Effects of oral copaiba-oil supplementation on visceral white adipose tissue content and histology of hypothalamic obese and non-obese male and female Wistar rats
Main Article Content
Abstract
Background. Obesity involves the excessive expansion of white adipose tissue, typically associated with adipocyte hypertrophy and inflammation, especially in visceral depots, a process influenced by sex. Natural compounds like Copaiba’s oil (CO) exhibit anti-inflammatory and anti-adiposity effects, though their impact on white adipose tissue histology is unknown.
Aims. This study evaluated the effect of oral CO supplementation on the histology and content of visceral WAT depots in hypothalamic obese male and female Wistar rats.
Methods. The litter size was adjusted to 6-8 pups per dam (3-4 males and females) at birth. Hypothalamic obesity was induced in the neonatal period via subcutaneous injection of Monosodium L-glutamate (4g.Kg-1). Non-obese group received equimolar saline (1.25 kg-1). Half of the animals from each group received oral CO-supplementation (0.5mL.kg-1; three times/week) from pos natal days 30 to 90, while non-supplemented groups received saline (0.9%) during the same period, via and frequency. At 92 pos natal days, following 12h of fasting, the animals were euthanized, blood samples were collected, and plasma was used to dosage glucose and triglycerides from which the TyG index was calculated to evaluate insulin resistance. Visceral Perigonadal and Perirenal depots were excised, weighed, and analyzed histologically.
Results. CO-supplementation showed nonsignificant effects in non-obese groups (males or females). Obese male and female animals show higher triglycerides, increased insulin resistance, heavier visceral adipose tissue depots, lower adipocyte numbers, and increased hypertrophy than males and females non-obese. Moreover, obese males displayed hyperglycemia compared to non-obese males. CO supplementation's effects were sex-dependent in obese males, CO worsened triglyceride levels without affecting visceral adipose tissue content or histology. Conversely, in obese females, CO supplementation improved triglyceride levels, decreased perigonadal weight, and increased adipocyte numbers in perigonadal and perirenal depots.
Conclusion. Chronic oral CO supplementation does not prevent adipose tissue expansion or metabolic dysfunction in male hypothalamic obese rats. In contrast, obese female CO-supplemented showed a slight reduction in adiposity with increased adipocyte proliferation and improved fasting triglycerides levels, indicating greater responsiveness in females to the beneficial effects of CO on obesity.
Keywords:
White Adipose Tissue, Obesity, Copaiba, Medicinal Plants
Article Details
How to Cite
KAILER, Helen de França et al.
Effects of oral copaiba-oil supplementation on visceral white adipose tissue content and histology of hypothalamic obese and non-obese male and female Wistar rats.
Medical Research Archives, [S.l.], v. 12, n. 10, oct. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5770>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i10.5770.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Kershaw EE, Flier JS. Adipose Tissue as an Endocrine Organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. doi:10.1210/jc.2004-0395
2. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. Journal of Clinical Investigation. 2005;115(5):1111-1119. doi:10.1172/JCI200525102
3. Kawai T, Autieri M V., Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. American Journal of Physiology-Cell Physiology. 2021;320(3):C375-C391. doi:10.1152/ajpcell.00379.2020
4. Alberti KGM, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. The Lancet. 2005;366(9491):1059-1062. doi:10.1016/S0140-6736(05)67402-8
5. Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020;7. doi:10.3389/fcvm.2020.00022
6. Gray SL, Vidal-Puig AJ. Adipose Tissue Expandability in the Maintenance of Metabolic Homeostasis. Nutr Rev. 2007;65(SUPPL.1):7-12. doi:10.1111/j.1753-4887.2007.tb00331.x
7. Suzuki M, Shinohara Y, Ohsaki Y, Fujimoto T. Lipid droplets: size matters. Microscopy. 2011;60(suppl 1):S101-S116. doi:10.1093/jmicro/dfr016
8. Crandall DL, Hausman GJ, Kral JG. A Review of the Microcirculation of Adipose Tissue: Anatomic, Metabolic, and Angiogenic Perspectives. Microcirculation. 1997;4(2):211-232. doi:10.3109/10739689709146786
9. Nookaew I, Svensson PA, Jacobson P, et al. Adipose Tissue Resting Energy Expenditure and Expression of Genes Involved in Mitochondrial Function Are Higher in Women than in Men. J Clin Endocrinol Metab. 2013;98(2):E370-E378. doi:10.1210/jc.2012-2764
10. Mauvais-Jarvis F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ. 2015;6(1):14. doi:10.1186/s13293-015-0033-y
11. Li J, Ruggiero-Ruff RE, He Y, et al. Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils. Elife. 2023;12. doi:10.7554/eLife.86001
12. Mauvais-Jarvis F. Sex differences in energy metabolism: natural selection, mechanisms and consequences. Nat Rev Nephrol. 2024;20(1):56-69. doi:10.1038/s41581-023-00781-2
13. Santos-Marcos JA, Mora-Ortiz M, Tena-Sempere M, Lopez-Miranda J, Camargo A. Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases. Biol Sex Differ. 2023;14(1):4. doi:10.1186/s13293-023-00490-2
14. Steiner BM, Berry DC. The Regulation of Adipose Tissue Health by Estrogens. Front Endocrinol (Lausanne). 2022;13. doi:10.3389/fendo.2022.889923
15. Li S ying, Zhao Y ling, Yang Y fan, et al. Metabolic Effects of Testosterone Replacement Therapy in Patients with Type 2 Diabetes Mellitus or Metabolic Syndrome: A Meta-Analysis. Int J Endocrinol. 2020:1-12. doi:10.1155/2020/4732021
16. Groti K, Žuran I, Antonič B, Foršnarič L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. The Aging Male. 2018;21(3):158-169. doi:10.1080/13685538.2018.1468429
17. World Health Organization. World Health Statistics 2023: Monitoring Health for the SDGs, Sustainable Development Goals.; 2023.
