Anti-adipogenic Activities of Alnus incana and Populus balsamifera Bark Extracts, Part I: Sites and Mechanisms of Action

Abstract

Obesity is an epidemic in most developed countries and novel therapeutic approaches are needed. In the course of a screening project of medicinal plants used by the Eastern James Bay Cree of Canada and having potential for the treatment of diabetes, we have identified several products that inhibit adipogenesis, suggesting potential antiobesity activities. The inhibitory activity of two of these, the extract of the inner bark of the deciduous trees Alnus incana ssp. rugosa (Speckled Alder) and Populus balsamifera L. (Balsam Poplar), was analyzed using the 3T3-L1 cell model of adipogenesis. Intracellular triglyceride accumulation, pre-adipocyte proliferation, and PPAR-γ activity were measured. Alnus incana extracts acted early in the differentiation process but did not affect clonal expansion of pre-adipocytes nor the morphological transformation from fibroblast-like to rounded fat-laden cells. Alnus incana extracts were found to act as partial agonists toward PPAR-γ activity. In contrast, Populus balsamifera extracts completely abrogated adipogenesis, severely limited clonal expansion of pre-adipocytes and generally maintained cells in an undifferentiated fibroblast-like morphology. Populus balsamifera extracts exerted antagonistic action against PPAR-γ activity. It is concluded that, through their actions on the adipocyte, these plant products may be useful for the treatment of obesity and related metabolic diseases.

Key words

Alnus incana ssp. rugosa - (Du roi) R. T. Clausen - Betulaceae - Populus balsamifera L. - Salicaceae - aboriginal traditional medicine - 3T3‐L1 adipocyte - peroxisome proliferator activated receptor gamma - obesity

