Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

Chrysoula Boutari; Nikolaos Perakakis; Christos Socrates Mantzoros

doi:10.3803/EnM.2018.33.1.33

Articles

Page Path: HOME > Endocrinol Metab > Volume 33(1); 2018 > Article

Review Article Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease: Chrysoula Boutari, Nikolaos Perakakis, Christos Socrates Mantzoros; Endocrinology and Metabolism 2018;33(1):33-43.
DOI: https://doi.org/10.3803/EnM.2018.33.1.33
Published online: March 21, 2018

6,668 Views
123 Download
93 Crossref
106 Scopus

Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Corresponding author: Christos Socrates Mantzoros. Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, FD-876, 330 Brookline Ave, Boston, MA 02215, USA. Tel: +1-617-667-8630, Fax: +1-617-667-8634, nperakak@bidmc.harvard.edu

• Received: January 21, 2018 • Revised: February 9, 2018 • Accepted: February 14, 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Full Article

Download PDF

ABSTRACT
INTRODUCTION
ADIPONECTIN
LEPTIN
RESISTIN
VISFATIN
CHEMERIN
RETINOL-BINDING PROTEIN 4
IRISIN
ADIPOKINES AS THERAPEUTIC TARGETS IN NAFLD
CONCLUSIONS
Article information
References

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokines called adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiency is associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the other hand, increased leptin levels, above the normal levels, act as a pro-inflammatory stimulus. Regarding other adipokines (resistin, visfatin, chemerin, retinol-binding protein 4, irisin), data about their contribution to NAFLD pathogenesis and progression are inconclusive. In addition, pharmacological agents like thiazolidinediones (pioglitazone and rosiglitazone), that are used in the management of NAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This review summarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possible therapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD.
Keywords: Non-alcoholic fatty liver disease; Adipokines; Adiponectin; Leptin; Resistin; Nicotinamide phosphoribosyltra; Chemerin; Retinol-binding protein 4

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD), a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals [1 2], is considered the hepatic manifestation of metabolic syndrome [3 4 5 6] and its prevalence increases continuously and concurrently with obesity and type 2 diabetes mellitus (T2DM) [7 8 9 10]. NAFLD is defined as the accumulation of excessive fat in the liver of patients without history of alcohol abuse or other causes of hepatic steatosis. NAFLD comprises a wide spectrum of diseases ranging from simple steatosis (SS) (i.e., fat accumulation in the liver) to nonalcoholic steatohepatitis (NASH), in which steatosis is combined with inflammation and fibrosis [11]. NAFLD can also progress to cirrhosis and is associated with increased risk for the development of hepatocellular carcinoma [12 13].

The pathogenesis of NAFLD is multifactorial. Factors like dietary elements (e.g., high fructose and fat intake) [14], insulin resistance (IR), inflammation, lipotoxicity [10 15], genetic predisposition and increased gut-derived microbial components [16] are supposed to contribute to the development and progression of the disease [11 17]. The liver closely interacts with adipose tissue [18], which is not only an energy-storage organ but also an endocrine organ secreting polypeptides called adipokines [19]. A growing body of literature demonstrates that adipokines are involved in various processes, such as inflammation, immunity, insulin sensitivity, simple liver steatosis, and NASH [10]. This review accumulates knowledge obtained by recent advances in the field of adipokines in relation to NAFLD (Table 1).