18. Ornellas F, Mello VS, Mandarim-de-Lacerda CA, Aguila MB. Sexual dimorphism in fat distribution and metabolic profile in mice offspring from diet-induced obese mothers. Life Sci. 2013;93(12-14):454-463. doi:10.1016/j.lfs.2013.08.005
19. Dhanraj P, van Heerden MB, Pepper MS, Ambele MA. Sexual Dimorphism in Changes That Occur in Tissues, Organs and Plasma during the Early Stages of Obesity Development. Biology (Basel). 2021;10(8):717. doi:10.3390/biology10080717
20. Shanley P, Margaret C, Murilo S, Gabriel M. Fruit trees and useful plants in Amazonian life. In: Food and Agriculture Organization of the United Nations, the Center for International Forestry Res; 2011.
21. Telles LO, Silva BS da, Paulino AMB, et al. Copaiba oleoresin presents anti-obesogenic effect and mitigates inflammation and redox imbalance in adipose tissue. Acta Amazon. 2022;52(4):331-338. doi:10.1590/1809-4392202201411
22. De Paula MG, Rocha LA, Telles LO, et al. Óleo-resina de Copaíba atenua ganho de peso e não altera marcadores inflamatórios e do sistema redox no tecido adiposo de animais saudáveis. Scientific Electronic Archives. 2023;16(4). doi:10.36560/16420231694
23. Veiga VF, Rosas EC, Carvalho MV, Henriques MGMO, Pinto AC. Chemical composition and anti-inflammatory activity of copaiba oils from Copaifera cearensis Huber ex Ducke, Copaifera reticulata Ducke and Copaifera multijuga Hayne—A comparative study. J Ethnopharmacol. 2007;112(2):248-254. doi:10.1016/j.jep.2007.03.005
24. Dias D, Fontes L, Crotti A, et al. Copaiba Oil Suppresses Inflammatory Cytokines in Splenocytes of C57Bl/6 Mice Induced with Experimental Autoimmune Encephalomyelitis (EAE). Molecules. 2014;19(8):12814-12826. doi:10.3390/molecules190812814
25. Santos AO dos, Ueda-Nakamura T, Dias Filho BP, Veiga Junior VF, Pinto AC, Nakamura CV. Antimicrobial activity of Brazilian copaiba oils obtained from different species of the Copaifera genus. Mem Inst Oswaldo Cruz. 2008;103(3):277-281. doi:10.1590/S0074-02762008005000015
26. Santos AO, Ueda-Nakamura T, Dias Filho BP, Veiga Junior VF, Pinto AC, Nakamura CV. Effect of Brazilian copaiba oils on Leishmania amazonensis. J Ethnopharmacol. 2008;120(2):204-208. doi:10.1016/j.jep.2008.08.007
27. Kian D, Lancheros CAC, Assolini JP, et al. Trypanocidal activity of copaiba oil and kaurenoic acid does not depend on macrophage killing machinery. Biomedicine & Pharmacotherapy. 2018;103:1294-1301. doi:10.1016/j.biopha.2018.04.164
28. Urasaki Y, Beaumont C, Talbot JN, Hill DK, Le TT. Akt3 Regulates the Tissue-Specific Response to Copaiba Essential Oil. Int J Mol Sci. 2020;21(8):2851. doi:10.3390/ijms21082851
29. Caputo LS, Campos MIC, Dias HJ, et al. Copaiba oil suppresses inflammation in asthmatic lungs of BALB/c mice induced with ovalbumin. Int Immunopharmacol. 2020;80:106177. doi:10.1016/j.intimp.2019.106177
30. Lopes LN, Santos FAF, Oliveira LCM, Percário S, Barros CAV de, Brito MVH. Copaiba oil effect on induced fecal peritonitis in rats. Acta Cir Bras. 2015;30(8):568-573. doi:10.1590/S0102-865020150080000008
31. Urasaki Y, Beaumont C, Workman M, Talbot JN, Hill DK, Le TT. Fast-Acting and Receptor-Mediated Regulation of Neuronal Signaling Pathways by Copaiba Essential Oil. Int J Mol Sci. 2020;21(7):2259. doi:10.3390/ijms21072259
32. Kuchler JC, Siqueira BS, Ceglarek VM, et al. The Vagus Nerve and Spleen: Influence on White Adipose Mass and Histology of Obese and Non-obese Rats. Front Physiol. 2021;12. doi:10.3389/fphys.2021.672027
