REVIEW ARTICLE
Hippokratia 2016, 20(4):259-263
Boutari C1, Tziomalos K2, Athyros VG1
1Second Propedeutic Department of Internal Medicine, Hippokration Hospital
2First Propedeutic Department of Internal Medicine, AHEPA Hospital Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Abstract
Insulin resistance, abdominal obesity, and inflammation play important roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Several adipokines, particularly adiponectin but also leptin, resistin, irisin, ghrelin, and visfatin modulate these pathogenetic mechanisms and appear to play a role in the development of hepatic steatosis and the progression to steatohepatitis and cirrhosis. Accordingly, these adipokines might represent attractive targets in patients with NAFLD. Notably, both lifestyle changes and many pharmacological agents that are used in the management of NAFLD, particularly pioglitazone and statins, exert favorable effects on adipokine levels. However, it is unclear whether these effects play a role in the improvement in liver histology. Therefore, mechanistic studies are needed to clarify the contribution of changes in adipokine levels to the effects of these interventions on hepatic steatosis, inflammation, and fibrosis. In parallel, the development of novel agents that specifically target adipokine levels might offer additional insights into the potential role of adipokines as therapeutic targets in NAFLD. Hippokratia 2016, 20(4): 259-263
Key words: Nonalcoholic fatty liver disease, leptin, adiponectin, resistin, irisin, ghrelin, visfatin, insulin resistance, fibrosis, steatosis, inflammation
Corresponding author: Konstantinos Tziomalos, MD, PhD, First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 1 Stilponos Kyriakidi street, Thessaloniki, 54636, Greece, tel: +302310994621, fax: +302310994773, e-mail: ktziomalos@yahoo.com
Introduction
Nonalcoholic fatty liver disease (NAFLD) is defined as the excessive accumulation of fat in the liver, in the absence of a history of alcohol abuse or of other causes of secondary hepatic steatosis1. NAFLD is considered the hepatic manifestation of metabolic syndrome, a cluster of metabolic abnormalities, such as impaired glucose tolerance, hypertension, dyslipidemia, and central obesity and is strongly associated with visceral obesity and insulin resistance2,3. The pathological spectrum of NAFLD ranges from isolated steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis4. The most widely accepted theory for the pathogenesis of NAFLD is the “two-hit” hypothesis5. According to this hypothesis, the first “hit” is the increased flux of free fatty acids (FFAs) to the liver5. The second “hit” involves oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis, that induce hepatic inflammation and fibrosis5. Abdominal obesity and insulin resistance (IR) play pivotal roles in both “hits”2,3. This review aims to discuss the significance of adipokines in the pathogenesis of NAFLD and their potential role as therapeutic targets in these patients.
The role of adipokines in the pathogenesis of NAFLD
Accumulating data suggest that several adipokines, particularly adiponectin, leptin, resistin, ghrelin, and visfatin are involved in the pathogenesis of NAFLD. Adiponectin appears to play a key role in the progression of NAFLD. It is the only adipokine whose levels are down-regulated in obesity6. Adiponectin reduces body fat and is inversely associated with body mass index7. It also improves insulin sensitivity7 and inhibits lipid accumulation in the liver by promoting β-oxidation of FFAs and by reducing the de novo synthesis of FFAs within hepatocytes8. Furthermore, adiponectin appears to exert anti-inflammatory, antifibrotic and antiapoptotic effects9. In mice, administration of recombinant adiponectin prevents steatosis and suppresses hepatic inflammation10. In clinical studies, adiponectin levels are lower in patients with NAFLD than in controls and are also lower in patients with NASH than in patients with isolated steatosis11. Adiponectin levels also correlate negatively with the severity of hepatic steatosis and inflammation11. Moreover, the expression of adiponectin receptors in the liver is lower in patients with NASH than in those with isolated steatosis and correlated negatively with the degree of inflammation and fibrosis12,13.
Leptin acts as an anorexigenic hormone and regulates food intake, body fat, and insulin activity14. In animal models, leptin prevents lipid accumulation in non-adipose tissues15. In the liver, it appears to contribute to both “hits” of the NASH pathogenesis. Specifically, it aggravates IR and consequently, steatosis and, on the other hand, it promotes liver fibrosis16,17. In rats, administration of leptin augments both proinflammatory and fibrogenic responses in the liver via increased expression of procollagen-I and transforming growth factor-β118. In contrast, leptin-deficient mice show decreased fibrogenesis in response to liver injury19. However, it is unclear whether these findings are applicable to humans. Serum leptin levels are higher in patients with NASH than in controls20,21. An early study also reported a positive correlation between leptin levels and the severity of steatosis20. However, others did not confirm this association22,23. Furthermore, leptin levels do not appear to correlate with the degree of inflammation or fibrosis21-24.
