Abstract
Our previous studies found that safflower yellow (SY) and its main component hydroxysafflor yellow A (HSYA) could alleviate obesity and improve leptin resistance in high-fat diet (HFD) induced obese mice. Therefore, our present study aimed to investigate whether the above effect of SY/HSYA was a direct effect or follow-up effect of weight loss and whether leptin was essential for the anti-obesity effect of SY/HSYA or not. HFD-induced obese mice were treated with SY or HSYA for 4 weeks, while ob/ob mice were treated with SY for 10 weeks. Body weight, food intake, fat mass, and serum leptin levels were measured. The leptin sensitivity experiment was conducted in HFD-induced obese mice. The expressions of leptin and its signaling-related genes were detected by RT-qPCR and Western blot methods. SY/HSYA treatment had no effect on food intake, energy expenditure, body weight, fat mass, and serum leptin levels in HFD-induced obese mice. However, the leptin sensitivity experiment showed that the food intake decreased by 18.4% in the HFD-SY group and the body weight gain decreased by 104.6% in the HFD-HSYA group, respectively (both P < 0.05). Furthermore, the expressions of leptin and leptin signaling inhibitory regulators were significantly decreased, while the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) were notably increased in WAT of HFD-induced obese mice, fully differentiated 3T3-L1 adipocytes after SY/HSYA intervention (all P < 0.05). Interestingly, SY treatment was ineffective on body weight, fat mass, and glucose metabolism in leptin-deficient ob/ob mice. SY/HSYA administration could firstly improve peripheral leptin resistance in adipose tissue of HFD-induced obese mice before their body weight was significantly changed, and leptin was essential for the anti-obesity effect of SY.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Asgarpanah J, Kazemivash N (2013) Phytochemistry, pharmacology and medicinal properties of Carthamus tinctorius L. Chin J Integr Med 19(2):153–159. https://doi.org/10.1007/s11655-013-1354-5
Caron A, Lee S, Elmquist JK, Gautron L (2018) Leptin and brain-adipose crosstalks. Nat Rev Neurosci 19(3):153–165. https://doi.org/10.1038/nrn.2018.7
Dodd GT, Decherf S, Loh K, Simonds SE, Wiede F, Balland E, Merry TL, Münzberg H, Zhang ZY, Kahn BB, Neel BG, Bence KK, Andrews ZB, Cowley MA, Tiganis T (2015) Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160(1–2):88–104. https://doi.org/10.1016/j.cell.2014.12.022
Engin A (2017) Diet-induced obesity and the mechanism of leptin resistance. Adv Exp Med Biol 960:381–397. https://doi.org/10.1007/978-3-319-48382-5_16
Fan S, Lin N, Shan G, Zuo P, Cui L (2014) Safflower yellow for acute ischemic stroke: a systematic review of randomized controlled trials. Complement Ther Med 22(2):354–361. https://doi.org/10.1016/j.ctim.2014.01.001
Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC (2019) Leptin, obesity, and leptin resistance: where are we 25 years later? Nutrients 11(11). https://doi.org/10.3390/nu11112704
Kwon O, Kim KW, Kim MS (2016) Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci 73(7):1457–1477. https://doi.org/10.1007/s00018-016-2133-1
Lee J, Liu J, Feng X, Salazar Hernández MA, Mucka P, Ibi D, Choi JW, Ozcan U (2016) Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med 22(9):1023–1032. https://doi.org/10.1038/nm.4145
Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U (2015) Treatment of obesity with celastrol. Cell 161(5):999–1011. https://doi.org/10.1016/j.cell.2015.05.011
Liu J, Yue S, Yang Z, Feng W, Meng X, Wang A, Peng C, Wang C, Yan D (2018a) Oral hydroxysafflor yellow A reduces obesity in mice by modulating the gut microbiota and serum metabolism. Pharmacol Res 134:40–50. https://doi.org/10.1016/j.phrs.2018.05.012
Liu J, Yang X, Yu S, Zheng R (2018b) The leptin signaling. Adv Exp Med Biol 1090:123–144. https://doi.org/10.1007/978-981-13-1286-1_7
Liu W, Zhou X, Li Y, Zhang S, Cai X, Zhang R, Gong S, Han X, Ji L (2020) Serum leptin, resistin, and adiponectin levels in obese and non-obese patients with newly diagnosed type 2 diabetes mellitus: a population-based study. Medicine (Baltimore) 99(6):e19052. https://doi.org/10.1097/md.0000000000019052