33. Balbo SL, Grassiolli S, Ribeiro RA, et al. Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat. Endocrine. 2007;31(2):142-148. doi:10.1007/s12020-007-0021-z
34. Olney JW. Brain Lesions, Obesity, and Other Disturbances in Mice Treated with Monosodium Glutamate. Science (1979). 1969;164(3880):719-721. doi:10.1126/science.164.3880.719
35. Lubaczeuski C, Balbo SL, Ribeiro RA, et al. Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats. Brazilian Journal of Medical and Biological Research. 2015;48(5):447-457. doi:10.1590/1414-431X20144340
36. Galúcio C de S, Benites CI, Rodrigues RAF, Maciel MRW. Sesquiterpenes Recovery Of Copaiba Oil-Resin From Molecular Distillation. Quim Nova. Published online 2016. doi:10.5935/0100-4042.20160096
37. Simental-Mendía LE, Rodríguez-Morán M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord. 2008;6(4):299-304. doi:10.1089/met.2008.0034
38. Waterson MJ, Horvath TL. Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. Cell Metab. 2015;22(6):962-970. doi:10.1016/j.cmet.2015.09.026
39. Meister B, Ceccatelli S, H�kfelt T, And�n NE, And�n M, Theodorsson E. Neurotransmitters, neuropeptides and binding sites in the rat mediobasal hypothalamus: effects of monosodium glutamate (MSG) lesions. Exp Brain Res. 1989;76(2). doi:10.1007/BF00247894
40. Scallet AC, Olney JW. Components of hypothalamic obesity: bipiperidyl-mustard lesions add hyperphagia to monosodium glutamate-induced hyperinsulinemia. Brain Res. 1986;374(2):380-384. doi:10.1016/0006-8993(86)90434-8
41. Balbo SL, Gravena C, Bonfleur ML, de Freitas Mathias PC. Insulin Secretion and Acetylcholinesterase Activity in Monosodium L-Glutamate-InducedObese Mice. Horm Res Paediatr. 2000;54(4):186-191. doi:10.1159/000053257
42. Hernández Bautista RJ, Mahmoud AM, Königsberg M, López Díaz Guerrero NE. Obesity: Pathophysiology, monosodium glutamate-induced model and anti-obesity medicinal plants. Biomedicine & Pharmacotherapy. 2019;111:503-516. doi:10.1016/j.biopha.2018.12.108
43. Hirata AE, Andrade IS, Vaskevicius P, Dolnikoff MS. Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake. Brazilian Journal of Medical and Biological Research. 1997;30(5):671-67. doi:10.1590/S0100-879X1997000500016
44. Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JOL. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol. 2020;16(3):135-146. doi:10.1038/s41574-019-0280-9
45. Miranda RA, Torrezan R, de Oliveira JC, et al. HPA axis and vagus nervous function are involved in impaired insulin secretion of MSG-obese rats. Journal of Endocrinology. 2016;230(1):27-38. doi:10.1530/JOE-15-0467
46. Scomparin DX, Gomes RM, Grassiolli S, et al. Autonomic activity and glycemic homeostasis are maintained by precocious and low intensity training exercises in MSG-programmed obese mice. Endocrine. 2009;36(3):510-517. doi:10.1007/s12020-009-9263-2
47. Roth CL, Zenno A. Treatment of hypothalamic obesity in people with hypothalamic injury: new drugs are on the horizon. Front Endocrinol (Lausanne). 2023;14. doi:10.3389/fendo.2023.1256514
48. Sara Cristina Sagae, Sabrina Grassiolli, Charlis Raineki, Sandra Lucinei Balbo, Ana Carla Marques da Silva. Sex differences in brain cholinergic activity in MSG-obese rats submitted to exercise. Can J Physiol Pharmacol. 2011;89(11):845-853.
