation, were downregulated by some concentrations of TBBPA. Furthermore, proliferating preadipocytes treated with TBBPA, only prior to differentiation, exhibited increased adipocyte number and lipid accumulation after 8 days in normal culture conditions. In conclusion, TBBPA influenced gene expression changes in GR, nontraditional ER, and known adipogenic regulatory genes, prior to PPARγ expression; effects suggesting early programming of adipogenic pathways.

Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma.

Obesity has become a global epidemic influencing the establishment and progression of a wide range of diseases, such as diabetes, cardiovascular disease, and cancer. In 2016, International Agency for Research on Cancer reported that obesity is now associated with 13 different cancers, one of which is multiple myeloma (MM), a destructive cancer of plasma cells that predominantly reside in the bone marrow. Obesity is the accumulation of excess body fat, which causes metabolic, endocrine, immunologic, and inflammatory-like changes. Obesity is usually associated with an increase in visceral and/or subcutaneous fat; however, an additional fat depot that also responds to diet-induced changes is bone marrow adipose tissue (BMAT). There have been several studies over the past few decades that have identified BMAT as a key driver in MM progression. Adipocytes secrete numerous adipokines, such as leptin, adiponectin, resistin, adipsin, and visfatin, which when secreted at normal controlled levels have protective properties. However, in obesity these levels of secretion change, coupled with an increase in adipocyte number and size causing a profound and lasting effect on the bone microenvironment, contributing to MM cell growth, survival, and migration as well as potentially fueling bone destruction. Obesity is a modifiable risk factor making it an attractive option for targeted therapy. This review discusses the link between obesity, monoclonal gammopathy of undetermined significance (a benign condition that precedes MM), and myeloma, and the contribution of key adipokines to disease establishment and progression.

Effect of Olmesartan on Glucose Metabolism Involving Angiotensin Converting Enzyme 2

Objectives: The angiotensin converting enzyme 2 (ACE2)/angiotensin-(1- 7)/Mas pathway has been expected to act as a protective arm of the renin-angiotensin system. Recently, the role of ACE2 in glucose metabolism has been highlighted. We previously reported that olmesartan increases ACE2 expression in injured arteries. Therefore, we hypothesized that treatment with olmesartan would improve glucose metabolism via ACE2 activation. Here, we investigated the effect of olmesartan on glucose metabolism using ACE2-deficient mice (ACE2KO). Methods: Ten-week-old WT and ACE2-deficient mice (ACE2KO) were employed in this study. Olmesartan or valsartan was administered intraperitoneally at a dose of 1.5 mg/kg/day in 8 weeks old mice. Insulin resistance was evaluated by oral glucose tolerance test and insulin tolerance test. Morphological changes in adipose tissue as well as adipocyte differentiation and inflammatory response and histological changes in the pancreas were examined. Results: ACE2KO showed significantly higher fasting blood glucose level and blood glucose level at 30 min after glucose load in the oral glucose tolerance test. Treatment with olmesartan reduced blood glucose level at 30 min after glucose load in both WT and ACE2KO, but valsartan did not. Treatment with olmesartan increased adipocyte number and reduced mean adipocyte size only in WT, but not in ACEKO. Treatment with olmesartan also prevented the reduced size of pancreatic islets in ACE2KO. Conclusion: The present study demonstrated that ACE2KO exhibited abnormal glucose metabolism. Treatment with olmesartan improved glucose metabolism in WT more than in ACEKO mice, indicating the possible existence of an ACE2-dependent pathway induced by olmesartan. Keywords: ACE2, olmesartan, glucose metabolism, pancreas, glucose tolerance, adipocyte.

Phytol increases adipocyte number and glucose tolerance through activation of PI3K/Akt signaling pathway in mice fed high-fat and high-fructose diet

It has been shown that adipose tissue hyperplasia (increased adipocyte number or adipogenesis) has beneficial effects on metabolic health. The aim of the present study was to determine whether phytol could modulate hyperplasia/adipogenesis and glucose homeostasis, and to explore the underlying mechanisms in mice fed high-fat and high fructose diet (HFFD). Our results demonstrated that phytol administration decreased body weight gain and inguinal subcutaneous white adipose tissue (iWAT) weight. However, phytol significantly increased the adipocyte number in iWAT, with the smaller average adipocyte diameter. Meanwhile, OGTT result showed that phytol improved glucose tolerance. In accord, phytol administration markedly increased expression of marker genes associated with adipogenesis (PPARγ and C/EBPα) and glucose uptake (AS160 and GLUT4) and activated PI3K/Akt signaling pathway in mice iWAT. In agreement with the in vivo findings, the in vitro results indicated that 100 μM phytol significantly enhanced 3T3-L1 adipogenesis and glucose uptake, and activated PI3K/Akt signaling pathway. However, phytol-induced enhancement of 3T3-L1 adipognesis and glucose uptake, activation of PI3K/Akt signaling pathway, elevation of marker genes involved in adipogensis and glucose uptake, as well as translocation of GLUT4 from cytoplasm to membrane were abolished by Wortmannin, a specific PI3K/Akt inhibitor. Taken together, phytol increased adipocyte number in iWAT and improved glucose tolerance in mice fed HFFD, which was coincident with the enhanced adipogenesis and glucose uptake in 3T3-L1, and was associated with activation of PI3K/Akt signaling pathway. These data suggested the application of phytol as a potential nutritional agent to combat obesity and type 2 diabetes.

Grape seed proanthocyanidin supplementation reduces adipocyte size and increases adipocyte number in obese rats

Objectives:White adipose tissue (WAT) expands through hypertrophy (increased adipocyte size) and/or hyperplasia (increased adipocyte number). Hypertrophy has been associated with insulin resistance and dyslipidemia independently of body composition and fat distribution. In contrast, hyperplasia protects against metabolic alterations. Proanthocyanidins, which are the most abundant flavonoids in the human diet, improve metabolic disturbances associated with diet-induced obesity without reducing body weight or adiposity. The aim of this study was to determine whether grape seed proanthocyanidin extract (GSPE) can modulate WAT expandability. Because GSPE also contains gallic acid, we also studied the capacity of gallic acid to remodel WAT.Design:Male Wistar rats were fed a standard chow diet (n=6) or a cafeteria diet (CAF) for 11 weeks. After 8 weeks, the CAF-fed animals were supplemented with 25 mg GSPE/kg body weight (n=6), 7 mg gallic acid/kg body weight (n=6) or the vehicle (n=6) for 3 weeks. Histological analyses were performed in the retroperitoneal (rWAT) and inguinal (iWAT) WAT to determine adipocyte size and number. Specific markers for adipogenesis and WAT functionality were analysed in rWAT using quantitative RT-PCR.Results:GSPE or gallic acid supplementation did not reduce weight gain or reverse and adiposity. However, GSPE reduced adipocyte size significantly in rWAT and moderately in iWAT and tripled the adipocyte number in rWAT. Gallic acid slightly reduced adipocyte size in rWAT and iWAT and doubled the adipocyte number in both WATs. In accordance with this adipogenic activity, Pref-1 and PPARγ tended to be overexpressed in rWAT of rats supplemented with GSPE. Moreover, GSPE supplementation increased Plin1 and Fabp4 expression and restored adiponectin expression completely, indicating a better functionality of visceral WAT.Conclusions:GSPE supplementation has anti-hypertrophic and hyperplasic activities in rats with established obesity, mainly in visceral WAT inducing a healthier expansion of WAT to match the surplus energy provided by the cafeteria diet.