Abstract
Background: Leptin is predominant in regulating body weight by stimulating energy expenditure through its neuronal action in the brain. Moreover, it is projected to adipose tissue and induces adipocyte browning by activating the β3-adrenergic receptor (β3AR). However, the expression of leptin receptor (Lep-R) and β3AR in people with obesity is downregulated.
Aim: We hypothesized that Hibiscus sabdariffa Linn. extract (HSE) would increase hypothalamus arcuate nucleus (ARC) Lep-R and white adipose tissue (WAT) β3AR mRNA expression in DIO rats. This study also analyzed the potency of H. sabdariffa bioactive compounds as activators of Lep-R and β3AR by an in-silico experiment.
Methods: Twenty-four male Sprague-Dawley rats were divided into four groups: Control (standard food), DIO (high-fat diet), DIO-Hib200 (HFD+HSE 200 mg/kg BW), and DIO-Hib400 (HFD+HSE400 mg/kg BW). HSE was administered orally for five weeks, once a day.
Results: HSE administration significantly (p <0,05) increased the ARC Lep-R expression. The Lee index significantly decreased to the normal range (≤ 310) with p <0,001 for DIO-Hib200 and p <0,01 for DIO-Hib400. Among 39 bioactive compounds, 5-O-caffeoyl shikimic acid exhibited high free binding scores (-8,63) for Lep-R, and myricetin_3_arabinogalactoside had high free binding scores (-9,39) for β3AR. These binding predictions could activate Lep-R and β3AR.
Conclusion: This study highlights that HSE could be a potential therapeutic target for obesity by increasing LepR mRNA and leptin sensitivity, enhancing energy expenditure, and reducing obesity.
Graphical Abstract
[1]
Guyenet, S.J.; Schwartz, M.W. Clinical review: Regulation of food intake, energy balance, and body fat mass: Implications for the pathogenesis and treatment of obesity. J. Clin. Endocrinol. Metab., 2012, 97(3), 745-755.
[http://dx.doi.org/10.1210/jc.2011-2525] [PMID: 22238401]
[http://dx.doi.org/10.1210/jc.2011-2525] [PMID: 22238401]
[2]
Lee, M.K.; Lee, B.; Kim, C.Y. Natural extracts that stimulate adipocyte browning and their underlying mechanisms. Antioxidants, 2021, 10(2), 308.
[3]
Varela, L.; Horvath, T.L. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep., 2012, 13(12), 1079-1086.
[http://dx.doi.org/10.1038/embor.2012.174] [PMID: 23146889]
[http://dx.doi.org/10.1038/embor.2012.174] [PMID: 23146889]
[4]
Vargas-Castillo, A.; Fuentes-Romero, R.; Rodriguez-Lopez, L.A.; Torres, N.; Tovar, A.R. Understanding the biology of thermogenic fat: Issss browning a new approach to the treatment of obesity? Arch. Med. Res., 2017, 48(5), 401-413.
[http://dx.doi.org/10.1016/j.arcmed.2017.10.002] [PMID: 29102386]
[http://dx.doi.org/10.1016/j.arcmed.2017.10.002] [PMID: 29102386]
[5]
Breslow, M.J.; An, Y.; Berkowitz, D.E. Beta-3 adrenoceptor (beta-3AR) expression in leptin treated Ob/Ob mice. Life Sci., 1997, 61(1), 59-64.
[http://dx.doi.org/10.1016/S0024-3205(97)00358-5] [PMID: 9200670]
[http://dx.doi.org/10.1016/S0024-3205(97)00358-5] [PMID: 9200670]
[6]
Morales-Luna, E.; Pérez-Ramírez, I.F.; Salgado, L.M.; Castaño-Tostado, E.; Gómez-Aldapa, C.A.; Reynoso-Camacho, R. The main beneficial effect of roselle (Hibiscus sabdariffa) on obesity is not only related to its anthocyanin content. J. Sci. Food Agric., 2019, 99(2), 596-605.
[http://dx.doi.org/10.1002/jsfa.9220] [PMID: 29943479]
[http://dx.doi.org/10.1002/jsfa.9220] [PMID: 29943479]
[7]
Anggraini, S.; Kartinah, N.T. Effectiveness of hibiscus sabdariffa linn for obesity treatment: A systematic review of randomized controlled trials. Ind. J. Med., 2021, 6(4), 439-451.