49. Pimenta F da S, Tose H, Jr ÉW, et al. Lipectomy associated to obesity produces greater fat accumulation in the visceral white adipose tissue of female compared to male rats. Lipids Health Dis. 2019;18(1):44. doi:10.1186/s12944-019-0988-5
50. Kong M, Xu M, Zhou Y, et al. Assessing Visceral Obesity and Abdominal Adipose Tissue Distribution in Healthy Populations Based on Computed Tomography: A Large Multicenter Cross-Sectional Study. Front Nutr. 2022;9. doi:10.3389/fnut.2022.871697
51. Allan CA, McLachlan RI. Androgens and obesity. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):224-232. doi:10.1097/MED.0b013e3283398ee2
52. Kelly DM, Jones TH. Testosterone and obesity. Obesity Reviews. 2015;16(7):581-606. doi:10.1111/obr.12282
53. Kayode OT, Rotimi DE, Kayode AAA, Olaolu TD, Adeyemi OS. Monosodium Glutamate (MSG)-Induced Male Reproductive Dysfunction: A Mini Review. Toxics. 2020;8(1):7. doi:10.3390/toxics8010007
54. Maric I, Krieger JP, van der Velden P, et al. Sex and Species Differences in the Development of Diet-Induced Obesity and Metabolic Disturbances in Rodents. Front Nutr. 2022;9. doi:10.3389/fnut.2022.828522
55. Muscogiuri G, Verde L, Vetrani C, Barrea L, Savastano S, Colao A. Obesity: a gender-view. J Endocrinol Invest. 2023;47(2):299-306. doi:10.1007/s40618-023-02196-z
56. D’Archivio M, Coppola L, Masella R, Tammaro A, La Rocca C. Sex and Gender Differences on the Impact of Metabolism-Disrupting Chemicals on Obesity: A Systematic Review. Nutrients. 2024;16(2):181. doi:10.3390/nu16020181
57. Paula MG de, Rocha LA, Silva IL, et al. Óleo-resina de copaíba diminui o índice de adiposidade e melhora o sistema redox, os níveis de IL-10 e função renal de ratos submetidos à dieta rica em sacarose. Brazilian Journal of Health Review. 2024;7(3):e70425. doi:10.34119/bjhrv7n3-332
58. Guareschi ZM, Ceglarek VM, Rodrigues PF, et al. Exercise and Vitamin D Supplementation Modify Spleen Morphology in Lean, but not, in Monosodium-Glutamate-Obese Rats. Journal of Spleen and Liver Research. 2019;1(3):1-14. doi:10.14302/issn.2578-2371.jslr-19-2819
59. Andreazzi AE, Scomparin DX, Mesquita FP, et al. Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium l-glutamate-obesity in mice. Journal of Endocrinology. 2009;201(3):351-359. doi:10.1677/JOE-08-0312
60. Soares GM, Cantelli KR, Balbo SL, et al. Liver steatosis in hypothalamic obese rats improves after duodeno-jejunal bypass by reduction in de novo lipogenesis pathway. Life Sci. 2017;188:68-75. doi:10.1016/j.lfs.2017.08.035
61. Nardelli TR, Ribeiro RA, Balbo SL, et al. Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats. Amino Acids. 2011;41(4):901-908. doi:10.1007/s00726-010-0789-7
62. Guareschi ZM, Valcanaia AC, Ceglarek VM, et al. The effect of chronic oral vitamin D supplementation on adiposity and insulin secretion in hypothalamic obese rats. British Journal of Nutrition. 2019;121(12):1334-1344. doi:10.1017/S0007114519000667
63. Willett RA, Tryndyak VP, Hughes Hanks JM, et al. A preclinical model of severe NASH-like liver injury by chronic administration of a high-fat and high-sucrose diet in mice. Toxicol Appl Pharmacol. 2024;491:117046. doi:10.1016/j.taap.2024.117046
64. Castro Ghizoni C V., Arssufi Ames AP, Lameira OA, et al. Anti‐Inflammatory and Antioxidant Actions of Copaiba Oil Are Related to Liver Cell Modifications in Arthritic Rats. J Cell Biochem. 2017;118(10):3409-3423. doi:10.1002/jcb.25998
65. Torrezan R, Malta A, de Souza Rodrigues W do N, et al. Monosodiuml ‐glutamate‐obesity onset is associated with disruption of central control of the hypothalamic‐pituitary‐adrenal axis and autonomic nervous system. J Neuroendocrinol. 2019;31(6). doi:10.1111/jne.12717
66. Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483-1496. doi:10.7150/ijbs.27173
67. Khan T, Muise ES, Iyengar P, et al. Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI. Mol Cell Biol. 2009;29(6):1575-1591. doi:10.1128/MCB.01300-08
68. Dong H, Sun W, Shen Y, et al. Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. Nat Metab. 2022;4(1):90-105. doi:10.1038/s42255-021-00509-1
69. Shao M, Vishvanath L, Busbuso NC, et al. De novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity. Nat Commun. 2018;9(1):890. doi:10.1038/s41467-018-03196-x
70. Shao M, Hepler C, Zhang Q, et al. Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity. Cell Stem Cell. 2021;28(4):685-701.e7. doi:10.1016/j.stem.2020.12.008