ADIPONECTIN

Adiponectin is an adipose tissue-expressed hormone which improves hepatic and peripheral IR and has anti-inflammatory and hepatoprotective activities [20]. The anti-inflammatory effects are achieved through blocking the activation of nuclear factor κB, by stimulating the secretion of anti-inflammatory cytokines such as interleukin-10 (IL-10) and IL-1 receptor antagonist and by suppressing the release of pro-inflammatory cytokines such as the tumor necrosis factor α (TNF-α), IL-6, and interferon-γ. Adiponectin peptide is detected in the circulation in various isoforms, such as trimers (low-molecular weight), hexamers (middle molecular weight), and 18-mers (high-molecular weight [HMW]). HMW is responsible for most of the metabolic actions of this hormone [21]. Adiponectin is involved in the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα) pathway [21] and it acts through two receptors (AdipoR1 and AdipoR2) [22]. Genetic deletion of them in mice resulted in metabolic dysfunction [23]. Moreover, adiponectin deficient mice showed high levels of TNF-α mRNA expression in adipose tissue and high TNF-α protein concentrations in the circulation [24]. In contrast to other adipokines, adiponectin serum levels paradoxically decrease with the onset of obesity while weight loss induces adiponectin production [25]. It is noteworthy that transgenic mice, which were morbidly obese (MO), had increased levels of circulating full-length adiponectin and showed a constriction in systemic inflammation and an improved metabolic profile [26]. Treatment with adiponectin reduces body weight and blood glucose levels in obese mice fed a high fat diet [27 28]. This is achieved by improving insulin sensitivity [27], increasing fat oxidation and regulating inflammatory response mainly through innate rather than adaptive immune system mechanisms [28].

In humans, circulating blood levels of adiponectin are markedly diminished in visceral obesity and states of IR, such as NASH or T2DM [29]. A meta-analysis of 27 cross-sectional studies by Polyzos et al. [30] including 2,243 individuals (1,545 patients with NAFLD and 698 controls) demonstrated that passing from SS to NASH, a further decrease in circulating adiponectin levels is observed. However in later stages, when NASH progresses to cirrhosis, adiponectin levels increase [31]. Two possible mechanisms have been suggested for this elevation in adiponectin levels in cirrhosis: the impaired hepatic clearance of adiponectin and a redeeming increase towards the exaggerated release of proinflammatory cytokines in cirrhosis [32]. It is also interesting that adiponectin levels increase in the late stage of NASH and of cirrhosis of any cause and are significantly associated with hepatic fat loss, independent of metabolic or liver dysfunction [33]. Finally, it has been suggested that HMW rather than total adiponectin is positively associated with the degree of liver steatosis [34].

Several prospective studies have investigated how adiponectin levels change in NAFLD with the course of the disease. A 3-year prospective study including 52 patients with biopsy-proven NAFLD and paired biopsies at month 36 showed that the changes in adiponectin levels from baseline to month 36 were not related to progression of liver fibrosis in these patients [35]. In contrast, a 7-year prospective study (n=213) with NAFLD diagnosis based on metabolic parameters and ultrasonographic findings demonstrated that baseline adiponectin was lower among individuals without NAFLD at baseline who developed the disease in the next 7 years of follow-up compared with these individuals who remained NAFLD free. Nevertheless, this finding could still not accurately predict NAFLD incidence [36]. In addition, three single nucleotide polymorphisms (SNPs) of adiponectin gene (rs2241767, rs1501299, rs3774261) have been suggested to increase NAFLD progression [37]. However, it was not examined whether these SNPs lead also to reduce circulating levels of adiponectin. Therefore, further studies are needed to identify the role of both various isoforms and polymorphisms of adiponectin gene.

There are several potential confounding factors that are related to the serum concentrations of adiponectin and may also explain some discrepancies between different studies. For example, the investigators of the Western Australian Pregnancy Cohort (Raine) Study (www.rainestudy.org.au) observed after a cross-sectional evaluation of 1,170 adolescents in Australia that men had lower adiponectin levels compared to women [38]. Furthermore, a recent study showed that lean patients with NAFLD have lower adiponectin concentrations compared to lean healthy subjects [39].

