Osthole Ameliorates Insulin Resistance by Increment of Adiponectin Release in High-Fat and High-Sucrose-Induced Fatty Liver Rats

Abstract

The objectives of this study were to determine the effect of osthole on the insulin resistance (IR) in high-fat and high-sucrose-induced fatty liver rats and to investigate its potential mechanisms. The rat model was established by orally feeding high-fat and high-sucrose emulsion by gavage for 9 weeks. The experimental rats were treated with osthole 5 and 10 mg/kg, lipanthyl 30 mg/kg, and rosiglitazone 4 mg/kg after oral high-fat and high-sucrose emulsion for 6 weeks and were sacrificed 4 weeks after administration. The total cholesterol (TC), triglycerides (TG), and free fatty acids (FFA) in serum and hepatic tissue, fasting blood glucose (FBG), fasting serum insulin (FINS), serum adiponectin, and liver weight were measured. The homeostasis model assessment of insulin resistance (HOMA‐IR) and coefficient of hepatic weight were calculated. The results showed that after treatment with osthole, the serum levels of TC, TG, and FFA, the contents of TG and FFA in hepatic tissue, and body weight gain were lowered, especially in the osthole 10 mg/kg group (p < 0.05 or p < 0.01). Moreover, the histological evaluation of liver specimens demonstrated that the steatosis and inflammation in liver in osthole-treated groups were improved, especially in the 10 mg/kg group (p < 0.05). Importantly, the levels of FBG, FINS, and HOMA‐IR in the osthole 10 mg/kg group were decreased (p < 0.01), while the level of serum adiponectin in the osthole-treated groups, like PPARα agonist lipanthyl and PPARγ agonist rosiglitazone, was increased (p < 0.05). These results revealed that osthole could improve the IR induced by high-fat and high-sucrose emulsion in fatty liver rats, and its mechanism might be associated with increment of adiponectin release via activation of PPARα/γ pathway.

Key words

osthole - Cnidium monnieri - Apiaceae - insulin resistance - fatty liver - PPARα/γ - adiponectin