Manna P, Jain SK (2015) Obesity, oxidative stress, adipose tissue dysfunction, and the associated health risks: causes and therapeutic strategies. Metab Syndr Relat Disord 13(10):423–444. https://doi.org/10.1089/met.2015.0095
Miao H, Pan H, Wang L, Yang H, Zhu H, Gong F (2019) Ghrelin promotes proliferation and inhibits differentiation of 3T3-L1 and human primary preadipocytes. Front Physiol 10:1296. https://doi.org/10.3389/fphys.2019.01296
Münzberg H, Morrison CD (2015) Structure, production and signaling of leptin. Metabolism 64(1):13–23. https://doi.org/10.1016/j.metabol.2014.09.010
Myers MG Jr, Heymsfield SB, Haft C, Kahn BB, Laughlin M, Leibel RL, Tschöp MH, Yanovski JA (2012) Challenges and opportunities of defining clinical leptin resistance. Cell Metab 15(2):150–156. https://doi.org/10.1016/j.cmet.2012.01.002
Pan WW, Myers MG Jr (2018) Leptin and the maintenance of elevated body weight. Nat Rev Neurosci 19(2):95–105. https://doi.org/10.1038/nrn.2017.168
Park HK, Ahima RS (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64(1):24–34. https://doi.org/10.1016/j.metabol.2014.08.004
Peng J, Yin L, Wang X (2021) Central and peripheral leptin resistance in obesity and improvements of exercise. Horm Behav 133:105006. https://doi.org/10.1016/j.yhbeh.2021.105006
Pretz D, Le Foll C, Rizwan MZ, Lutz TA, Tups A (2021) Hyperleptinemia as a contributing factor for the impairment of glucose intolerance in obesity. Faseb j 35(2):e21216. https://doi.org/10.1096/fj.202001147R
Ropelle ER, Pauli JR, Prada PO, de Souza CT, Picardi PK, Faria MC, Cintra DE, Fernandes MF, Flores MB, Velloso LA, Saad MJ, Carvalheira JB (2006) Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol 577(Pt 3):997–1007. https://doi.org/10.1113/jphysiol.2006.120006
Sáinz N, Barrenetxe J, Moreno-Aliaga MJ, Martínez JA (2015) Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism 64(1):35–46. https://doi.org/10.1016/j.metabol.2014.10.015
Sarvas JL, Otis JS, Khaper N, Lees SJ (2015) Voluntary physical activity prevents insulin resistance in a tissue specific manner. Physiol Rep 3(2). https://doi.org/10.14814/phy2.12277
Seoane-Collazo P, Martínez-Sánchez N, Milbank E, Contreras C (2020) Incendiary leptin. Nutrients 12(2). https://doi.org/10.3390/nu12020472
Wang-Yun LI, Ya-Ting YU, Yang BH, Pharmacology DO, Hospital HC, Pharmacology DO (2018) Protective effect of hydroxysafflor yellow A against nonalcoholic fatty liver in high-fat diet induced mice by targeting Sirt1 signaling pathway. Central South Pharmacy 16(11):5
Wang P, Loh KH, Wu M, Morgan DA, Schneeberger M, Yu X, Chi J, Kosse C, Kim D, Rahmouni K, Cohen P, Friedman J (2020) A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 583(7818):839–844. https://doi.org/10.1038/s41586-020-2527-y
Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W, Wang J (2019) Oxidative stress in cell death and cardiovascular diseases. Oxid Med Cell Longev 2019:9030563. https://doi.org/10.1155/2019/9030563
Xu H, Wang L, Yan K, Zhu H, Pan H, Yang H, Liu M, Gong F (2021) Nuciferine inhibited the differentiation and lipid accumulation of 3T3-L1 preadipocytes by regulating the expression of lipogenic genes and adipokines. Front Pharmacol 12:632236. https://doi.org/10.3389/fphar.2021.632236
Yan K, Wang X, Zhu H, Pan H, Wang L, Yang H, Liu M, Jin M, Zang B, Gong F (2020a) Safflower yellow improves insulin sensitivity in high-fat diet-induced obese mice by promoting peroxisome proliferator-activated receptor-γ2 expression in subcutaneous adipose tissue. J Diabetes Investig 11(6):1457–1469. https://doi.org/10.1111/jdi.13285
Yan K, Zhu H, Xu J, Pan H, Li N, Wang L, Yang H, Liu M, Gong F (2017) Lotus leaf aqueous xtract reduces visceral fat mass and ameliorates insulin resistance in HFD-induced obese rats by regulating PPARγ2 expression. Front Pharmacol 8:409. https://doi.org/10.3389/fphar.2017.00409