71. Saavedra-Peña R del M, Taylor N, Flannery C, Rodeheffer MS. Estradiol cycling drives female obesogenic adipocyte hyperplasia. Cell Rep. 2023;42(4):112390. doi:10.1016/j.celrep.2023.112390
72. Shan B, Barker CS, Shao M, Zhang Q, Gupta RK, Wu Y. Multilayered omics reveal sex- and depot-dependent adipose progenitor cell heterogeneity. Cell Metab. 2022;34(5):783-799.e7. doi:10.1016/j.cmet.2022.03.012
73. Jung KM, Lin L, Piomelli D. The endocannabinoid system in the adipose organ. Rev Endocr Metab Disord. 2022;23(1):51-60. doi:10.1007/s11154-020-09623-z
74. Ruhl T, Karthaus N, Kim BS, Beier JP. The endocannabinoid receptors CB1 and CB2 affect the regenerative potential of adipose tissue MSCs. Exp Cell Res. 2020;389(1):111881. doi:10.1016/j.yexcr.2020.111881
75. Miralpeix C, Fosch A, Casas J, et al. Hypothalamic endocannabinoids inversely correlate with the development of diet-induced obesity in male and female mice. J Lipid Res. 2019;60(7):1260-1269. doi:10.1194/jlr.M092742
76. Hawwal MF, Ali Z, Wang M, et al. (E)-2,6,10-Trimethyldodec-8-en-2-ol: An Undescribed Sesquiterpenoid from Copaiba Oil. Molecules. 2021;26(15):4456. doi:10.3390/molecules26154456
2. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. Journal of Clinical Investigation. 2005;115(5):1111-1119. doi:10.1172/JCI200525102
3. Kawai T, Autieri M V., Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. American Journal of Physiology-Cell Physiology. 2021;320(3):C375-C391. doi:10.1152/ajpcell.00379.2020
4. Alberti KGM, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. The Lancet. 2005;366(9491):1059-1062. doi:10.1016/S0140-6736(05)67402-8
5. Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020;7. doi:10.3389/fcvm.2020.00022
6. Gray SL, Vidal-Puig AJ. Adipose Tissue Expandability in the Maintenance of Metabolic Homeostasis. Nutr Rev. 2007;65(SUPPL.1):7-12. doi:10.1111/j.1753-4887.2007.tb00331.x
7. Suzuki M, Shinohara Y, Ohsaki Y, Fujimoto T. Lipid droplets: size matters. Microscopy. 2011;60(suppl 1):S101-S116. doi:10.1093/jmicro/dfr016
8. Crandall DL, Hausman GJ, Kral JG. A Review of the Microcirculation of Adipose Tissue: Anatomic, Metabolic, and Angiogenic Perspectives. Microcirculation. 1997;4(2):211-232. doi:10.3109/10739689709146786
9. Nookaew I, Svensson PA, Jacobson P, et al. Adipose Tissue Resting Energy Expenditure and Expression of Genes Involved in Mitochondrial Function Are Higher in Women than in Men. J Clin Endocrinol Metab. 2013;98(2):E370-E378. doi:10.1210/jc.2012-2764
10. Mauvais-Jarvis F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ. 2015;6(1):14. doi:10.1186/s13293-015-0033-y
11. Li J, Ruggiero-Ruff RE, He Y, et al. Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils. Elife. 2023;12. doi:10.7554/eLife.86001
12. Mauvais-Jarvis F. Sex differences in energy metabolism: natural selection, mechanisms and consequences. Nat Rev Nephrol. 2024;20(1):56-69. doi:10.1038/s41581-023-00781-2
13. Santos-Marcos JA, Mora-Ortiz M, Tena-Sempere M, Lopez-Miranda J, Camargo A. Interaction between gut microbiota and sex hormones and their relation to sexual dimorphism in metabolic diseases. Biol Sex Differ. 2023;14(1):4. doi:10.1186/s13293-023-00490-2
14. Steiner BM, Berry DC. The Regulation of Adipose Tissue Health by Estrogens. Front Endocrinol (Lausanne). 2022;13. doi:10.3389/fendo.2022.889923
15. Li S ying, Zhao Y ling, Yang Y fan, et al. Metabolic Effects of Testosterone Replacement Therapy in Patients with Type 2 Diabetes Mellitus or Metabolic Syndrome: A Meta-Analysis. Int J Endocrinol. 2020:1-12. doi:10.1155/2020/4732021
16. Groti K, Žuran I, Antonič B, Foršnarič L, Pfeifer M. The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. The Aging Male. 2018;21(3):158-169. doi:10.1080/13685538.2018.1468429
17. World Health Organization. World Health Statistics 2023: Monitoring Health for the SDGs, Sustainable Development Goals.; 2023.
18. Ornellas F, Mello VS, Mandarim-de-Lacerda CA, Aguila MB. Sexual dimorphism in fat distribution and metabolic profile in mice offspring from diet-induced obese mothers. Life Sci. 2013;93(12-14):454-463. doi:10.1016/j.lfs.2013.08.005
19. Dhanraj P, van Heerden MB, Pepper MS, Ambele MA. Sexual Dimorphism in Changes That Occur in Tissues, Organs and Plasma during the Early Stages of Obesity Development. Biology (Basel). 2021;10(8):717. doi:10.3390/biology10080717
20. Shanley P, Margaret C, Murilo S, Gabriel M. Fruit trees and useful plants in Amazonian life. In: Food and Agriculture Organization of the United Nations, the Center for International Forestry Res; 2011.