[http://dx.doi.org/10.26911/theijmed.2021.06.04.10]
[http://dx.doi.org/10.26911/theijmed.2021.06.04.10]
[8]
Kartinah, N.T.; Komara, N.; Noviati, N.D.; Dewi, S.; Yolanda, S.; Radhina, A. Potential of Hibiscus sabdariffa Linn. in managing FGF21 resistance in diet-induced-obesity rats via miR-34a regulation. Vet. Med. Sci., 2021, 8(1), 309-317.
[PMID: 34687158]
[PMID: 34687158]
[9]
Bryda, E.C. The Mighty Mouse: The impact of rodents on advances in biomedical research. Mo. Med., 2013, 110(3), 207-211.
[PMID: 23829104]
[PMID: 23829104]
[10]
Olfert, E.D.; Cross, B.M.; McWilliam, A.A. Guide to the care and use of experimental animals; Canadian Council on Animal Care: Ontario, 1993.
[11]
Jamali, E.; Asad, M.R.; Rasoli, A. The effect of high-intensity interval training (HIIT) on resistin gene expression in visceral adipose tissue in obese male rats. Int. J. Appl. Exerc. Physiol., 2016.
[12]
Shukla, S.S.; Sharwan, G.; Jain, P.; Pandey, R. Toxicity and safety profiles of methanolic extract of pistacia integerrima J. L. Stewart ex brandis (PI) for wistar rats. J. Pharmacopuncture, 2016, 19(3), 253-258.
[http://dx.doi.org/10.3831/KPI.2016.19.027] [PMID: 27695635]
[http://dx.doi.org/10.3831/KPI.2016.19.027] [PMID: 27695635]
[13]
Salehi, M.S.; Namavar, M.R.; Shirazi, M.R.J.; Rahmanifar, F. A simple method for isolation of the anteroventral periventricular and arcuate nuclei of the rat hypothalamus. Anatomy, 2013, 7(1), 48-51.
[14]
Herranz-López, M.; Olivares-Vicente, M.; Encinar, J.; Barrajón-Catalán, E.; Segura-Carretero, A.; Joven, J.; Micol, V. Multi-targeted molecular effects of Hibiscus sabdariffa polyphenols: An opportunity for a global approach to obesity. Nutrients, 2017, 9(8), 907.
[http://dx.doi.org/10.3390/nu9080907] [PMID: 28825642]
[http://dx.doi.org/10.3390/nu9080907] [PMID: 28825642]
[15]
Timper, K.; Brüning, J.C. Hypothalamic circuits regulating appetite and energy homeostasis: Pathways to obesity. Dis. Model. Mech., 2017, 10(6), 679-689.
[http://dx.doi.org/10.1242/dmm.026609] [PMID: 28592656]
[http://dx.doi.org/10.1242/dmm.026609] [PMID: 28592656]
[16]
Straat, M.E.; Schinkelshoek, M.S.; Fronczek, R.; Lammers, G.J.; Rensen, P.C.N.; Boon, M.R. Role of brown adipose tissue in adiposity associated with narcolepsy type 1. Front. Endocrinol., 2020, 11, 145.
[http://dx.doi.org/10.3389/fendo.2020.00145] [PMID: 32373062]
[http://dx.doi.org/10.3389/fendo.2020.00145] [PMID: 32373062]
[17]
Martin, R.L.; Perez, E.; He, Y.J.; Dawson, R., Jr; Millard, W.J. Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation. Metabolism, 2000, 49(11), 1479-1484.
[http://dx.doi.org/10.1053/meta.2000.17695] [PMID: 11092515]
[http://dx.doi.org/10.1053/meta.2000.17695] [PMID: 11092515]
[18]
Wauman, J.; Zabeau, L.; Tavernier, J. The leptin receptor complex: Heavier than expected? Front. Endocrinol., 2017, 8(FEB), 30.
[http://dx.doi.org/10.3389/fendo.2017.00030] [PMID: 28270795]
[http://dx.doi.org/10.3389/fendo.2017.00030] [PMID: 28270795]
[19]
Liu, Z.J.; Bian, J.; Liu, J.; Endoh, A. Obesity reduced the gene expressions of leptin receptors in hypothalamus and liver. Horm. Metab. Res., 2007, 39(7), 489-494.