Lifestyle interventions consisting of healthy eating habits and physical exercise seem to increase adiponectin levels [40]. In a study which enrolled one hundred obese patients with NASH, it was demonstrated that the patients who received moderate aerobic exercise training in addition to diet regimen increased their adiponectin levels by approximately 40% [41] and improved noninvasive markers of hepatic function, such as alanine transaminase (ALT) and aspartate aminotransferase (AST) [42]. Moreover, it has been suggested that weight loss (>10%) elevates adiponectin [20]. Also, it has been shown that PPARγ agonists lead to an increase in circulating adiponectin in parallel with histological improvements in NASH patients [43]. Specifically, a sub-study of the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) Trial included 190 participants with T2DM who underwent abdominal computed tomography and dual-energy X-ray absorptiometry scans. Subjects receiving rosiglitazone for 3.5 years, after adjusting for total fat, had increased adiponectin 15 µg/mL compared to placebo (0.4 µg/mL). Moreover, rosiglitazone's effect on fat distribution was dependent from changes in adiponectin [44]. Furthermore, 1-year metformin treatment decreased ALT and AST levels while serum adiponectin levels tended to increase in patients with NAFLD [45]. However, there are no interventional studies investigating improvement of NAFLD by altering of adiponectin levels.

LEPTIN

Leptin is expressed principally in adipose tissue and it is involved in the regulation of energy homeostasis, neuroendocrine function (i.e., appetite and hypothalamic-pituitary hormonal axes), hematopoiesis and angiogenesis [41 46]. Leptin levels reflect the amount of fat stored in adipose tissue. Additionally, leptin has proinflammatory functions and prevents lipid accumulation in non-adipose tissues [47].

In the liver, leptin acts through its receptor (leptin receptor type b [LEPRb]) and decreases the expression of sterol regulatory element-binding transcription factor 1 (SREBP-1) [48]. SREBP-1 regulates genes required for glucose metabolism, fatty acid, and lipid production [49]. Leptin has also a key-role in hepatic fibrogenesis [50] by up-regulating the expression of transforming growth factor β1, leading to activation of stellate cells; thereby, augmenting the fibrogenic response in the liver.

In humans, in a meta-analysis of 33 studies which included 2,612 individuals (775 controls and 1,837 NAFLD patients) [51], patients with SS and patients with NASH had higher circulating leptin levels compared to controls and elevated leptin concentrations were associated with increased severity of the disease. Similarly, in a 3-year prospective study with paired biopsies it was demonstrated that patients with stable or improved disease status had a higher reduction of circulating leptin (−5.8 ng/mL), compared to those with disease progress (−2.2 ng/mL). Nevertheless, the multivariate analysis revealed that only the increase in body mass index (BMI) remained as an independent factor associated with disease progression [35]. In another 7-year prospective study, subjects without NAFLD at baseline that developed though NAFLD in the next 7 years had higher baseline leptin concentrations compared with those who remained free of disease [36]. Furthermore, it has been suggested that polymorphisms like LEPR Q223R lead to a predisposition for NAFLD and coronary atherosclerosis [52].

An interventional study which demonstrated the beneficial effect of combined low dose of spironolactone plus vitamin E in patients with NAFLD did not report a significant decrease of leptin levels in the group which received the regimen [53]. Similarly, another study with rosiglitazone treatment in patients with NAFLD showed that the significant improvement in liver function was not accompanied by significant changes in plasma leptin levels [54].

Collectively and based on the current findings, both adiponectin and leptin seem to be related with NAFLD development and progression. Interventional studies with these molecules and/or their antagonists may help therefore to clarify their role in NAFLD and evaluate their potential use as treatments of the more advanced levels of the disease, i.e., NASH with/without fibrosis.

RESISTIN

Resistin is produced by adipose tissue, inflammatory cells, such as macrophages and monocytes, and hepatic stellate cells [55]. The liver seems to be the major target organ of resistin and hyperresistinemia results in increased glucose secretion and hepatic IR [56]. Administration of recombinant resistin in normal mice impairs glucose tolerance and induces IR, whereas dispensing anti-resistin antibody improves insulin sensitivity in a mice model of diet-induced obesity [57]. Resistin is also expressed in the liver, where its production seems to increase with increasing liver damage [55 58]. This peptide decreases the expression of hepatic gluconeogenic enzymes and thus, mice lacking resistin exhibit low glucose levels after fasting due to restricted hepatic glucose production [59].