21. Telles LO, Silva BS da, Paulino AMB, et al. Copaiba oleoresin presents anti-obesogenic effect and mitigates inflammation and redox imbalance in adipose tissue. Acta Amazon. 2022;52(4):331-338. doi:10.1590/1809-4392202201411
22. De Paula MG, Rocha LA, Telles LO, et al. Óleo-resina de Copaíba atenua ganho de peso e não altera marcadores inflamatórios e do sistema redox no tecido adiposo de animais saudáveis. Scientific Electronic Archives. 2023;16(4). doi:10.36560/16420231694
23. Veiga VF, Rosas EC, Carvalho MV, Henriques MGMO, Pinto AC. Chemical composition and anti-inflammatory activity of copaiba oils from Copaifera cearensis Huber ex Ducke, Copaifera reticulata Ducke and Copaifera multijuga Hayne—A comparative study. J Ethnopharmacol. 2007;112(2):248-254. doi:10.1016/j.jep.2007.03.005
24. Dias D, Fontes L, Crotti A, et al. Copaiba Oil Suppresses Inflammatory Cytokines in Splenocytes of C57Bl/6 Mice Induced with Experimental Autoimmune Encephalomyelitis (EAE). Molecules. 2014;19(8):12814-12826. doi:10.3390/molecules190812814
25. Santos AO dos, Ueda-Nakamura T, Dias Filho BP, Veiga Junior VF, Pinto AC, Nakamura CV. Antimicrobial activity of Brazilian copaiba oils obtained from different species of the Copaifera genus. Mem Inst Oswaldo Cruz. 2008;103(3):277-281. doi:10.1590/S0074-02762008005000015
26. Santos AO, Ueda-Nakamura T, Dias Filho BP, Veiga Junior VF, Pinto AC, Nakamura CV. Effect of Brazilian copaiba oils on Leishmania amazonensis. J Ethnopharmacol. 2008;120(2):204-208. doi:10.1016/j.jep.2008.08.007
27. Kian D, Lancheros CAC, Assolini JP, et al. Trypanocidal activity of copaiba oil and kaurenoic acid does not depend on macrophage killing machinery. Biomedicine & Pharmacotherapy. 2018;103:1294-1301. doi:10.1016/j.biopha.2018.04.164
28. Urasaki Y, Beaumont C, Talbot JN, Hill DK, Le TT. Akt3 Regulates the Tissue-Specific Response to Copaiba Essential Oil. Int J Mol Sci. 2020;21(8):2851. doi:10.3390/ijms21082851
29. Caputo LS, Campos MIC, Dias HJ, et al. Copaiba oil suppresses inflammation in asthmatic lungs of BALB/c mice induced with ovalbumin. Int Immunopharmacol. 2020;80:106177. doi:10.1016/j.intimp.2019.106177
30. Lopes LN, Santos FAF, Oliveira LCM, Percário S, Barros CAV de, Brito MVH. Copaiba oil effect on induced fecal peritonitis in rats. Acta Cir Bras. 2015;30(8):568-573. doi:10.1590/S0102-865020150080000008
31. Urasaki Y, Beaumont C, Workman M, Talbot JN, Hill DK, Le TT. Fast-Acting and Receptor-Mediated Regulation of Neuronal Signaling Pathways by Copaiba Essential Oil. Int J Mol Sci. 2020;21(7):2259. doi:10.3390/ijms21072259
32. Kuchler JC, Siqueira BS, Ceglarek VM, et al. The Vagus Nerve and Spleen: Influence on White Adipose Mass and Histology of Obese and Non-obese Rats. Front Physiol. 2021;12. doi:10.3389/fphys.2021.672027
33. Balbo SL, Grassiolli S, Ribeiro RA, et al. Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat. Endocrine. 2007;31(2):142-148. doi:10.1007/s12020-007-0021-z
34. Olney JW. Brain Lesions, Obesity, and Other Disturbances in Mice Treated with Monosodium Glutamate. Science (1979). 1969;164(3880):719-721. doi:10.1126/science.164.3880.719
35. Lubaczeuski C, Balbo SL, Ribeiro RA, et al. Vagotomy ameliorates islet morphofunction and body metabolic homeostasis in MSG-obese rats. Brazilian Journal of Medical and Biological Research. 2015;48(5):447-457. doi:10.1590/1414-431X20144340
36. Galúcio C de S, Benites CI, Rodrigues RAF, Maciel MRW. Sesquiterpenes Recovery Of Copaiba Oil-Resin From Molecular Distillation. Quim Nova. Published online 2016. doi:10.5935/0100-4042.20160096
37. Simental-Mendía LE, Rodríguez-Morán M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord. 2008;6(4):299-304. doi:10.1089/met.2008.0034
38. Waterson MJ, Horvath TL. Neuronal Regulation of Energy Homeostasis: Beyond the Hypothalamus and Feeding. Cell Metab. 2015;22(6):962-970. doi:10.1016/j.cmet.2015.09.026