[http://dx.doi.org/10.1055/s-2007-981680] [PMID: 17611900]
[http://dx.doi.org/10.1055/s-2007-981680] [PMID: 17611900]
[20]
Zhai, L.; Zhao, J.; Zhu, Y.; Liu, Q.; Niu, W.; Liu, C.; Wang, Y. Downregulation of leptin receptor and kisspeptin/GPR54 in the murine hypothalamus contributes to male hypogonadism caused by high-fat diet-induced obesity. Endocrine, 2018, 62(1), 195-206.
[http://dx.doi.org/10.1007/s12020-018-1646-9] [PMID: 29948931]
[http://dx.doi.org/10.1007/s12020-018-1646-9] [PMID: 29948931]
[21]
Mazor, R.; Friedmann-Morvinski, D.; Alsaigh, T.; Kleifeld, O.; Kistler, E.B.; Rousso-Noori, L.; Huang, C.; Li, J.B.; Verma, I.M.; Schmid-Schönbein, G.W. Cleavage of the leptin receptor by matrix metalloproteinase-2 promotes leptin resistance and obesity in mice. Sci. Transl. Med., 2018, 10(455), eaah6324.
[http://dx.doi.org/10.1126/scitranslmed.aah6324] [PMID: 30135249]
[http://dx.doi.org/10.1126/scitranslmed.aah6324] [PMID: 30135249]
[22]
Kumar, G.B.; Nair, B.G.; Perry, J.J.P.; Martin, D.B.C. Recent insights into natural product inhibitors of matrix metalloproteinases. MedChemComm, 2019, 10(12), 2024-2037.
[http://dx.doi.org/10.1039/C9MD00165D] [PMID: 32904148]
[http://dx.doi.org/10.1039/C9MD00165D] [PMID: 32904148]
[23]
Riaz, G.; Chopra, R. A review on phytochemistry and therapeutic uses of Hibiscus sabdariffa L. Biomed. Pharmacother., 2018, 102(102), 575-586.
[http://dx.doi.org/10.1016/j.biopha.2018.03.023] [PMID: 29597091]
[http://dx.doi.org/10.1016/j.biopha.2018.03.023] [PMID: 29597091]
[24]
Meng, X-Y.; Zhang, H-X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Comput. Aided. Drug Des., 2012, 7(2), 146-157.
[25]
Lenin, M.; Ramakrishnan, E.; Sankaran, M. Structure-based molecular docking studies toward exploring phytoestrogen against breast cancer. Eurasian J. Med. Oncol., 2022, 6(2), 142-149.
[26]
Maruthanila, V.L.; Elancheran, R.; Mirunalini, S. In Silico approach and molecular docking studies of potent bioactive compounds of carica papaya as anti-breast cancer agents. Curr. Comput. Aided Drug Des., 2022, 18(3), 196-212.
[http://dx.doi.org/10.2174/1573409918666220519112027] [PMID: 35598239]
[http://dx.doi.org/10.2174/1573409918666220519112027] [PMID: 35598239]
[27]
Fenzl, A.; Kiefer, F.W. Brown adipose tissue and thermogenesis. Horm. Mol. Biol. Clin. Investig., 2014, 19(1), 25-37.
[http://dx.doi.org/10.1515/hmbci-2014-0022] [PMID: 25390014]
[http://dx.doi.org/10.1515/hmbci-2014-0022] [PMID: 25390014]
[28]
Dodd, G.T.; Decherf, S.; Loh, K.; Simonds, S.E.; Wiede, F.; Balland, E.; Merry, T.L.; Münzberg, H.; Zhang, Z.Y.; Kahn, B.B.; Neel, B.G.; Bence, K.K.; Andrews, Z.B.; Cowley, M.A.; Tiganis, T. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell, 2015, 160(1-2), 88-104.
[http://dx.doi.org/10.1016/j.cell.2014.12.022] [PMID: 25594176]
[http://dx.doi.org/10.1016/j.cell.2014.12.022] [PMID: 25594176]
[29]
Collins, S.; Daniel, K.W.; Rohlfs, E.M. Depressed expression of adipocyte β-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents. Int. J. Obes., 1999, 23(7), 669-677.
