A Flavonoid-rich Zuccagnia punctata Extract Prevents High Fat Diet-induced Normal Weight Obesity in a Rabbit Model

Abstract

Oral administration of rich in flavonoids hydroalcoholic extract from Zuccagnia punctata (ZpE) improves lipid profile and prevents vascular dysfunction in hypercholesterolemic rabbits. This study aimed to evaluate the ability of ZpE to prevent metabolic and vascular alterations induced by high fat diet (HFD) on a metabolically obese and normal weight rabbit model. The major components of ZpE were analyzed by HPLC method. Rabbits were separated into six groups: 1-fed on standard chow (CD); 2-fed on HFD; 3, 4, 5- fed on HFD and orally administrated 2.5 mg, 5 mg or 10 mg GAE/day of ZpE, respectively (ZpE- HFD); 6- fed on HFD and orally administered 30 mg orlistat/day (Or-HFD). All diets were administrated by 6 weeks. The major compounds of ZpE identified were chalcones: 2′,4′-dihydroxy-3′-methoxychalcone and 2′,4′-dihydroxychalcone. Oral treatment with ZpE 5 mg GAE/day as well as orlistat prevented the HFD-induced increase of triglycerides, fasting glucose, intraperitoneal glucose test, white cells, and TyG index. Acetylcholine relaxation was reduced in arteries from HFD group and oral administration of ZpE reached this response to CD values. Contractile response to angiotensin II was lower in arteries from rabbits fed on HFD treated with ZpE 5 and 10 mg GAE/day than those of untreated rabbits. Moreover, ZpE could inhibit the activity of pancreatic lipase in vitro and in vivo. In conclusion the ZpE may prevent normal weight obesity by inhibiting the pancreatic lipase. Thus, the use of ZpE as a natural product in the prevention of metabolic syndrome and endothelial dysfunction is very promising.

Key words

high fat diet - Zuccagnia punctata - Fabaceae - metabolic syndrome - flavonoids - endothelial function