39. Meister B, Ceccatelli S, H�kfelt T, And�n NE, And�n M, Theodorsson E. Neurotransmitters, neuropeptides and binding sites in the rat mediobasal hypothalamus: effects of monosodium glutamate (MSG) lesions. Exp Brain Res. 1989;76(2). doi:10.1007/BF00247894
40. Scallet AC, Olney JW. Components of hypothalamic obesity: bipiperidyl-mustard lesions add hyperphagia to monosodium glutamate-induced hyperinsulinemia. Brain Res. 1986;374(2):380-384. doi:10.1016/0006-8993(86)90434-8
41. Balbo SL, Gravena C, Bonfleur ML, de Freitas Mathias PC. Insulin Secretion and Acetylcholinesterase Activity in Monosodium L-Glutamate-InducedObese Mice. Horm Res Paediatr. 2000;54(4):186-191. doi:10.1159/000053257
42. Hernández Bautista RJ, Mahmoud AM, Königsberg M, López Díaz Guerrero NE. Obesity: Pathophysiology, monosodium glutamate-induced model and anti-obesity medicinal plants. Biomedicine & Pharmacotherapy. 2019;111:503-516. doi:10.1016/j.biopha.2018.12.108
43. Hirata AE, Andrade IS, Vaskevicius P, Dolnikoff MS. Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake. Brazilian Journal of Medical and Biological Research. 1997;30(5):671-67. doi:10.1590/S0100-879X1997000500016
44. Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JOL. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol. 2020;16(3):135-146. doi:10.1038/s41574-019-0280-9
45. Miranda RA, Torrezan R, de Oliveira JC, et al. HPA axis and vagus nervous function are involved in impaired insulin secretion of MSG-obese rats. Journal of Endocrinology. 2016;230(1):27-38. doi:10.1530/JOE-15-0467
46. Scomparin DX, Gomes RM, Grassiolli S, et al. Autonomic activity and glycemic homeostasis are maintained by precocious and low intensity training exercises in MSG-programmed obese mice. Endocrine. 2009;36(3):510-517. doi:10.1007/s12020-009-9263-2
47. Roth CL, Zenno A. Treatment of hypothalamic obesity in people with hypothalamic injury: new drugs are on the horizon. Front Endocrinol (Lausanne). 2023;14. doi:10.3389/fendo.2023.1256514
48. Sara Cristina Sagae, Sabrina Grassiolli, Charlis Raineki, Sandra Lucinei Balbo, Ana Carla Marques da Silva. Sex differences in brain cholinergic activity in MSG-obese rats submitted to exercise. Can J Physiol Pharmacol. 2011;89(11):845-853.
49. Pimenta F da S, Tose H, Jr ÉW, et al. Lipectomy associated to obesity produces greater fat accumulation in the visceral white adipose tissue of female compared to male rats. Lipids Health Dis. 2019;18(1):44. doi:10.1186/s12944-019-0988-5
50. Kong M, Xu M, Zhou Y, et al. Assessing Visceral Obesity and Abdominal Adipose Tissue Distribution in Healthy Populations Based on Computed Tomography: A Large Multicenter Cross-Sectional Study. Front Nutr. 2022;9. doi:10.3389/fnut.2022.871697
51. Allan CA, McLachlan RI. Androgens and obesity. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):224-232. doi:10.1097/MED.0b013e3283398ee2
52. Kelly DM, Jones TH. Testosterone and obesity. Obesity Reviews. 2015;16(7):581-606. doi:10.1111/obr.12282
53. Kayode OT, Rotimi DE, Kayode AAA, Olaolu TD, Adeyemi OS. Monosodium Glutamate (MSG)-Induced Male Reproductive Dysfunction: A Mini Review. Toxics. 2020;8(1):7. doi:10.3390/toxics8010007
54. Maric I, Krieger JP, van der Velden P, et al. Sex and Species Differences in the Development of Diet-Induced Obesity and Metabolic Disturbances in Rodents. Front Nutr. 2022;9. doi:10.3389/fnut.2022.828522
55. Muscogiuri G, Verde L, Vetrani C, Barrea L, Savastano S, Colao A. Obesity: a gender-view. J Endocrinol Invest. 2023;47(2):299-306. doi:10.1007/s40618-023-02196-z
56. D’Archivio M, Coppola L, Masella R, Tammaro A, La Rocca C. Sex and Gender Differences on the Impact of Metabolism-Disrupting Chemicals on Obesity: A Systematic Review. Nutrients. 2024;16(2):181. doi:10.3390/nu16020181