Although the role of resistin and its association with IR and metabolic dysregulation is adequately recorded in animals, its pathophysiological role in human diseases is unclear, with some studies even reporting no association of resistin with obesity or IR [60]. Nevertheless, it has been suggested that it exerts proinflammatory effects and provokes the release of many cytokines involved in inflammatory processes, such as TNF-α, IL-1β, IL-6, and IL-12 [61 62].

Regarding the association of circulating resistin levels in humans with NAFLD, the studies provided contradictory results so far. Some of them suggested that SS or NASH patients have higher serum resistin levels than controls [63]. However, others did not find any difference between the resistin levels in subjects with SS, NASH or healthy controls [64]. As for the comparison between the levels in NASH and SS, some authors showed higher circulating resistin levels in NASH compared to SS patients [65] and some others reported similar levels [66]. In addition, the 7-year prospective study by Musso et al. [67] demonstrated that resistin levels were not associated with the development and progression of NAFLD. Altogether from 12 studies investigating the association between resistin and liver histological parameters in NAFLD, only six reported significant differences. Among them, the strongest association was with the grade of steatosis and then with portal information [68] Finally, in a recent evaluation of plasma biomarkers in a large well characterized biopsy proven NAFLD population (n=648) by the NASH Clinical Research Network, resistin levels were similar between patients with a definite diagnosis of NASH vs borderline cases and healthy subjects, but were higher in patients with fibrosis stages 2 to 4 versus 0 to 1 (odds ratio, 1.12) [69]. These findings confirm previous results from smaller observational studies, that reported higher resistin levels in patients with histology proven NAFLD and advanced fibrosis [70].

Collectively, current findings show that resistin cannot be reliable used for the differentiation between SS and NASH, but its levels may have diagnostic value for differentiating between different fibrosis stages.

VISFATIN

Visfatin is also called pre-B cell colony-enhancing factor and it is a proinflammatory cytokine that stimulates the secretion of other cytokines such as TNF-α and IL-6. Also, visfatin exerts intracellular activity since it is a key enzyme in nicotinamide adenine dinucleotide production [71]. It has been suggested, that visfatin may be involved in the development of NAFLD by regulating hepatic inflammation as well as glucose homeostasis and IR [72].

Several studies have investigated associations of circulating and adipose-tissue expressed visfatin with histological parameters of NAFLD, reporting though contradictory results. Most studies showed that there is no difference in serum visfatin levels between SS, NASH patients and controls [73 74]. On the other hand, some authors found higher visfatin levels in NAFLD patients than controls [75] and some reported increased levels with steatosis grade above 33% [70]. Additionally, in a case-control study the levels of visfatin, IL-8, and TNF-α were positively correlated with the presence of NASH [76]. Another group indicated that hepatic expression of this peptide was not associated with liver steatosis and inflammation but was positively associated with the fibrosis stage [77]. In contrast, Aller et al. [78] showed that serum visfatin levels are related to portal inflammation and not to steatosis or fibrosis. In another study including 95 MO women who underwent bariatric surgery and 38 normal weight women, circulating visfatin levels as well as expression of visfatin from the liver was higher in MO group and were both positively associated with inflammatory factors [75]. Finally in a study aiming to develop predictive models, visfatin together with adiponectin, TNF-α and IL-8 were included in the algorithm achieving to differentiate NASH from SS with a sensitivity of 90% and specificity of 66% [76].

The data inconsistency about visfatin can be attributed to many factors. Since visfatin is produced from many organs, the comorbidities may be an important confounder. Furthermore, circulating visfatin levels probably do not reflect its local hepatic or adipose tissue levels. Therefore, more studies are needed to provide more homogeneous data in terms of visfatin changes in NAFLD and its exact role.

