Distinct Fractions of an Artemisia scoparia Extract Contain Compounds With Novel Adipogenic Bioactivity

Adipocytes are important players in metabolic health and disease, and disruption of adipocyte development or function contributes to metabolic dysregulation. Hence, adipocytes are significant targets for therapeutic intervention in obesity and metabolic syndrome. Plants have long been sources for bioactive compounds and drugs. In previous studies, we screened botanical extracts for effects on adipogenesis in vitro and discovered that an ethanolic extract of Artemisia scoparia (SCO) could promote adipocyte differentiation. To follow up on these studies, we have used various separation methods to identify the compound(s) responsible for SCO's adipogenic properties. Fractions and subfractions of SCO were tested for effects on lipid accumulation and adipogenic gene expression in differentiating 3T3-L1 adipocytes. Fractions were also analyzed by Ultra Performance Liquid Chromatography- Mass Spectrometry (UPLC-MS), and resulting peaks were putatively identified through high resolution, high mass accuracy mass spectrometry, literature data, and available natural products databases. The inactive fractions contained mostly quercetin derivatives and chlorogenates, including chlorogenic acid and 3,5-dicaffeoylquinic acid, which had no effects on adipogenesis when tested individually, thus ruling them out as pro-adipogenic bioactives in SCO. Based on these studies we have putatively identified the principal constituents in SCO fractions and subfractions that promoted adipocyte development and fat cell gene expression as prenylated coumaric acids, coumarin monoterpene ethers, 6-demethoxycapillarisin and two polymethoxyflavones.

[1]  Z. Wang,et al.  Chlorogenic Acid Functions as a Novel Agonist of PPARγ2 during the Differentiation of Mouse 3T3-L1 Preadipocytes , 2018, BioMed research international.

[2]  J. Rood,et al.  An ethanolic extract of Artemisia scoparia inhibits lipolysis in vivo and has antilipolytic effects on murine adipocytes in vitro. , 2018, American journal of physiology. Endocrinology and metabolism.

[3]  M. Barbieri,et al.  Dehydroleucodine inhibits mitotic clonal expansion during adipogenesis through cell cycle arrest , 2018, Phytotherapy research : PTR.

[4]  L. Forney,et al.  Dietary Quercetin Attenuates Adipose Tissue Expansion and Inflammation and Alters Adipocyte Morphology in a Tissue-Specific Manner , 2018, International journal of molecular sciences.

[5]  A. Remky,et al.  Acute Effect of Hypervolemic Hemodilution on Retrobulbar Hemodynamics in Anterior Ischemic Optic Neuropathy , 2018, BioMed research international.

[6]  Na‐Ra Han,et al.  Anti-inflammatory effects of Artemisia scoparia and its active constituent, 3,5-dicaffeoyl-epi-quinic acid against activated mast cells , 2018, Immunopharmacology and immunotoxicology.

[7]  T. Yi,et al.  The Beneficial Effects of Quercetin, Curcumin, and Resveratrol in Obesity , 2017, Oxidative medicine and cellular longevity.

[8]  P. Nisha,et al.  Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line , 2017, Front. Pharmacol..

[9]  H. Rocha,et al.  Baccharis trimera (Less.) DC Exhibits an Anti-Adipogenic Effect by Inhibiting the Expression of Proteins Involved in Adipocyte Differentiation , 2017, Molecules.

[10]  K. Sutthanut,et al.  Purple corn silk: A potential anti-obesity agent with inhibition on adipogenesis and induction on lipolysis and apoptosis in adipocytes. , 2017, Journal of ethnopharmacology.

[11]  L. Cisneros-Zevallos,et al.  Chlorogenic Acid: Recent Advances on Its Dual Role as a Food Additive and a Nutraceutical against Metabolic Syndrome , 2017, Molecules.

[12]  Inas H. Thomas,et al.  Metformin; a review of its history and future: from lilac to longevity , 2017, Pediatric diabetes.

[13]  W. Kalt,et al.  Fermented blueberry juice extract and its specific fractions have an anti-adipogenic effect in 3 T3-L1 cells , 2017, BMC Complementary and Alternative Medicine.