[http://dx.doi.org/10.1038/sj.ijo.0800894] [PMID: 10454099]
[http://dx.doi.org/10.1038/sj.ijo.0800894] [PMID: 10454099]
[30]
Vernon Rayner, D. The sympathetic nervous system in white adipose tissue regulation. Proc. Nutr. Soc., 2001, 60(3), 357-364.
[http://dx.doi.org/10.1079/PNS2001101] [PMID: 11681810]
[http://dx.doi.org/10.1079/PNS2001101] [PMID: 11681810]
[31]
Valentine, J.M.; Ahmadian, M.; Keinan, O.; Abu-Odeh, M.; Zhao, P.; Zhou, X. β3-adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity. J. Clin. Invest., 2021, 132(2), e153357.
[32]
Rayner, D.V.; Trayhurn, P. Regulation of leptin production: Sympathetic nervous system interactions. J. Mol. Med., 2001, 79(1), 8-20.
[http://dx.doi.org/10.1007/s001090100198] [PMID: 11327106]
[http://dx.doi.org/10.1007/s001090100198] [PMID: 11327106]
[33]
de Jong, J.M.A.; Wouters, R.T.F.; Boulet, N.; Cannon, B.; Nedergaard, J.; Petrovic, N. The β3-adrenergic receptor is dispensable for browning of adipose tissues. Am. J. Physiol. Endocrinol. Metab., 2017, 312(6), E508-E518.
[http://dx.doi.org/10.1152/ajpendo.00437.2016]
[http://dx.doi.org/10.1152/ajpendo.00437.2016]
[34]
Santoso, D.I.S.; Sianipar, I.R.; Kartinah, N.T. The role of physical exercise in obesity managemenT: Irisin in action in the brown process. Ind. J. Sports Phys. Sci., 2021, 3(1), 27.
[http://dx.doi.org/10.51671/jifo.v3i1.86]
[http://dx.doi.org/10.51671/jifo.v3i1.86]
[35]
Kuppusamy, U.R.; Das, N.P. Potentiation of β-adrenoceptor agonist-mediated lipolysis by quercetin and fisetin in isolated rat adipocytes. Biochem. Pharmacol., 1994, 47(3), 521-529.
[http://dx.doi.org/10.1016/0006-2952(94)90184-8] [PMID: 7906943]
[http://dx.doi.org/10.1016/0006-2952(94)90184-8] [PMID: 7906943]
[36]
Concha, F.; Prado, G.; Quezada, J.; Ramirez, A.; Bravo, N.; Flores, C.; Herrera, J.J.; Lopez, N.; Uribe, D.; Duarte-Silva, L.; Lopez-Legarrea, P.; Garcia-Diaz, D.F. Nutritional and non-nutritional agents that stimulate white adipose tissue browning. Rev. Endocr. Metab. Disord., 2019, 20(2), 161-171.
[http://dx.doi.org/10.1007/s11154-019-09495-y] [PMID: 31020455]
[http://dx.doi.org/10.1007/s11154-019-09495-y] [PMID: 31020455]
[37]
Marhuenda, J.; Perez, S.; Victoria-Montesinos, D.; Abellán, M.S.; Caturla, N.; Jones, J.; López-Román, J. A randomized, double-blind, placebo controlled trial to determine the effectiveness a polyphenolic extract (Hibiscus sabdariffa and lippia citriodora) in the reduction of body fat mass in healthy subjects. Foods, 2020, 9(1), 55.
[http://dx.doi.org/10.3390/foods9010055]
[http://dx.doi.org/10.3390/foods9010055]
[38]
Boix-Castejón, M.; Herranz-López, M.; Pérez Gago, A.; Olivares-Vicente, M.; Caturla, N.; Roche, E. Hibiscus and lemon verbena polyphenols modulate appetite-related biomarkers in overweight subjects: A randomized controlled trial. Food Funct., 2018, 9(6), 3173-3184.
[39]
Chang, H.C.; Peng, C.H.; Yeh, D.M.; Kao, E.S.; Wang, C.J. Hibiscus sabdariffa extract inhibits obesity and fat accumulation, and improves liver steatosis in humans. Food Funct., 2014, 5(4), 734-739.
[http://dx.doi.org/10.1039/c3fo60495k] [PMID: 24549255]
[http://dx.doi.org/10.1039/c3fo60495k] [PMID: 24549255]
