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


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

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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: This email address is being protected from spambots. You need JavaScript enabled to view it.



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).


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.


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