A combination of Citrus aurantifolia fruit rind and Theobroma cacao seed extracts supplementation enhances metabolic rates in overweight subjects: a randomized, placebo-controlled, cross-over study

Keywords: Body fat mass;, Citrus aurantifolia, Fat and Carbohydrate oxidation, Resting energy expenditure, Thermogenic botanical composition, Theobroma cacao

Abstract

Background and objective: LN19183 is a proprietary, synergistic combination of Citrus aurantifolia fruit rind and Theobroma cacao seed extracts that increased resting energy expenditure (REE) in high-fat diet (HFD)-fed obese rats. The objective of this study was to validate the thermogenic potential of LN19183 in obese Sprague Dawley (SD) rats and to assess its clinical efficacy in a proof-of-concept, randomized, placebo-controlled, cross-over human trial.

Methods: In the rat study, HFD-fed obese rats were supplemented with either HFD alone or with 45, 90, or 180 mg LN19183 per kg body weight (BW) for 28 days. In the human study, 60 overweight adults (male and female, aged 20–39 years) were randomized. Subjects took LN19183 (450 mg) or a matched placebo capsule on two consecutive days in phases one and two of the study, separated by a 10-day washout period. In each phase, on day 1, REE at pre-dose, 60-, 120-, and 180-min post-dose, and on day 2, metabolic rates at pre-dose and post-dose during and 20 min after exercise were measured using indirect calorimetry.

Results: In rats, LN19183 significantly increased REE, reduced BW gain and fat masses, and increased fat and carbohydrate metabolism marker proteins including beta 3 adrenergic receptor (β3-AR), phospho-AMP-activated protein kinase (AMPK), glucagon-like peptide-1 receptor (GLP-1R) in the liver, and serum adiponectin levels. Furthermore, LN19183-supplemented human volunteers increased (P < 0.05, vs. placebo) the metabolic rates at rest and with exercise; their fat oxidation was increased (P < 0.05, vs. placebo) at rest and 20 min post-exercise. The groups’ systolic and diastolic blood pressure (BP), heart rates (HR), and safety parameters were comparable.

Conclusion: These observations suggest that LN19183 is a thermogenic botanical composition with no stimulatory effects on BP and HR.

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References


1.
Maddahi NS, Yarizadeh H, Setayesh L, Nasir Y, Alizadeh S, Mirzaei K. Association between dietary energy density with mental health and sleep quality in women with overweight/obesity. BMC Res Notes 2020; 13(1): 189. doi: 10.1186/s13104-020-05025-1


2.
De Hert MARC, Correll CU, Bobes J, Cetkovich-Bakmas M, Cohen D, Asai I, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry 2011; 10: 52–77. doi: 10.1002/j.2051-5545.2011.tb00014.x


3.
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006; 113(6): 898–918. doi: 10.1161/CIRCULATIONAHA.106.171016


4.
Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995; 332(10): 621–8. doi: 10.1056/NEJM199503093321001


5.
Church T, Martin CK. The obesity epidemic: a consequence of reduced energy expenditure and the uncoupling of energy intake. Obesity 2018; 26(1): 14–16. doi: 10.1002/oby.22072


6.
Astrup A. Macronutrient balances and obesity: the role of diet and physical activity. Public Health Nutr 1999; 2(3A): 341–7. doi: 10.1017/s1368980099000464


7.
Jimenez-Munoz CM, López M, Albericio F, Makowski K. Targeting energy expenditure-drugs for obesity treatment. Pharmaceuticals 2021; 14(5): 435. doi: 10.3390/ph14050435


8.
Gimeno RE, Moller DE. FGF21-based pharmacotherapy – potential utility for metabolic disorders. Trends Endocrinol Metab 2014; 25(6): 303–11. doi: 10.1016/j.tem.2014.03.001


9.
Flippo KH, Jensen-Cody SO, Claflin KE, Potthoff MJ. FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution. Sci Rep 2020; 10(1): 19521. doi: 10.1038/s41598-020-76593-2


10.
Le TDV, Fathi P, Watters AB, Ellis BJ, Besing GK, Bozadjieva-Kramer N, et al. Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets. Mol Metab 2023; 72: 101718. doi: 10.1016/j.molmet.2023.101718


11.
Zouhar P, Janovska P, Stanic S, Bardova K, Funda J, Haberlova B, et al. A pyrexic effect of FGF21 independent of energy expenditure and UCP1. Mol Metab 2021; 53: 101324. doi: 10.1016/j.molmet.2021.101324


12.
Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 2014; 5: 5493. doi: 10.1038/ncomms6493


