Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Chen,Chin-Chang; Lee,Tzung-Yan; Kwok,Ching-Fai; Hsu,Yung-Pei; Shih,Kuang-Chung; Lin,Yan-Jie; Ho,Low-Tone

doi:10.3892/ijmm.2016.2475

Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Authors:
- Chin-Chang Chen
- Tzung-Yan Lee
- Ching-Fai Kwok
- Yung-Pei Hsu
- Kuang-Chung Shih
- Yan-Jie Lin
- Low-Tone Ho
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Affiliations: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan, R.O.C., Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Tao-Yuan, Taiwan, R.O.C., Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C., Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
Published online on: January 29, 2016 https://doi.org/10.3892/ijmm.2016.2475
Pages: 743-754

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Abstract

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA‑IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.

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1	Anstee QM, McPherson S and Day CP: How big a problem is non-alcoholic fatty liver disease? BMJ. 343:d38972011. View Article : Google Scholar : PubMed/NCBI
2	Zámbó V, Simon-Szabó L, Szelényi P, Kereszturi E, Bánhegyi G and Csala M: Lipotoxicity in the liver. World J Hepatol. 5:550–557. 2013.PubMed/NCBI
3	Crescenzo R, Bianco F, Falcone I, Coppola P, Liverini G and Iossa S: Increased hepatic de novo lipogenesis and mitochondrial efficiency in a model of obesity induced by diets rich in fructose. Eur J Nutr. 52:537–545. 2013. View Article : Google Scholar
4	Begriche K, Igoudjil A, Pessayre D and Fromenty B: Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion. 6:1–28. 2006. View Article : Google Scholar : PubMed/NCBI
5	Serviddio G, Bellanti F, Vendemiale G and Altomare E: Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 5:233–244. 2011. View Article : Google Scholar : PubMed/NCBI
6	Mantena SK, King AL, Andringa KK, Eccleston HB and Bailey SM: Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med. 44:1259–1272. 2008. View Article : Google Scholar : PubMed/NCBI
7	Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, Doeller JE, Kraus DW, Darley-Usmar VM and Bailey SM: High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem J. 417:183–193. 2009. View Article : Google Scholar :
8	Rector RS, Thyfault JP, Uptergrove GM, Morris EM, Naples SP, Borengasser SJ, Mikus CR, Laye MJ, Laughlin MH, Booth FW and Ibdah JA: Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol. 52:727–736. 2010. View Article : Google Scholar : PubMed/NCBI
9	Marí M, Colell A, Morales A, von Montfort C, Garcia-Ruiz C and Fernández-Checa JC: Redox control of liver function in health and disease. Antioxid Redox Signal. 12:1295–1331. 2010. View Article : Google Scholar :
10	Pessayre D and Fromenty B: NASH: a mitochondrial disease. J Hepatol. 42:928–940. 2005. View Article : Google Scholar : PubMed/NCBI
11	Sandri M: FOXOphagy path to inducing stress resistance and cell survival. Nat Cell Biol. 14:786–788. 2012. View Article : Google Scholar : PubMed/NCBI
12	Nakae J, Kitamura T, Silver DL and Accili D: The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest. 108:1359–1367. 2001. View Article : Google Scholar : PubMed/NCBI
13	Samuel VT, Choi CS, Phillips TG, Romanelli AJ, Geisler JG, Bhanot S, McKay R, Monia B, Shutter JR, Lindberg RA, et al: Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes. 55:2042–2050. 2006. View Article : Google Scholar : PubMed/NCBI
14	Matsumoto M, Han S, Kitamura T and Accili D: Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest. 116:2464–2472. 2006.PubMed/NCBI
15	Nakae J, Cao Y, Oki M, Orba Y, Sawa H, Kiyonari H, Iskandar K, Suga K, Lombes M and Hayashi Y: Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure. Diabetes. 57:563–576. 2008. View Article : Google Scholar
16	Kim JJ, Li P, Huntley J, Chang JP, Arden KC and Olefsky JM: FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue. Diabetes. 58:1275–1282. 2009. View Article : Google Scholar : PubMed/NCBI
17	Caro JF, Dohm LG, Pories WJ and Sinha MK: Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev. 5:665–689. 1989. View Article : Google Scholar : PubMed/NCBI
18	Wajngot A, Chandramouli V, Schumann WC, Ekberg K, Jones PK, Efendic S and Landau BR: Quantitative contributions of gluconeogenesis to glucose production during fasting in type 2 diabetes mellitus. Metabolism. 50:47–52. 2001. View Article : Google Scholar : PubMed/NCBI