CHEMERIN

Chemerin is an adipokine produced by liver and adipose tissue as well [79]. Its levels are higher in obesity and IR states and decrease after weight loss with parallel significant reduction of high-sensitivity C-reactive protein levels [80]. Binding of chemerin to its chemokine-like receptor 1 (CMLKR-1) promotes the activation of cells of the innate immune system, i.e., macrophages and natural killer cells to tissue injury sites [81]. Regarding the liver, the hepatocytes represent a major source of chemerin production [82]. Chemerin contributes also to inflammatory procedures as it is positively associated with visceral adipose tissue macrophages [83], hepatic expression of CD68 cells (e.g., Kupffer cells) [84], and proinflammatory cytokines, including hepatic expression of TNF-α [82]. This close relationship with inflammation could explain the role of chemerin in NASH.

Most studies have measured higher chemerin serum levels in NAFLD patients than controls [85]. Also, hepatic chemerin expression was higher in NAFLD patients than controls [82]. Comparing chemerin serum levels in NASH and SS patients, some studies found higher levels in NASH [85], while others did not find any differences [84]. One study demonstrated that although the circulating chemerin levels did not differ between NASH and SS patients, NASH patients had higher hepatic chemerin and CMKLR1 mRNA expression than the others [84]. In the context of the association of chemerin levels with specific hepatic lesions in NAFLD data are also controversial. Notably, a study suggested that hepatic chemerin expression is positively associated with hepatic steatosis, lobular inflammation, ballooning, and fibrosis [84]. Also, another study reported that visceral chemerin expression and not hepatic expression or circulating levels were negatively associated with hepatic steatosis and inflammation [86]. Altogether, most studies so far indicate an association of chemerin with NAFLD (NASH or SS). However, chemerin has not been measured in large cohorts or clinical trials involving patients with NAFLD; thus, the available findings should be interpreted cautiously and need to be verified and extended in future studies.

RETINOL-BINDING PROTEIN 4

Retinol-binding protein 4 (RBP-4) was initially identified as a transport protein for retinol (vitamin A) from the liver to peripheral sites [87], but is also secreted by liver [87] and visceral adipose tissue [88] and may therefore have important metabolic effects. RBP-4 increases in IR, obesity, and T2DM [89] and promotes basal glucose production in the liver, since it increases the hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase [90]. Furthermore, RBP-4 levels seem to be inversely related to the adipocyte glucose transporter 4, which plays a pivotal role in the liver IR [89].

Regarding NAFLD, data about RBP-4 are inconclusive. RBP-4 seems to be positively associated with liver fat in healthy subjects [91] and it is higher in NAFLD patients than controls [92]. However, as it has been reported in a recent systematic review [68], an association between serum RBP-4 levels and liver histology among patients with biopsy proven NAFLD was found only in three out of seven studies. Some authors found higher circulating RBP-4 levels in SS or NASH patients than controls [93]. Comparing NASH with SS patients, some studies reported similar levels [93] and some others found lower levels in NASH than SS [94]. Furthermore, it has been suggested that circulating RBP-4 levels are positively associated with ballooning [95] and inversely associated with fibrosis [94]. In summary, more studies in larger cohorts are needed in order to investigate whether RBP-4 is related to NAFLD development and progress.

IRISIN

Irisin is primarily a myokine secreted after exercise, but it is an adipokine too, since it is secreted by white adipose tissue [96 97]. Irisin has been associated with increased thermogenesis due to stimulation of “browning” of adipose tissue and improved glucose profile through reduction of IR in mice [96 97 98]. Additionally, irisin demonstrates hepatoprotective effects by stimulating glycogenesis and by reducing gluconeogenesis, lipogenesis and lipid accumulation [96 97] in vitro and in vivo animal models.