57. Paula MG de, Rocha LA, Silva IL, et al. Óleo-resina de copaíba diminui o índice de adiposidade e melhora o sistema redox, os níveis de IL-10 e função renal de ratos submetidos à dieta rica em sacarose. Brazilian Journal of Health Review. 2024;7(3):e70425. doi:10.34119/bjhrv7n3-332
58. Guareschi ZM, Ceglarek VM, Rodrigues PF, et al. Exercise and Vitamin D Supplementation Modify Spleen Morphology in Lean, but not, in Monosodium-Glutamate-Obese Rats. Journal of Spleen and Liver Research. 2019;1(3):1-14. doi:10.14302/issn.2578-2371.jslr-19-2819
59. Andreazzi AE, Scomparin DX, Mesquita FP, et al. Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium l-glutamate-obesity in mice. Journal of Endocrinology. 2009;201(3):351-359. doi:10.1677/JOE-08-0312
60. Soares GM, Cantelli KR, Balbo SL, et al. Liver steatosis in hypothalamic obese rats improves after duodeno-jejunal bypass by reduction in de novo lipogenesis pathway. Life Sci. 2017;188:68-75. doi:10.1016/j.lfs.2017.08.035
61. Nardelli TR, Ribeiro RA, Balbo SL, et al. Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats. Amino Acids. 2011;41(4):901-908. doi:10.1007/s00726-010-0789-7
62. Guareschi ZM, Valcanaia AC, Ceglarek VM, et al. The effect of chronic oral vitamin D supplementation on adiposity and insulin secretion in hypothalamic obese rats. British Journal of Nutrition. 2019;121(12):1334-1344. doi:10.1017/S0007114519000667
63. Willett RA, Tryndyak VP, Hughes Hanks JM, et al. A preclinical model of severe NASH-like liver injury by chronic administration of a high-fat and high-sucrose diet in mice. Toxicol Appl Pharmacol. 2024;491:117046. doi:10.1016/j.taap.2024.117046
64. Castro Ghizoni C V., Arssufi Ames AP, Lameira OA, et al. Anti‐Inflammatory and Antioxidant Actions of Copaiba Oil Are Related to Liver Cell Modifications in Arthritic Rats. J Cell Biochem. 2017;118(10):3409-3423. doi:10.1002/jcb.25998
65. Torrezan R, Malta A, de Souza Rodrigues W do N, et al. Monosodium
66. Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int J Biol Sci. 2018;14(11):1483-1496. doi:10.7150/ijbs.27173
67. Khan T, Muise ES, Iyengar P, et al. Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI. Mol Cell Biol. 2009;29(6):1575-1591. doi:10.1128/MCB.01300-08
68. Dong H, Sun W, Shen Y, et al. Identification of a regulatory pathway inhibiting adipogenesis via RSPO2. Nat Metab. 2022;4(1):90-105. doi:10.1038/s42255-021-00509-1
69. Shao M, Vishvanath L, Busbuso NC, et al. De novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity. Nat Commun. 2018;9(1):890. doi:10.1038/s41467-018-03196-x
70. Shao M, Hepler C, Zhang Q, et al. Pathologic HIF1α signaling drives adipose progenitor dysfunction in obesity. Cell Stem Cell. 2021;28(4):685-701.e7. doi:10.1016/j.stem.2020.12.008
71. Saavedra-Peña R del M, Taylor N, Flannery C, Rodeheffer MS. Estradiol cycling drives female obesogenic adipocyte hyperplasia. Cell Rep. 2023;42(4):112390. doi:10.1016/j.celrep.2023.112390
72. Shan B, Barker CS, Shao M, Zhang Q, Gupta RK, Wu Y. Multilayered omics reveal sex- and depot-dependent adipose progenitor cell heterogeneity. Cell Metab. 2022;34(5):783-799.e7. doi:10.1016/j.cmet.2022.03.012
73. Jung KM, Lin L, Piomelli D. The endocannabinoid system in the adipose organ. Rev Endocr Metab Disord. 2022;23(1):51-60. doi:10.1007/s11154-020-09623-z
74. Ruhl T, Karthaus N, Kim BS, Beier JP. The endocannabinoid receptors CB1 and CB2 affect the regenerative potential of adipose tissue MSCs. Exp Cell Res. 2020;389(1):111881. doi:10.1016/j.yexcr.2020.111881
75. Miralpeix C, Fosch A, Casas J, et al. Hypothalamic endocannabinoids inversely correlate with the development of diet-induced obesity in male and female mice. J Lipid Res. 2019;60(7):1260-1269. doi:10.1194/jlr.M092742
76. Hawwal MF, Ali Z, Wang M, et al. (E)-2,6,10-Trimethyldodec-8-en-2-ol: An Undescribed Sesquiterpenoid from Copaiba Oil. Molecules. 2021;26(15):4456. doi:10.3390/molecules26154456