19	Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, Meseck M, Accili D and Dong H: Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab. 285:E718–E728. 2003. View Article : Google Scholar : PubMed/NCBI
20	Haeusler RA, Han S and Accili D: Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia. J Biol Chem. 285:26861–26868. 2010. View Article : Google Scholar : PubMed/NCBI
21	Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers JT, Depinho RA, Puigserver P and White MF: Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med. 15:1307–1311. 2009. View Article : Google Scholar : PubMed/NCBI
22	Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, et al: International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 54:161–202. 2002. View Article : Google Scholar : PubMed/NCBI
23	Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L and Kunos G: Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 115:1298–1305. 2005. View Article : Google Scholar : PubMed/NCBI
24	Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai S, Marsicano G, Lutz B, Buettner C and Kunos G: Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest. 118:3160–3169. 2008. View Article : Google Scholar : PubMed/NCBI
25	Cinar R, Godlewski G, Liu J, Tam J, Jourdan T, Mukhopadhyay B, Harvey-White J and Kunos G: Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology. 59:143–153. 2014. View Article : Google Scholar
26	Chanda D, Kim YH, Kim DK, Lee MW, Lee SY, Park TS, Koo SH, Lee CH and Choi HS: Activation of cannabinoid receptor type 1 (Cb1r) disrupts hepatic insulin receptor signaling via cyclic AMP-response element-binding protein H (Crebh)-mediated induction of Lipin1 gene. J Biol Chem. 287:38041–38049. 2012. View Article : Google Scholar : PubMed/NCBI
27	Liu J, Zhou L, Xiong K, Godlewski G, Mukhopadhyay B, Tam J, Yin S, Gao P, Shan X, Pickel J, et al: Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology. 142:1218–1228.e1. 2012. View Article : Google Scholar : PubMed/NCBI
28	Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J, et al: Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 120:2953–2966. 2010. View Article : Google Scholar : PubMed/NCBI
29	Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow JS, et al: Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 16:167–179. 2012. View Article : Google Scholar : PubMed/NCBI
30	Tedesco L, Valerio A, Dossena M, Cardile A, Ragni M, Pagano C, Pagotto U, Carruba MO, Vettor R and Nisoli E: Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: The role of eNOS, p38 MAPK, and AMPK pathways. Diabetes. 59:2826–2836. 2010. View Article : Google Scholar : PubMed/NCBI
31	Kohli R, Pan X, Malladi P, Wainwright MS and Whitington PF: Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. J Biol Chem. 282:21327–21336. 2007. View Article : Google Scholar : PubMed/NCBI
32	Tedesco L, Valerio A, Cervino C, Cardile A, Pagano C, Vettor R, Pasquali R, Carruba MO, Marsicano G, Lutz B, et al: Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes. Diabetes. 57:2028–2036. 2008. View Article : Google Scholar : PubMed/NCBI
33	Chen CC, Lee TY, Kwok CF, Hsu YP, Shih KC, Lin YJ and Ho LT: Major urinary protein 1 interacts with cannabinoid receptor type 1 in fatty acid-induced hepatic insulin resistance in a mouse hepatocyte model. Biochem Biophys Res Commun. 15:1063–1068. 2015. View Article : Google Scholar
34	Yabaluri N and Bashyam MD: Hormonal regulation of gluconeogenic gene transcription in the liver. J Biosci. 35:473–484. 2010. View Article : Google Scholar : PubMed/NCBI
35	Medina-Santillán R, López-Velázquez JA, Chávez-Tapia N, Torres-Villalobos G, Uribe M and Méndez-Sánchez N: Hepatic manifestations of metabolic syndrome. Diabetes Metab Res Rev. Mar 7–2013.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
36	Lottenberg AM, Afonso MS, Lavrador MS, Machado RM and Nakandakare ER: The role of dietary fatty acids in the pathology of metabolic syndrome. J Nutr Biochem. 23:1027–1040. 2012. View Article : Google Scholar : PubMed/NCBI
37	Utzschneider KM and Kahn SE: Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 91:4753–4761. 2006. View Article : Google Scholar : PubMed/NCBI
38	Gao CL, Zhu C, Zhao YP, Chen XH, Ji CB, Zhang CM, Zhu JG, Xia ZK, Tong ML and Guo XR: Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol. 320:25–33. 2010. View Article : Google Scholar : PubMed/NCBI