Resistin also induces hepatic IR25. Moreover, this adipokine exerts proinflammatory effects26, is implicated in hepatic lipogenesis and triggers liver fibrogenesis27. In patients with NAFLD, serum resistin levels correlate with the severity of steatosis, inflammation and fibrosis28-30.
Irisin is a newly discovered, exercise-induced adipokine31. It increases energy expenditure due to heat loss, independently of exercise or food intake and it improves glucose homeostasis, reduces IR and induces weight loss31. Irisin levels are higher in patients with NAFLD than in lean controls and are positively associated with the presence of portal inflammation, probably as a part of a compensatory mechanism32.
Ghrelin reduces the release of pro-inflammatory cytokines and attenuates apoptosis, oxidative stress, inflammation, and restores hepatic lipid metabolism33. Visfatin also has proinflammatory properties and is increased in patients with IR. Visfatin levels correlate with the severity of hepatic steatosis and fibrosis34 (Table 1).
Interventions targeting adipokines
Given the role of adipokines in the pathogenesis of NAFLD, interventions aiming at modulating adipokine levels might have beneficial effects on liver histology. Notably, both lifestyle changes and many pharmacologic agents used in the management of NAFLD affect adipokine levels. Lifestyle changes represent the cornerstone of the management of NAFLD1. However, weight loss induced by diet and exercise did not affect adiponectin levels in most studies35. However, others reported that low-carbohydrate diets could increase adiponectin levels, particularly when weight loss >10 % is achieved36. Orlistat, a lipase inhibitor, reduces body weight but also has no effect on adiponectin levels in patients with NASH37. On the other hand, adiponectin levels consistently increase following bariatric surgery, again suggesting that substantial weight loss is required to increase adiponectin levels38.
Several studies have shown that pioglitazone improves liver histology in patients with NASH39,40. An increase in adiponectin levels has also been observed during treatment with pioglitazone39. Vitamin E is another choice for the management of patients with NASH1,40. Limited data suggest that vitamin E might also increase adiponectin levels41. On the other hand, ursodeoxycholic acid does not appear to affect adiponectin levels41 and also has no effect on liver histology in patients with NASH42. Metformin decreases adiponectin levels43 and does not improve liver histology in NAFLD44,45.
Accumulating data suggest that statins are safe in patients with NAFLD, reduce transaminase levels and might also improve liver histology46-49. However, conflicting data have been reported regarding the effects of statins on adiponectin levels, with most studies reporting an increase50,51 but others showing no change52 or even a decrease53. Limited data suggest that fibrates might also reduce transaminase levels in patients with NAFLD48,54 and that they increase adiponectin levels55. Angiotensin receptor blockers exert antioxidant actions in addition to blood pressure lowering and have thus been evaluated in some small studies in patients with NAFLD yielding promising results56. These agents also increase adiponectin levels57-59.
There are more limited data on the effects of various treatments of NAFLD on leptin, resistin, irisin, ghrelin, and visfatin levels. Weight loss consistently lowers leptin levels60,61 but has no effect on resistin levels62. Additionally, irisin levels increase with exercise63. Pioglitazone and metformin reduce both leptin and resistin levels64-66. In contrast, treatment with vitamin E, ursodeoxycholic acid or statins does not appear to affect leptin or resistin levels41. On the other hand, preliminary data suggest that metformin reduces whereas statins increase irisin levels67,68. The effects of vitamin E, pioglitazone and ursodeoxycholic acid on this novel adipokine have not been evaluated yet (Table 2).
Conclusions
Adiponectin appears to play an important role in the pathogenesis and progression of NAFLD. Leptin, resistin, and visfatin might also be implicated in the development of hepatic steatosis and the progression to NASH whereas irisin and ghrelin might play a protective role. Both lifestyle changes and most pharmacological agents that are used in the management of NAFLD affect adipokine levels. Notably, interventions that improve liver histology also exert favorable effects on adipokine levels whereas less effective treatments do not change adipokine levels. Therefore, the use of medications directly targeting adipokines appears to represent an attractive and promising possibility. However, there are no studies that evaluated whether the changes in adipokine levels during lifestyle changes or pharmacotherapy correlate with the change in liver histology. Moreover, there are no agents that specifically modulate adipokine levels. Therefore, both mechanistic studies using established treatments of NAFLD and development of agents specifically targeting adipokines are needed to clarify the role of adipokines as targets of treatment in patients with NAFLD.
Conflict of interest
Authors have no conflict of interest to declare.
References
1. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al; American Gastroenterological Association; American Association for the Study of Liver Diseases; American College of Gastroenterology. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012; 142: 1592-1609.
2. Tsochatzis E, Papatheodoridis GV, Manesis EK, Kafiri G, Tiniakos DG, Archimandritis AJ. Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008; 27: 80-89.