In humans, circulating levels of irisin have been associated with a wide spectrum of metabolic diseases, ranging from obesity and IR to diabetes [99 100], cardiovascular diseases [101 102], bone metabolism and thyroid function [102 103]. Regarding NAFLD, data are controversial so far. In the first study including biopsy-proven NAFLD patients, irisin levels did not differ between NASH, SS and obese controls and were lower compared to lean controls [95]. Additionally, irisin levels were associated with portal inflammation and showed a trend to higher levels by increasing steatosis grade, fibrosis, and lobular inflammation [95]. In other studies, irisin levels have been higher in NAFLD group compared to healthy controls and increased with higher fibrosis and steatosis grade [104 105]. Furthermore, irisin has been inversely related to hepatic triglyceride content in an obese Chinese population [106]. Additionally, in a children-cohort irisin levels have been positively associated with the presence of mutations in PNPLA3 (patatin-like phospholipase domain containing 3), which is considered a strong genetic factor for development and progress of NAFLD [107]. There are many possible explanations for the discrepant results in the studies so far. These include mainly differences in the criteria used to diagnose NAFLD, differences between enzyme-linked immunosorbent assays for measurement of irisin and differences in population characteristics (i.e., age, BMI, ethnicity etc.) [108].

Altogether, irisin has hepatoprotective effects in animal and in vitro studies, while in human studies the results are inconclusive. Future research should aim to investigate in large prospective cohorts the association of irisin with NAFLD development and progress.

ADIPOKINES AS THERAPEUTIC TARGETS IN NAFLD

Given the role of adipokines in the pathogenesis of NAFLD, interventions aiming at modulating adipokine levels might have beneficial effects on liver histology. Notably, many pharmacologic agents used in the management of NAFLD affect adipokine levels.

Several studies have shown that thiazolidinediones (TZDs), pioglitazone, and rosiglitazone, besides liver histology, also improve adiponectin levels [109]. A recent systematic review of four studies [43] demonstrated an increase in circulating adiponectin levels after TZD treatment. Similarly, statins, that it is speculated to be effective against NAFLD by regulation of dyslipidemia increase significantly circulating adiponectin levels [110]. Finally, metformin that is widely used for treatment of T2DM and exerts hepatoprotective function is associated with increased levels of adiponectin and decreased levels of chemerin [111 112].

The effect of direct replacement of adiponectin or other adipokines on NAFLD has not been investigated yet, since with the exception of leptin, no other “adipokine drug” is currently approved by U.S. Food and Drug Administration. Regarding leptin, treatment with recombinant human leptin (metreleptin) is currently under evaluation in conditions of extreme hypoleptinemia, i.e., in patients with congenital leptin deficiency and congenital or acquired lipodystrophy. In these rare cases, profound IR, dyslipidemia, and accumulation of fat in the liver are observed [113]. Results from interventional study investigating the efficacy of metreleptin in NASH or NAFLD associated with lipodystrophy are expected.

CONCLUSIONS

In conclusion, based on literature, there is no doubt that adipokines play a crucial role in the pathogenesis and progression of NAFLD through their contribution to the low-grade inflammation which is closely related to the disease. Despite the extended investigation that has been conducted by now, a considerable amount of issues remains controversial and further meticulous studies are needed to this direction. Novel pathogenetic evidence may lead to a better comprehension and beyond that, to non-invasive diagnostic and therapeutic tools as well.