39	Chanda D, Kim DK, Li T, Kim YH, Koo SH, Lee CH, Chiang JY and Choi HS: Cannabinoid receptor type 1 (CB1R) signaling regulates hepatic gluconeogenesis via induction of endoplasmic reticulum-bound transcription factor cAMP-responsive element-binding protein H (CREBH) in primary hepatocytes. J Biol Chem. 286:27971–27979. 2011. View Article : Google Scholar : PubMed/NCBI
40	Ruby MA, Nomura DK, Hudak CS, Barber A, Casida JE and Krauss RM: Acute overactive endocannabinoid signaling induces glucose intolerance, hepatic steatosis, and novel cannabinoid receptor 1 responsive genes. PLoS One. 6:e264152011. View Article : Google Scholar : PubMed/NCBI
41	Merroun I, Sánchez-González C, Martínez R, López-Chaves C, Porres JM, Aranda P, Llopis J, Galisteo M, Zarzuelo A, Errami M and López-Jurado M: Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats. Metabolism. 62:1641–1650. 2013. View Article : Google Scholar : PubMed/NCBI
42	Jourdan T, Demizieux L, Gresti J, Djaouti L, Gaba L, Vergès B and Degrace P: Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: Evidence from cultured explants. Hepatology. 55:790–799. 2012. View Article : Google Scholar
43	Poli G and Schaur RJ: 4-Hydroxynonenal in the pathomechanisms of oxidative stress. IUBMB Life. 50:315–321. 2000. View Article : Google Scholar
44	Pérez-Carreras M, Del Hoyo P, Martín MA, Rubio JC, Martín A, Castellano G, Colina F, Arenas J and Solis-Herruzo JA: Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 38:999–1007. 2003. View Article : Google Scholar : PubMed/NCBI
45	Violi F and Cangemi R: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 363:1185–1186; author reply 1186. 2010. View Article : Google Scholar : PubMed/NCBI
46	Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, et al: Nonalcoholic Steatohepatitis Clinical Research Network: Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 305:1659–1668. 2011. View Article : Google Scholar : PubMed/NCBI
47	Aharoni-Simon M, Hann-Obercyger M, Pen S, Madar Z and Tirosh O: Fatty liver is associated with impaired activity of PPARγ-coactivator 1α (PGC1α) and mitochondrial biogenesis in mice. Lab Invest. 91:1018–1028. 2011. View Article : Google Scholar : PubMed/NCBI
48	Wang S, Kamat A, Pergola P, Swamy A, Tio F and Cusi K: Metabolic factors in the development of hepatic steatosis and altered mitochondrial gene expression in vivo. Metabolism. 60:1090–1099. 2011. View Article : Google Scholar : PubMed/NCBI
49	St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, et al: Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 127:397–408. 2006. View Article : Google Scholar : PubMed/NCBI
50	Tsvetanova E, Kessiova M, Alexandrova A, Petrov L, Kirkova M and Todorov S: In vivo effects of CB1 receptor ligands on lipid peroxidation and antioxidant defense systems in the rat brain of healthy and ethanol-treated rats. Pharmacol Rep. 58:876–883. 2006.
51	Klover PJ and Mooney RA: Hepatocytes: critical for glucose homeostasis. Int J Biochem Cell Biol. 36:753–758. 2004. View Article : Google Scholar : PubMed/NCBI
52	Garber AJ: Obesity and type 2 diabetes: which patients are at risk? Diabetes Obes Metab. 14:399–408. 2012. View Article : Google Scholar
53	Mukhopadhyay B, Schuebel K, Mukhopadhyay P, Cinar R, Godlewski G, Xiong K, Mackie K, Lizak M, Yuan Q, Goldman D and Kunos G: Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms. Hepatology. 61:1615–1626. 2015. View Article : Google Scholar : PubMed/NCBI
54	Sesti G, Fiorentino TV, Hribal ML, Sciacqua A and Perticone F: Association of hepatic insulin resistance indexes to nonalcoholic fatty liver disease and related biomarkers. Nutr Metab Cardiovasc Dis. 23:1182–1187. 2013. View Article : Google Scholar : PubMed/NCBI
55	Christensen R, Kristensen PK, Bartels EM, Bliddal H and Astrup A: Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 370:1706–1713. 2007. View Article : Google Scholar : PubMed/NCBI
56	Chang CP, Wu CH, Song JS, Chou MC, Wong YC, Lin Y, Yeh TK, Sadani AA, Ou MH, Chen KH, et al: Discovery of 1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido) methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1 receptor antagonist with significant weight-loss efficacy in diet-induced obese mice. J Med Chem. 56:9920–9933. 2013. View Article : Google Scholar : PubMed/NCBI