13.
Kundimi S, Chinta G, Alluri KV, Golakoti T, Veeramachaneni S, Ramanathan G, et al. A synergistic botanical composition increases resting energy expenditure and reduces adiposity in high-fat diet-fed rats. J Am Nutr Assoc 2023; 43(3): 1–10. doi: 10.1080/27697061.2023.2280777


14.
Burke AC, Sutherland BG, Telford DE, Morrow MR, Sawyez CG, Edwards JY, et al. Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr-/- mice. J Lipid Res 2018; 59(9): 1714–28. doi: 10.1194/jlr.M087387


15.
Shabrova EV, Tarnopolsky O, Singh AP, Plutzky J, Vorsa N, Quadro L. Insights into the molecular mechanisms of the anti-atherogenic actions of flavonoids in normal and obese mice. PLoS One 2011; 6(10): e24634. doi: 10.1371/journal.pone.0024634


16.
Gandhi GR, Vasconcelos ABS, Wu DT, Li HB, Antony PJ, Li H, et al. Citrus flavonoids as promising phytochemicals targeting diabetes and related complications: a systematic review of in vitro and in vivo studies. Nutrients 2020; 12(10): 2907. doi: 10.3390/nu12102907


17.
Shin EJ, Hur HJ, Sung MJ, Park JH, Yang HJ, Kim MS, et al. Ethanol extract of the prunus mume fruits stimulates glucose uptake by regulating PPAR-γ in C2C12 myotubes and ameliorates glucose intolerance and fat accumulation in mice fed a high-fat diet. Food Chem 2013; 141(4): 4115–21. doi: 10.1016/j.foodchem.2013.06.059


18.
Preza AM, Jaramillo ME, Puebla AM, Mateos JC, Hernández R, Lugo E. Antitumor activity against murine lymphoma L5178Y model of proteins from cacao (Theobroma cacao L.) seeds in relation with in vitro antioxidant activity. BMC Complement Altern Med 2010; 10: 61. doi: 10.1186/1472-6882-10-61


19.
Tovar-Pérez EG, Guerrero-Becerra L, Lugo-Cervantes E. Antioxidant activity of hydrolysates and peptide fractions of glutelin from cocoa (Theobroma cacao L.) seed. CyTA-J Food 2017; 15(4): 489–96. doi: 10.1080/19476337.2017.1297963


20.
Rabadan-Chávez G, Quevedo-Corona L, Garcia AM, Reyes-Maldonado E, Jaramillo-Flores ME. Cocoa powder, cocoa extract and epicatechin attenuate hypercaloric diet-induced obesity through enhanced β-oxidation and energy expenditure in white adipose tissue. J Funct Foods 2016; 20: 54–67. doi: 10.1016/j.jff.2015.10.016


21.
Jang MH, Kang NH, Mukherjee S, Yun JW. Theobromine, a methylxanthine in cocoa bean, stimulates thermogenesis by inducing white fat browning and activating brown adipocytes. Biotechnol Bioprocess Eng 2018; 23: 617–26. doi: 10.1007/s12257-018-0434-y


22.
Awasthi S, Kumar D, Dixit S, Mahdi AA, Gupta B, Agarwal GG, et al. Association of dietary intake with micronutrient deficiency in Indian school children: a cross-sectional study. J Nutr Sci 2023; 12: e104. doi: 10.1017/jns.2023.83


23.
Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol 1983; 55(2): 628–34. doi: 10.1152/jappl.1983.55.2.628


24.
Roberts AT, De Jonge-Levitan L, Parker CC, Greenway F. The effect of an herbal supplement containing black tea and caffeine on metabolic parameters in humans. Altern Med Rev 2005; 10(4): 321–5.


25.
Arabi YM, Tamimi W, Jones G, Jawdat D, Tamim H, Al-Dorzi HM, et al. Free fatty acids’ level and nutrition in critically ill patients and association with outcomes: a prospective sub-study of PermiT trial. Nutrients 2019; 11(2): 384. doi: 10.3390/nu11020384


26.
Alshahrani SH, Atia YA, Badir RA, Almalki SG, Tayyib NA, Shahab S, et al. Dietary caffeine intake is associated with favorable metabolic profile among apparently healthy overweight and obese individuals. BMC Endocr Disord 2023; 23(1): 227. doi: 10.1186/s12902-023-01477-1


27.
Campbell BI, Colquhoun RJ, Zito G, Martinez N, Kendall K, Buchanan L, et al. The effects of a fat loss supplement on resting metabolic rate and hemodynamic variables in resistance trained males: a randomized, double-blind, placebo-controlled, cross-over trial. J Int Soc Sports Nutr 2016; 13: 14. doi: 10.1186/s12970-016-0125-z