[14]  U. Smith,et al.  Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids , 2016, Journal of internal medicine.

[15]  G. Dorado,et al.  Effects of quercetin, a natural phenolic compound, in the differentiation of human mesenchymal stem cells (MSC) into adipocytes and osteoblasts. , 2016, The Journal of nutritional biochemistry.

[16]  Frank B Hu,et al.  Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications. , 2016, Circulation research.

[17]  B. Jang Artesunate inhibits adipogeneis in 3T3-L1 preadipocytes by reducing the expression and/or phosphorylation levels of C/EBP-α, PPAR-γ, FAS, perilipin A, and STAT-3. , 2016, Biochemical and biophysical research communications.

[18]  Trevor Coward,et al.  An In-Vitro Study , 2016 .

[19]  J. Sohng,et al.  7,8-Dihydroxyflavone inhibits adipocyte differentiation via antioxidant activity and induces apoptosis in 3T3-L1 preadipocyte cells. , 2016, Life sciences.

[20]  Dong-Seon Kim,et al.  Akebia quinata extract exerts anti-obesity and hypolipidemic effects in high-fat diet-fed mice and 3T3-L1 adipocytes. , 2015, Journal of ethnopharmacology.

[21]  Lan-ying Chen,et al.  Shp2 regulates chlorogenic acid-induced proliferation and adipogenic differentiation of bone marrow-derived mesenchymal stem cells in adipogenesis. , 2015, Molecular medicine reports.

[22]  S. Gogg,et al.  Insulin resistance and impaired adipogenesis , 2015, Trends in Endocrinology & Metabolism.

[23]  M. Funakoshi-Tago,et al.  Coffee inhibits adipocyte differentiation via inactivation of PPARγ. , 2014, Biological & pharmaceutical bulletin.

[24]  Makoto Inoue,et al.  Identification of a naturally occurring retinoid X receptor agonist from Brazilian green propolis. , 2014, Biochimica et biophysica acta.

[25]  G. Wolber,et al.  Identification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches , 2014, Planta Medica.

[26]  D. Ribnicky,et al.  Artemisia extracts activate PPARγ, promote adipogenesis, and enhance insulin sensitivity in adipose tissue of obese mice. , 2014, Nutrition.

[27]  T. Shimada,et al.  Suppression of adipocyte hypertrophy by polymethoxyflavonoids isolated from Kaempferia parviflora. , 2014, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[28]  A. Dávalos,et al.  Reduction of Adipogenesis and Lipid Accumulation by Taraxacum officinale (Dandelion) Extracts in 3T3L1 Adipocytes: An in vitro Study , 2014, Phytotherapy research : PTR.

[29]  D. Ribnicky,et al.  Artemisia scoparia Enhances Adipocyte Development and Endocrine Function In Vitro and Enhances Insulin Action In Vivo , 2014, PloS one.

[30]  T. Kawada,et al.  Phenolic compounds from leaves of Casimiroa edulis showed adipogenesis activity , 2014, Bioscience, biotechnology, and biochemistry.

[31]  A. Gambero,et al.  The in vitro and in vivo effects of yerba mate (Ilex paraguariensis) extract on adipogenesis. , 2013, Food chemistry.

[32]  S. Kitanaka,et al.  Inhibitory effect of chemical constituents from Artemisia scoparia Waldst. et Kit. on triglyceride accumulation in 3T3-L1 cells and nitric oxide production in RAW 264.7 cells , 2013, Journal of Natural Medicines.

[33]  M. Tsai,et al.  Suppression of adipogenesis and obesity in high-fat induced mouse model by hydroxylated polymethoxyflavones. , 2013, Journal of agricultural and food chemistry.

[34]  Min-Jeong Shin,et al.  Antiobesity effects of quercetin-rich onion peel extract on the differentiation of 3T3-L1 preadipocytes and the adipogenesis in high fat-fed rats. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[35]  J. Gimble,et al.  Tools for the identification of bioactives impacting the metabolic syndrome: screening of a botanical extract library using subcutaneous and visceral human adipose-derived stem cell-based assays. , 2012, The Journal of nutritional biochemistry.