References

• 1 James P T, Rigby N, Leach R. The obesity epidemic, metabolic syndrome and future prevention strategies.  Eur J Cardiovasc Prev Rehabil. 2004;  11 3-8
• 2 Prentice A M. The emerging epidemic of obesity in developing countries.  Int J Epidemiol. 2006;  35 93-99
• 3 Hainer V, Toplak H, Mitrakou A. Treatment modalities of obesity: what fits whom?.  Diab Care. 2008;  31 (Suppl. 2) S269-S277
• 4 Chaput J P, Tremblay A. Current and novel approaches to the drug therapy of obesity.  Eur J Clin Pharmacol. 2006;  62 793-803
• 5 Harp J B. New insights into inhibitors of adipogenesis.  Curr Opin Lipidol. 2004;  15 303-307
• 6 Petersen K F, Shulman G I. Etiology of insulin resistance.  Am J Med. 2006;  119 S10-S16
• 7 Wang P, Mariman E, Renes J, Keijer J. The secretory function of adipocytes in the physiology of white adipose tissue.  J Cell Physiol. 2008;  216 3-13
• 8 Feve B. Adipogenesis: cellular and molecular aspects.  Best Pract Res Clin Endocrinol Metab. 2005;  19 483-499
• 9 Fajas L, Miard S, Briggs M R, Auwerx J. Selective cyclo-oxygenase-2 inhibitors impair adipocyte differentiation through inhibition of the clonal expansion phase.  J Lipid Res. 2003;  44 1652-1659
• 10 Yan H, Kermouni A, Abdel-Hafez M, Lau D C. Role of cyclooxygenases COX-1 and COX-2 in modulating adipogenesis in 3T3-L1 cells.  J Lipid Res. 2003;  44 424-429
• 11 Engelman J A, Berg A H, Lewis R Y, Lin A, Lisanti M P, Scherer P E. Constitutively active mitogen-activated protein kinase kinase 6 (MKK6) or salicylate induces spontaneous 3T3-L1 adipogenesis.  J Biol Chem. 1999;  274 35630-35638
• 12 Bouloumie A, Sengenes C, Portolan G, Galitzky J, Lafontan M. Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation.  Diabetes. 2001;  50 2080-2086
• 13 Oberfield J L, Collins J L, Holmes C P, Goreham D M, Cooper J P, Cobb J E, Lenhard J M, Hull-Ryde E A, Mohr C P, Blanchard S G, Parks D J, Moore L B, Lehmann J M, Plunket K, Miller A B, Milburn M V, Kliewer S A, Willson T M. A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.  Proc Natl Acad Sci USA. 1999;  96 6102-6106
• 14 Hwang J T, Park I J, Shin J I, Lee Y K, Lee S K, Baik H W, Ha J, Park O J. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase.  Biochem Biophys Res Commun. 2005;  338 694-699
• 15 Vane J R, Botting R M. Anti-inflammatory drugs and their mechanism of action.  Inflamm Res. 1998;  47 (Suppl. 2) S78-S87
• 16 Demeule M, Brossard M, Page M, Gingras D, Beliveau R. Matrix metalloproteinase inhibition by green tea catechins.  Biochim Biophys Acta. 2000;  1478 51-60
• 17 Polya G. Biochemical targets of plant bioactive compounds: a pharmacological reference guide to sites of action and biological effects. Boca Raton, FL; CRC Press 2003
• 18 Liu X, Kim J K, Li Y, Li J, Liu F, Chen X. Tannic acid stimulates glucose transport and inhibits adipocyte differentiation in 3T3-L1 cells.  J Nutr. 2005;  135 165-171
• 19 Pinent M, Blade M C, Salvado M J, Arola L, Hackl H, Quackenbush J, Trajanoski Z, Ardévol A. Grape-seed derived procyanidins interfere with adipogenesis of 3T3-L1 cells at the onset of differentiation.  Int J Obes (London). 2005;  29 934-941
• 20 Spoor D C, Martineau L C, Leduc C, Benhaddou-Andaloussi A, Meddah B, Harris C, Burt A, Fraser M H, Coonishish J, Joly E, Cuerrier A, Bennett S A, Johns T, Prentki M, Arnason J T, Haddad P S. Selected plant species from the Cree pharmacopoeia of northern Quebec possess anti-diabetic potential.  Can J Physiol Pharmacol. 2006;  84 847-858
• 21 Harbilas D, Martineau L C, Harris C S, Adeyiwola-Spoor D C, Saleem A, Lambert J, Caves D, Johns T, Prentki M, Cuerrier A, Arnason J T, Bennett S A, Haddad P S. Evaluation of the anti-diabetic potential of selected medicinal plant extracts from the Canadian Boreal Forest used to treat symptoms of diabetes: part II.  Can J Physiol Pharmacol. 2009;  87 479-492
• 22 Leduc C, Coonishish J, Haddad P, Cuerrier A. Plants used by the Cree Nation of Eeyou Istchee (Quebec, Canada) for the treatment of diabetes: a novel approach in quantitative ethnobotany.  J Ethnopharmacol. 2006;  105 55-63
• 23 Martineau L C, Muhammad A, Saleem A, Hervé J, Harris C S, Arnason J T, Haddad P S. Anti-adipogenic activities of Alnus incana and Populus balsamifera bark extracts, part II: bioassay-guided identification of actives salicortin and oregonin.  Planta Med. 2010;  DOI: 10.1055/s-0029-1240991 , advance online publication
  
• 24 Benhaddou-Andaloussi A, Martineau L C, Vallerand D, Haddad Y, Afshar A, Settaf A, Haddad P S. Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells.  Diab Obes Metab. 2010;  12 148-157
• 25 Harris C S, Burt A J, Saleem A, Le P M, Martineau L C, Haddad P S, Bennett S A, Arnason J T. A single HPLC-PAD-APCI/MS method for the quantitative comparison of phenolic compounds found in leaf, stem, root and fruit extracts of Vaccinium angustifolium.  Phytochem Anal. 2007;  18 161-169
• 26 Arnason J T, Hebda R J, Johns T. Use of plants for food and medicine by Native Peoples of Eastern Canada.  Can J Bot. 1981;  59 2189-2325
• 27 Marles R J, Clavelle C, Monteleone L, Tays N, Burns D. Aboriginal plant use in Canada's northwest boreal forest. Vancouver; UBC Press 2000
• 28 Yu K, Bayona W, Kallen C B, Harding H P, Ravera C P, McMahon G, Brown M, Lazar M A. Differential activation of peroxisome proliferator-activated receptors by eicosanoids.  J Biol Chem. 1995;  270 23975-23983