28.
Guest NS, VanDusseldorp TA, Nelson MT, Grgic J, Schoenfeld BJ, Jenkins NDM, et al. International society of sports nutrition position stand: caffeine and exercise performance. J Int Soc Sports Nutr 2021; 18(1): 1. doi: 10.1186/s12970-020-00383-4


29.
Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26(3): 271–81. doi: 10.1101/gad.177857.111


30.
Cuevas-Ramos D, Mehta R, Aguilar-Salinas CA. Fibroblast growth factor 21 and browning of white adipose tissue. Front Physiol 2019; 10: 37. doi: 10.3389/fphys.2019.00037


31.
Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. PPAR-α agonist elicits metabolically active brown adipocytes and weight loss in diet-induced obese mice. Cell Biochem Funct 2015; 33(4): 249–56. doi: 10.1002/cbf.3111


32.
Song NJ, Chang SH, Li DY, Villanueva CJ, Park KW. Induction of thermogenic adipocytes: molecular targets and thermogenic small molecules. Exp Mol Med 2017; 49(7): e353. doi: 10.1038/emm.2017.70


33.
Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, et al. Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab 2020; 32(2): 287–300.e7. doi: 10.1016/j.cmet.2020.07.005


34.
Cinti S. Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ. J Endocrinol Invest 2002; 25(10): 823–35. doi: 10.1007/BF03344046


35.
Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150(2): 366–76. doi: 10.1016/j.cell.2012.05.016


36.
Danysz W, Han Y, Li F, Nicoll J, Buch P, Hengl T, et al. Browning of white adipose tissue induced by the ß3 agonist CL-316,243 after local and systemic treatment – PK-PD relationship. Biochim Biophys Acta Mol Basis Dis 2018; 1864(9B): 2972–82. doi: 10.1016/j.bbadis.2018.06.007


37.
Diepvens K, Westerterp KR, Westerterp-Plantenga MS. Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Am J Physiol, Regul Integr Comp Physiol 2007; 292(1): R77–85. doi: 10.1152/ajpregu.00832.2005


38.
Mund RA, Frishman WH. Brown adipose tissue thermogenesis: β3-adrenoreceptors as a potential target for the treatment of obesity in humans. Cardiol Rev 2013; 21(6): 265–9. doi: 10.1097/CRD.0b013e31829cabff


39.
Stohs SJ, Badmaev V. A review of natural stimulant and non-stimulant thermogenic agents. Phytother Res 2016; 30(5): 732–40. doi: 10.1002/ptr.5583


40.
Dzamko N, Schertzer JD, Ryall JG, Steel R, Macaulay SL, Wee S, et al. AMPK-independent pathways regulate skeletal muscle fatty acid oxidation. J Physiol 2008; 586(23): 5819–31. doi: 10.1113/jphysiol.2008.159814


41.
Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 2015; 21(1): 33–8. doi: 10.1016/j.cmet.2014.12.009


42.
Baskin AS, Linderman JD, Brychta RJ, McGehee S, Anflick-Chames E, Cero C, et al. Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a β3-Adrenergic receptor agonist. Diabetes 2018; 67(10): 2113–25. doi: 10.2337/db18-0462


43.
Finlin BS, Memetimin H, Zhu B, Confides AL, Vekaria HJ, El Khouli RH, et al. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J Clin Invest 2020; 130(5): 2319–31. doi: 10.1172/JCI134892


44.
González-García I, Milbank E, Diéguez C, López M, Contreras C. Glucagon, GLP-1 and thermogenesis. Int J Mol Sci 2019; 20(14): 3445. doi: 10.3390/ijms20143445


45.
Wang X, Ma B, Chen J, You H, Sheng C, Yang P, et al. Glucagon-like Peptide-1 improves fatty liver and enhances thermogenesis in brown adipose tissue via inhibiting BMP4-related signaling pathway in high-fat-diet-induced obese mice. Int J Endocrinol 2021; 2021: 6620289. doi: 10.1155/2021/6620289


46.
Wang JY, Wang QW, Yang XY, Yang W, Li DR, Jin JY, et al. GLP−1 receptor agonists for the treatment of obesity: role as a promising approach. Front Endocrinol 2023; 14: 1085799. doi: 10.3389/fendo.2023.1085799
Published
2024-08-01
How to Cite
Ammatalli N. K. R., Kuricheti S. S. S. K., Veeramachaneni S., Koo Y. K., Ramanathan G., & Yalamanchi A. (2024). A combination of <em>Citrus aurantifolia</em> fruit rind and <em>Theobroma cacao</em&gt; seed extracts supplementation enhances metabolic rates in overweight subjects: a randomized, placebo-controlled, cross-over study. Food & Nutrition Research, 68. https://doi.org/10.29219/fnr.v68.10745
Section
Original Articles