Yan K, Wang X, Pan H, Wang L, Yang H, Liu M, Zhu H, Gong F (2020b) Safflower yellow and its main component HSYA alleviate diet-induced obesity in mice: possible involvement of the increased antioxidant enzymes in liver and adipose tissue. Front Pharmacol 11:482. https://doi.org/10.3389/fphar.2020.00482
Yin WJ, Liang YQ, Chen Q (2018) Effect of hydroxysafflor yellow A and panax Notoginseng saponins on the high risk factor for atherosclerosis and mechanism. Chinese Journal of Drug Evaluation 35(1):30–33
Zhang Y, Chua S Jr (2017) Leptin function and regulation. Compr Physiol 8(1):351–369. https://doi.org/10.1002/cphy.c160041
Zhang LL, Tian K, Tang ZH, Chen XJ, Bian ZX, Wang YT, Lu JJ (2016) Phytochemistry and pharmacology of Carthamus tinctorius L. Am J Chin Med 44(2):197–226. https://doi.org/10.1142/s0192415x16500130
Zhao S, Kusminski CM, Elmquist JK, Scherer PE (2020) Leptin: less is more. Diabetes 69(5):823–829. https://doi.org/10.2337/dbi19-0018
Zhao S, Li N, Zhu Y, Straub L, Zhang Z, Wang MY, Zhu Q, Kusminski CM, Elmquist JK, Scherer PE (2020b) Partial leptin deficiency confers resistance to diet-induced obesity in mice. Mol Metab 37:100995. https://doi.org/10.1016/j.molmet.2020.100995
Zhu H, Wang X, Pan H, Dai Y, Li N, Wang L, Yang H, Gong F (2016) The mechanism by which safflower yellow decreases body fat mass and improves insulin sensitivity in HFD-induced obese mice. Front Pharmacol 7:127. https://doi.org/10.3389/fphar.2016.00127
Zhu HJ, Wang LJ, Wang XQ, Pan H, Li NS, Yang HB, Jin M, Zang BX, Gong FY (2014) Hormone-sensitive lipase is involved in the action of hydroxysafflor yellow A (HYSA) inhibiting adipogenesis of 3T3-L1 cells. Fitoterapia 93:182–188. https://doi.org/10.1016/j.fitote.2014.01.001
Zhu HJ, Wang LJ, Wang XQ, Pan H, Li NS, Yang HB, Jin M, Zang BX, Gong FY (2015) Hydroxysafflor yellow A (HYSA) inhibited the proliferation and differentiation of 3T3-L1 preadipocytes. Cytotechnology 67(5):885–892. https://doi.org/10.1007/s10616-014-9783-3
Zhao S, Zhu Y, Schultz RD, Li N, He Z, Zhang Z, Caron A, Zhu Q, Sun K, Xiong W, Deng H, Sun J, Deng Y, Kim M, Lee CE, Gordillo R, Liu T, Odle AK, Childs GV, Zhang N, Kusminski CM, Elmquist JK, Williams KW, An Z, Scherer PE (2019) Partial leptin reduction as an insulin sensitization and weight loss strategy. Cell Metab 30(4):706-719.e706. https://doi.org/10.1016/j.cmet.2019.08.005
Zhao, M., Zhu, P., Fujino, M., Zhuang, J., Guo, H., Sheikh, I., Zhao, L., Li, X.K. (2016) Oxidative stress in hypoxic-ischemic encephalopathy: molecular mechanisms and therapeutic strategies. Int J Mol Sci 17(12). https://doi.org/10.3390/ijms17122078
Funding
The study was supported by grants from the Beijing Natural Science Foundation (Nos. 7222137, 7182130, 7082079), the National Natural Science Foundation of China (Nos. 81370898, 30771026), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021–1-I2M-002), the China Diabetes Young Scientific Talent Research Project (No. 2020-N-01–10), the National Key Program of Clinical Science (WBYZ2011-873), and the PUMCH Foundation (pumch-2013–020).
Author information
Authors and Affiliations
Contributions
XL wrote the primary manuscript and performed the cell experiments and molecular biology experiments. KY and HX performed animal experiments. HZ and HP helped to design and supervise the experiments. LW and HY collected blood samples and helped to measure serum biochemical parameters. FG designed the experiment, supervised all of the experiments, and revised the primary manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
Corresponding author
Ethics declarations
Ethics approval
All animal experimental procedures were approved by the ethics committee of Peking Union Medical College Hospital (XHDW-2017–001).
Consent to participate
This is an animal study.
Consent for publication
All authors agree to publish this study.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Lyu, X., Yan, K., Xu, H. et al. Intragastric safflower yellow and its main component HSYA improve leptin sensitivity before body weight change in diet-induced obese mice. Naunyn-Schmiedeberg's Arch Pharmacol 395, 579–591 (2022). https://doi.org/10.1007/s00210-022-02220-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-022-02220-8