[36]  T. Shimada,et al.  Polymethoxyflavonoids from Kaempferia parviflora induce adipogenesis on 3T3-L1 preadipocytes by regulating transcription factors at an early stage of differentiation. , 2012, Biological & pharmaceutical bulletin.

[37]  Hsiang-Ru Lin Sesquiterpene lactones from Tithonia diversifolia act as peroxisome proliferator-activated receptor agonists. , 2012, Bioorganic & medicinal chemistry letters.

[38]  A. Segura‐Carretero,et al.  Synergism of plant-derived polyphenols in adipogenesis: perspectives and implications. , 2012, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[39]  M. Barbieri,et al.  The effect of dehydroleucodine in adipocyte differentiation. , 2011, European journal of pharmacology.

[40]  Hyeonmi Ham,et al.  Nobiletin suppresses adipogenesis by regulating the expression of adipogenic transcription factors and the activation of AMP-activated protein kinase (AMPK). , 2011, Journal of agricultural and food chemistry.

[41]  B. Cha,et al.  Artepillin C, as a PPARγ ligand, enhances adipocyte differentiation and glucose uptake in 3T3-L1 cells. , 2011, Biochemical pharmacology.

[42]  M. Mahmoudi,et al.  Sesquiterpene lactone fraction from Artemisia khorassanica inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression through the inactivation of NF-κB , 2010, Immunopharmacology and immunotoxicology.

[43]  Y. Nozawa,et al.  Ethanolic extracts of Brazilian red propolis promote adipocyte differentiation through PPARγ activation. , 2010, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[44]  J. Bland,et al.  Antidiabetic screening of commercial botanical products in 3T3-L1 adipocytes and db/db mice. , 2010, Journal of medicinal food.

[45]  Kathrine B. Christensen,et al.  Identification of bioactive compounds from flowers of black elder (Sambucus nigra L.) that activate the human peroxisome proliferator‐activated receptor (PPAR) γ , 2010, Phytotherapy research : PTR.

[46]  M. Ramanathan,et al.  Inhibition of protein tyrosine phosphatase 1B and regulation of insulin signalling markers by caffeoyl derivatives of chicory (Cichorium intybus) salad leaves , 2010, British Journal of Nutrition.

[47]  M. González-Chávez,et al.  Cecropia obtusifolia Bertol and its active compound, chlorogenic acid, stimulate 2-NBDglucose uptake in both insulin-sensitive and insulin-resistant 3T3 adipocytes. , 2008, Journal of ethnopharmacology.

[48]  Chien-Fu Huang,et al.  Bioassay‐guided purification and identification of PPARα/γ agonists from Chlorella sorokiniana , 2008, Phytotherapy research : PTR.

[49]  Xiangnian Fang,et al.  Kaempferol and quercetin isolated from Euonymus alatus improve glucose uptake of 3T3-L1 cells without adipogenesis activity. , 2008, Life sciences.

[50]  R. Yu,et al.  Citrus auraptene acts as an agonist for PPARs and enhances adiponectin production and MCP-1 reduction in 3T3-L1 adipocytes. , 2008, Biochemical and biophysical research communications.

[51]  G. Shulman,et al.  Obesity-associated improvements in metabolic profile through expansion of adipose tissue. , 2007, The Journal of clinical investigation.

[52]  Daigo Abe,et al.  Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes. , 2007, Biochemical and biophysical research communications.

[53]  U. Smith,et al.  The effect of PPARγ ligands on the adipose tissue in insulin resistance , 2005 .

[54]  M. Ubukata,et al.  Inhibition of Preadipocyte Differentiation by Germacranolides from Calea urticifolia in 3T3-L1 Cells , 2005, Bioscience, biotechnology, and biochemistry.

[55]  S. Smith Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones. , 2003, Biochimie.

[56]  J. Prins,et al.  Effects of rosiglitazone and linoleic acid on human preadipocyte differentiation , 2003, European Journal of Clinical Investigation.

[57]  L. Witters The blooming of the French lilac. , 2001, The Journal of clinical investigation.

[58]  E. Danforth Failure of adipocyte differentiation causes type II diabetes mellitus? , 2000, Nature Genetics.