References

• 1 Biddinger S B, Kahn C R. From mice to men, insights into the insulin resistance syndromes.  Annu Rev Physiol. 2006;  68 123-158
• 2 Hotamisligil G S. Inflammation and metabolic disorders.  Nature. 2006;  444 860-867
• 3 Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Marchand-Brustel Y L, Tanti J F, Giorgetti-Peraldi S. Hypoxia decreases insulin signaling pathways in adipocytes.  Diabetes. 2009;  58 95-103
• 4 Mendez-Sanchez N, Arrese M, Zamora-Valdes D, Uribe M. Current concepts in the pathogenesis of nonalcoholic fatty liver disease.  Liver Int. 2007;  27 423-433
• 5 Utzschneider K M, Kahn S E. Review: the role of insulin resistance in nonalcoholic fatty liver disease.  Clin Endocrinol Metab. 2006;  91 4753-4761
• 6 Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism.  Endocr Rev. 1999;  20 649-688
• 7 Reddy J K. Nonalcoholic steatosis and steatohepatitis: III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis.  Am J Physiol Gastrointest Liver Physiol. 2001;  281 G1333-G1339
• 8 Jay M A, Ren J. Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus.  Curr Diabetes Rev. 2007;  3 33-39
• 9 Ferreira A V, Parreira G G, Porto L C, Mario E G, Delpuerto H L, Martins A S, Botion L M. Fenofibrate prevents orotic acid-induced hepatic steatosis in rats.  Life Sci. 2008;  82 876-883
• 10 Fernández-Miranda C, Pérez-Carreras M, Colina F, López-Alonso G, Vargas C, Solís-Herruzo J A. A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.  Digest Liver Dis. 2008;  40 200-205
• 11 Neuschwander-Tetri B A, Brunt E M, Wehmeier K R, Sponseller C A, Hampton K, Bacon B R. Interim results of a pilot study demonstrating the early effects of the PPAR-γ ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis.  J Hepatol. 2003;  38 434-440
• 12 Parra J L, Reddy K R. Hepatotoxicity of hypolipidemic drugs.  Clin Liver Dis. 2003;  7 415-433
• 13 Nesto R W, Bell D, Bonow R O, Fonseca V, Grundy S M, Horton E S, Winter M L, Porte D, Semenkovich C F, Smith S, Young L H, Kahn R. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association.  Diabetes Care. 2004;  27 256-263
• 14 Nissen S E, Wolski K, Topol E J. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.  Am Med Assoc. 2005;  294 2581-2586
• 15 Chang F, Jaber L A, Berlie H D, O'Connell M B. Evolution of peroxisome proliferator-activated receptor agonists.  Ann Pharmacother. 2007;  41 973-983
• 16 Song F, Xie M L, Zhu L J, Zhang K P, Xue J, Gu Z L. Experimental study of osthole on treatment of hyperlipidemic and alcoholic fatty liver in animals.  World J Gastroenterol. 2006;  12 4359-4363
• 17 Zhang Y, Xie M L, Zhu L J, Gu Z L. Therapeutic effect of osthole on hyperlipidemic fatty liver in rats.  Acta Pharmacol Sin. 2007;  28 398-403
• 18 Sun F, Xie M L, Zhu L J, Xue J, Gu Z L. Inhibitory effect of osthole on alcohol-induced fatty liver in mice.  Dig Liver Dis. 2009;  41 127-133
• 19 Zhang Y, Xie M L, Xue J, Gu Z L. Osthole improves fat milk-induced fatty liver in rats: modulation of hepatic PPAR-alpha/gamma-mediated lipogenic gene expression.  Planta Med. 2007;  73 718-724
• 20 Zhang Y, Xie M L, Xue J, Gu Z L. Osthole regulates enzyme protein expression of CYP7A1 and DGAT2 via activation of PPARalpha/gamma in fat milk-induced fatty liver rats.  Asian Nat Prod Res. 2008;  10 807-812
• 21 Sun F, Xie M L, Xue J, Wang H B. Osthole regulates hepatic PPARα-mediated lipogenic gene expression in alcoholic fatty liver murine.  Phytomedicine. 2009;  17 669-673
• 22 Liang H J, Suk F M, Wang C K, Hung L F, Liu D Z, Chen N Q, Chen Y C, Chang C C, Liang Y C. Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice.  Chem Biol Interact. 2009;  181 309-315
• 23 Zou Y H, Li J, Lu C, Wang J Q, Ge J F, Huang Y, Zhang L, Wang Y Y. High-fat emulsion-induced rat model of nonalcoholic steatohepatitis.  Life Sci. 2006;  79 1100-1107
• 24 Spranger J, Kroke A, Mohlig M, Bergmann M M, Ristow M, Boeing H, Pfeiffer A F H. Adiponectin and protection against type 2 diabetes mellitus.  Lancet. 2003;  361 226-228
• 25 Yesilova Z, Yaman H, Oktenli C, Ozcan A, Uygun A, Cakir E, Sanisoglu S Y, Erdil A, Ates Y, Aslan M, Musabak U, Erbil M K, Karaeren N, Dagalp K. Systemic markers of lipid peroxidation and antioxidants in patients with non-alcoholic fatty liver disease.  Am J Gastroenterol. 2005;  100 850-855
• 26 Fruebis J, Tsao T S, Javorschi S, Ebbets-Reed D, Erickson M R, Yen F T, Bihain B E, Lodish H F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.  Proc Natl Acad Sci USA. 2001;  98 2005-2010
• 27 Chinetti G, Zawadski C, Fruchart J C, Staels B. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARalpha, PPARgamma, and LXR.  Biochem Biophys Res Commun. 2004;  314 151-158
• 28 Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T, Kadowaki T. Peroxisome proliferator-activated receptor (PPAR) alpha activation increases adiponectin receptors and reduces obesity related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination.  Diabetes. 2005;  54 3358-3370