• References

• 1 Kaur JA. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014; 2014: 943162
• 2 Dobson R, Burgess MI, Sprung VS, Irwin A, Hamer M, Jones J. Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity. Int J Obes (Lond) 2015; 40: 153-161
• 3 Wijayatunga NN, Dhurandhar EJ. Normal weight obesity and unaddressed cardiometabolic health risk – a narrative review. Int J Obes (Lond) 2021; 45: 2141-2155
• 4 Romero-Corral A, Somers VK, Sierra-Johnson J, Korenfeld Y, Boarin S, Korinek J, Jensen MD, Parati G, Lopez-Jimenez F. Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality. Eur Heart J 2010; 31: 737-746
• 5 Alarcon G, Roco J, Medina M, Medina A, Peral M, Jerez S. High fat diet-induced metabolically obese and normal weight rabbit model shows early vascular dysfunction: mechanisms involved. Int J Obes (Lond) 2018; 42: 1535-1543
• 6 Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194-1199
• 7 Payab M, Hasani-Ranjbar S, Shahbal N, Qorbani M, Aletaha A, Haghi-Aminjan H, Soltani A, Khatami F, Nikfar S, Hassani S, Abdollahi M, Larijani B. Effect of the herbal medicines in obesity and metabolic syndrome: A systematic review and meta-analysis of clinical trials. Phytother Res 2020; 34: 526-545
• 8 Mahapatra DK, Bharti SK. Therapeutic potential of chalcones as cardiovascular agents. Life Sci 2016; 148: 154-172
• 9 Cabrera AL. Territorios fitogeográficos de la República Argentina. Bol Soc Argent Bot 1951; 4: 1-2
• 10 Isla MI, Moreno MA, Nuño G, Rodriguez F, Carabajal A, Alberto MR, Zampini IC. Zuccagnia punctata: A review of its traditional uses, phytochemistry, pharmacology and toxicology. Nat Prod Commun 2016; 11: 1749-1755
• 11 Svetaz L, Tapia A, López SN, Furlán RL, Petenatti E, Pioli R, Schmeda-Hirschmann G, Zacchino SA. Antifungal chalcones and new caffeic acid esters from Zuccagnia punctata acting against soybean infecting fungi. J Agric Food Chem 2004; 52: 3297-3300
• 12 Solorzano ER, Bortolini C, Bogialli S, Di Gangi IM, Favaro G, Maldonado L, Pastore P. Use of a LC-DAD-QTOF system for the characterization of the phenolic profile of the argentinean plant Zuccagnia punctata and of the related propolis: New biomarkers. J Func Foods 2017; 33: 425-435
• 13 Roco J, Alarcon G, Medina M, Zampini C, Isla MI, Jerez S. Oral administration of Zuccagnia punctata extract improves lipid profile, reduces oxidative stress and normalizes vascular function in hypercholesterolemic rabbits. Phytomedicine 2018; 48: 104-111
• 14 Williams JW, Morrison JF. The kinetics of reversible tight-binding inhibition. Methods Enzymol 1979; 63: 437-467
• 15 Filippatos T, Erdemezis CS, Gazi IF, Nakou ES, Mikhailidis DP, Elisaf MS. Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf 2008; 31: 53-65
• 16 Buchholz T, Melzig MF. Polyphenolic compounds as pancreatic lipase inhibitors. Planta Med 2015; 81: 771-783
• 17 Huo PC, Hu Q, Shu S, Zhou QH, He RJ, Hou J, Guan XQ, Tu DZ, Hou XD, Liu P, Zhang N, Liu ZG, Ge GB. Design, synthesis, and biological evaluation of novel chalcone-like compounds as potent and reversible pancreatic lipase inhibitors. Bioorg Med Chem 2021; 29: 115853
• 18 Roco J, Alarcon G, Sierra L, Zampini C, Isla MI, Jerez S. Beneficial effects of hydroalcoholic extract and flavonoids from Zuccagnia punctata in a rabbit model of vascular dysfunction induced by high cholesterol diet. Med Chem Res 2017; 26: 2336-2344
• 19 Martinez-Gonzalez AI, Alvarez-Parrilla E, Díaz-Sánchez ÁG, de la Rosa LA, Núñez-Gastélum JA, Vazquez-Flores AA, Gonzalez-Aguilar GA. In vitro inhibition of pancreatic lipase by polyphenols: a kinetic, fluorescence spectroscopy and molecular docking study. Food Technol Biotechnol 2017; 55: 519-530
• 20 Gidez LI. Effect of dietary fat on pancreatic lipase levels in the rat. J Lipid Res 1973; 14: 169-177
• 21 Mironidou Tzouveleki M, Anogeianaki A, Dokos Ch, Koutsonikolas D, Liagouris J, Anogeianakis G. The effect of Orlistat on blood glucose and body weight in an onset diabetic rat model. Rev Clin Pharmacol Pharmacokinet Int Ed 2008; 22: 256-258
• 22 Mulder H, Yang S, Winzell MS, Holm C, Ahrén B. Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion. Diabetes 2004; 53: 122-128
• 23 Salas AL, Mercado MI, Orqueda ME, Correa Uriburu FM, García ME, Pérez MJ, de los Angeles Alvarez M, Ponessa GI, Maldonado Maldonado L, Zampini IC, Isla MI. Zuccagnia-type Propolis from Argentina: A potential functional ingredient in food to pathologies associated to metabolic syndrome and oxidative stress. J Food Sci 2020; 85: 2578-2588
• 24 Bale AT, Khan KM, Salar U, Chigurupati S, Fasina T, Ali F, Perveen S. Chalcones and bis-chalcones: As potential α-amylase inhibitors; synthesis, in vitro screening, and molecular modelling studies. Bioorg Chem 2018; 79: 179-189
• 25 Cai CY, Rao L, Rao Y, Guo JX, Xiao ZZ, Cao JY, Huang ZS, Wang B. Analogues of xanthones chalcones and bis-chalcones as α-glucosidase inhibitors and anti-diabetes candidates. Eur J Med Chem 2017; 130: 51-59
• 26 Mahapatra DK, Asati V, Bharti SK. Chalcones and their therapeutic targets for the management of diabetes: structural and pharmacological perspectives. Eur J Med Chem 2015; 92: 839-865
• 27 Kim JA, Montagnani M, Chandrasekran S, Quon M. Role of lipotoxicity in endothelial dysfunction. Heart Fail Clin 2012; 8: 589-607
• 28 Kajikawa M, Maruhashi T, Matsumoto T, Iwamoto Y, Iwamoto A, Oda N, Kishimoto S, Matsui S, Aibara Y, Hidaka T, Kihara Y, Chayama K, Goto C, Noma K, Nakashima A, Tomiyama H, Takase B, Yamashina A, Higashi Y. Relationship between serum triglyceride levels and endothelial function in a large community-based study. Atherosclerosis 2016; 249: 70-75
• 29 Hodgson JM, Croft KD. Dietary flavonoids: effects on endothelial function and blood pressure. J Sci Food Agric 2006; 86: 2492-2498
• 30 Papageorgiou N, Tousoulis D, Katsargyris A, Charakida M, Androulakis E, Siasos G, Tentolouris C, Stefanadis C. Antioxidant treatment and endothelial dysfunction: Is it time for flavonoids?. Recent Pat Cardiovasc Drug Discov 2013; 8: 81-92
• 31 Lau YS, Kwan CY, Kub TC, Hsiehb WT, Wang HD, Nishibed S, Mustafa MR. Apocynum venetum leaf extract, an antihypertensive herb, inhibits rat aortic contraction induced by angiotensin II: A nitric oxide and superoxide connection. J Ethnopharmacol 2012; 143: 565-571
• 32 Guerrero-Romero F, Simental-Mendía LE, González-Ortiz M, Martínez-Abundis E, Ramos-Zavala MG, Hernández-González SO, Jacques-Camarena O, Rodríguez-Morán M. The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab 2010; 95: 3347-3351
• 33 Sahani KM, Khan IM, Chandan RC. Bovine pancreatic lipase: isolation, homogeneity, and characterization. J Dairy Sci 1976; 59: 369-375
• 34 Hasan F, Shah AA, Hameed A. Methods for detection and characterization of lipases: a comprehensive review. Biotech Adv 2009; 27: 782-798