3. Tsochatzis EA, Manolakopoulos S, Papatheodoridis GV, Archimandritis AJ. Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications. Scand J Gastroenterol. 2009; 44: 6-14.
4. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999; 116: 1413-1419.
5. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998; 114: 842-845.
6. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995; 270: 26746-26749.
7. Bełtowski J. Adiponectin and resistin–new hormones of white adipose tissue. Med Sci Monit. 2003; 9: RA55-RA61.
8. You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology. 2005; 42: 568-577.
9. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem. 2003; 278: 9073-9085.
10. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003; 112: 91-100.
11. Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J. Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism. 2011; 60: 313-326.
12. Ma H, Gomez V, Lu L, Yang X, Wu X, Xiao SY. Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2009; 24: 233-237.
13. Kaser S, Maschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005; 54: 117-121.
14. Stenvinkel P, Lönnqvist F, Schalling M. Molecular studies of leptin: implications for renal disease. Nephrol Dial Transplant. 1999; 14: 1103-1112.
15. Unger RH. Lipotoxic diseases. Annu Rev Med. 2002; 53: 319-336.
16. Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol. 2006; 101: 2629-2640.
17. Polyzos SA, Kountouras J, Mantzoros CS. Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism. 2015; 64: 60-78.
18. Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology. 2001; 34: 288-297.
19. Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology. 2002; 35: 762-771.
20. Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology. 2002; 36: 403-409.
21. Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS. Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia. 2016; 59: 30-43.
22. Chalasani N, Crabb DW, Cummings OW, Kwo PY, Asghar A, Pandya PK, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol. 2003; 98: 2771-2776.
23. Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Fagà E, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005; 42: 1175-1183.
24. Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol. 2004; 41: 943-949.
25. Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, Rossetti L, et al. Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes. 2004; 53: 1937-1941.
26. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun. 2005; 334: 1092-1101.
27. Bertolani C, Sancho-Bru P, Failli P, Bataller R, Aleffi S, DeFranco R, et al. Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol. 2006; 169: 2042-2053.
28. Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab. 2006; 91: 1081-1086.
29. Aller R, de Luis DA, Fernandez L, Calle F, Velayos B, Olcoz JL, et al. Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease. Dig Dis Sci. 2008; 53: 1088-1092.
30. Jamali R, Razavizade M, Arj A, Aarabi MH. Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease. World J Gastroenterol. 2016; 22: 5096-5103.
31. Polyzos SA, Mathew H, Mantzoros CS. Irisin: A true, circulating hormone. Metabolism. 2015; 64: 1611-1618.
32. Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV, Mantzoros CS. Irisin in patients with nonalcoholic fatty liver disease. Metabolism. 2014; 63: 207-217.
33. Li Y, Hai J, Li L, Chen X, Peng H, Cao M, et al. Administration of ghrelin improves inflammation, oxidative stress, and apoptosis during and after non-alcoholic fatty liver disease development. Endocrine. 2013; 43: 376-386.
34. Jamali R, Arj A, Razavizade M, Aarabi MH. Prediction of nonalcoholic fatty liver disease via a novel panel of serum adipokines. Medicine (Baltimore). 2016; 95: e2630.
35. Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert MO, et al. Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes. 2005; 54: 2712-2719.
36. Summer SS, Brehm BJ, Benoit SC, D’Alessio DA. Adiponectin changes in relation to the macronutrient composition of a weight-loss diet. Obesity (Silver Spring). 2011; 19: 2198-2204.
37. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: A randomized, prospective trial. Hepatology. 2009; 49: 80-86.
38. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Cardiovascular benefits of bariatric surgery in morbidly obese patients. Obes Rev. 2011; 12: 515-524.
39. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355: 2297-2307.
40. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010; 362: 1675-1685.
41. Balmer ML, Siegrist K, Zimmermann A, Dufour JF. Effects of ursodeoxycholic acid in combination with vitamin E on adipokines and apoptosis in patients with nonalcoholic steatohepatitis. Liver Int. 2009; 29: 1184-1188.
42. Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004; 39: 770-778.
43. Garinis GA, Fruci B, Mazza A, De Siena M, Abenavoli S, Gulletta E, et al. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond). 2010; 34: 1255-1264.
44. Rakoski MO, Singal AG, Rogers MA, Conjeevaram H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2010; 32: 1211-1221.
45. Tziomalos K, Athyros VG, Karagiannis A. Non-alcoholic fatty liver disease in type 2 diabetes: pathogenesis and treatment options. Curr Vasc Pharmacol. 2012; 10: 162-172.
46. Athyros VG, Giouleme O, Ganotakis ES, Elisaf M, Tziomalos K, Vassiliadis T, et al. Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study. Arch Med Sci. 2011; 7: 796-805.
47. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al; GREACE Study Collaborative Group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet. 2010; 376: 1916-1922.
48. Athyros VG, Mikhailidis DP, Didangelos TP, Giouleme OI, Liberopoulos EN, Karagiannis A, et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin. 2006; 22: 873-883.
49. Tziomalos K, Athyros VG, Paschos P, Karagiannis A. Nonalcoholic fatty liver disease and statins. Metabolism. 2015; 64: 1215-1223.
50. Blanco-Colio LM, Martín-Ventura JL, Gómez-Guerrero C, Masramon X, de Teresa E, Farsang C, et al. Adiponectin plasma levels are increased by atorvastatin treatment in subjects at high cardiovascular risk. Eur J Pharmacol. 2008; 586: 259-265.
51. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Park JB, et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis. 2009; 204: 483-490.
52. Chan KC, Chou HH, Huang CN, Chou MC. Atorvastatin administration after percutaneous coronary intervention in patients with coronary artery disease and normal lipid profiles: impact on plasma adiponectin level. Clin Cardiol. 2008; 31: 253-258.
53. Chu CH, Lee JK, Lam HC, Lu CC, Sun CC, Wang MC, et al. Atorvastatin does not affect insulin sensitivity and the adiponectin or leptin levels in hyperlipidemic Type 2 diabetes. J Endocrinol Invest. 2008; 31: 42-47.
54. Tziomalos K. Lipid-lowering agents in the management of nonalcoholic fatty liver disease. World J Hepatol. 2014; 6: 738-744.
55. Filippatos TD, Gazi IF, Liberopoulos EN, Athyros VG, Elisaf MS, Tselepis AD, et al. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. 2007; 193: 428-437.
56. Paschos P, Tziomalos K. Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. World J Hepatol. 2012; 4: 327-331.
57. Karagiannis A, Mikhailidis DP, Athyros VG, Kakafika AI, Tziomalos K, Liberopoulos EN, et al. The role of renin-angiotensin system inhibition in the treatment of hypertension in metabolic syndrome: are all the angiotensin receptor blockers equal? Expert Opin Ther Targets. 2007; 11: 191-205.
58. Makita S, Abiko A, Naganuma Y, Moriai Y, Nakamura M. Effects of telmisartan on adiponectin levels and body weight in hypertensive patients with glucose intolerance. Metabolism. 2008; 57: 1473-1478.
59. Copaci I, Lupescu I, Caceaune E, Chiriac G, Ismail G. Noninvasive Markers of Improvement of Liver Steatosis Achieved by Weight Reduction in Patients with Nonalcoholic Fatty Liver Disease. Rom J Intern Med. 2015; 53: 54-62.
60. Oh S, Tanaka K, Tsujimoto T, So R, Shida T, Shoda J. Regular exercise coupled to diet regimen accelerates reduction of hepatic steatosis and associated pathological conditions in nonalcoholic fatty liver disease. Metab Syndr Relat Disord. 2014; 12: 290-298.
61. Ho TP, Zhao X, Courville AB, Linderman JD, Smith S, Sebring N, et al. Effects of a 12-month moderate weight loss intervention on insulin sensitivity and inflammation status in nondiabetic overweight and obese subjects. Horm Metab Res. 2015; 47: 289-296.
62. Huh JY, Siopi A, Mougios V, Park KH, Mantzoros CS. Irisin in response to exercise in humans with and without metabolic syndrome. J Clin Endocrinol Metab. 2015; 100: E453-E457.
63. Nishio K, Shigemitsu M, Kodama Y, Itoh S, Konno N, Satoh R, et al. The effect of pioglitazone on nitric oxide synthase in patients with type 2 diabetes mellitus. J Cardiometab Syndr. 2008; 3: 200-204.
64. Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol. 2009; 46: 113-118.
65. Rasouli N, Yao-Borengasser A, Miles LM, Elbein SC, Kern PA. Increased plasma adiponectin in response to pioglitazone does not result from increased gene expression. Am J Physiol Endocrinol Metab. 2006; 290: E42-E46.
66. Ichida Y, Hasegawa G, Fukui M, Obayashi H, Ohta M, Fujinami A, et al. Effect of atorvastatin on in vitro expression of resistin in adipocytes and monocytes/macrophages and effect of atorvastatin treatment on serum resistin levels in patients with type 2 diabetes. Pharmacology. 2006; 76: 34-39.
67. Li M, Yang M, Zhou X, Fang X, Hu W, Zhu W, et al. Elevated circulating levels of irisin and the effect of metformin treatment in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2015; 100: 1485-1493.
68. Gouni-Berthold I, Berthold HK, Huh JY, Berman R, Spenrath N, Krone W, et al. Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS One. 2013; 8: e72858.