Article information

CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

References

1. Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism 2016;65:1017–1025. Article PubMed
2. Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, et al. Non-alcoholic fatty liver disease: a sign of systemic disease. Metabolism 2017;72:94–108. Article PubMed
3. Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: an update. Metabolism 2016;65:1109–1123. Article PubMed
4. Polyzos SA, Bugianesi E, Kountouras J, Mantzoros CS. Nonalcoholic fatty liver disease: updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-γ agonists. Metabolism 2017;66:64–68. Article PubMed
5. Huh JH, Kim KJ, Kim SU, Han SH, Han KH, Cha BS, et al. Obesity is more closely related with hepatic steatosis and fibrosis measured by transient elastography than metabolic health status. Metabolism 2017;66:23–31. Article PubMed
6. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274–285. Article PubMed
7. Polyzos SA, Mantzoros CS. Nonalcoholic fatty future disease. Metabolism 2016;65:1007–1016. Article PubMed
8. Karajamaki AJ, Bloigu R, Kauma H, Kesaniemi YA, Koivurova OP, Perkiomaki J, et al. Non-alcoholic fatty liver disease with and without metabolic syndrome: different long-term outcomes. Metabolism 2017;66:55–63. Article PubMed
9. Hazlehurst JM, Woods C, Marjot T, Cobbold JF, Tomlinson JW. Non-alcoholic fatty liver disease and diabetes. Metabolism 2016;65:1096–1108. Article PubMed PMC
10. Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med 2009;9:299–314. Article PubMed
11. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016;65:1038–1048. Article PubMed
12. Zoller H, Tilg H. Nonalcoholic fatty liver disease and hepatocellular carcinoma. Metabolism 2016;65:1151–1160. Article PubMed
13. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, Saracco G, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology 2011;54:1208–1216. Article PubMed PMC
14. Chung M, Ma J, Patel K, Berger S, Lau J, Lichtenstein AH. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am J Clin Nutr 2014;100:833–849. Article PubMed PMC PDF
15. Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016;65:1049–1061. Article PubMed PMC
16. Tilg H. Adipocytokines in nonalcoholic fatty liver disease: key players regulating steatosis, inflammation and fibrosis. Curr Pharm Des 2010;16:1893–1895. Article PubMed
17. Polyzos SA, Kountouras J, Zavos Ch. The multi-hit process and the antagonistic roles of tumor necrosis factor-alpha and adiponectin in non alcoholic fatty liver disease. Hippokratia 2009;13:127PubMed PMC
18. Scheja L, Heeren J. Metabolic interplay between white, beige, brown adipocytes and the liver. J Hepatol 2016;64:1176–1186. Article PubMed
19. Polyzos SA, Mantzoros CS. Leptin in health and disease: facts and expectations at its twentieth anniversary. Metabolism 2015;64:5–12. Article PubMed
20. Polyzos SA, Kountouras J, Zavos C, Tsiaousi E. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab 2010;12:365–383. Article PubMed
21. Heiker JT, Kosel D, Beck-Sickinger AG. Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors. Biol Chem 2010;391:1005–1018. Article PubMed
22. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–769. Article PubMed PDF
23. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007;13:332–339. Article PubMed PDF
24. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adiposederived protein. Diabetes 2001;50:2094–2099. Article PubMed
25. Moschen AR, Molnar C, Geiger S, Graziadei I, Ebenbichler CF, Weiss H, et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut 2010;59:1259–1264. Article PubMed
26. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007;117:2621–2637. Article PubMed PMC
27. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941–946. Article PubMed PDF
28. Liu X, Perakakis N, Gong H, Chamberland JP, Brinkoetter MT, Hamnvik OR, et al. Adiponectin administration prevents weight gain and glycemic profile changes in diet-induced obese immune deficient Rag1−/− mice lacking mature lymphocytes. Metabolism 2016;65:1720–1730. Article PubMed PMC
29. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46–54. Article PubMed
30. 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. Article PubMed
31. Polyzos SA, Kountouras J, Zavos C. Nonlinear distribution of adiponectin in patients with nonalcoholic fatty liver disease limits its use in linear regression analysis. J Clin Gastroenterol 2010;44:229–230. Article PubMed
32. Polyzos SA, Kountouras J, Zavos C, Stergiopoulos C. Adipocytokines in insulin resistance and non-alcoholic fatty liver disease: the two sides of the same coin. Med Hypotheses 2010;74:1089–1090.Article
33. van der Poorten D, Samer CF, Ramezani-Moghadam M, Coulter S, Kacevska M, Schrijnders D, et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause? Hepatology 2013;57:2180–2188. Article PubMed
34. Engl J, Sturm W, Sandhofer A, Kaser S, Tschoner A, Tatarczyk T, et al. Effect of pronounced weight loss on visceral fat, liver steatosis and adiponectin isoforms. Eur J Clin Invest 2008;38:238–244. Article PubMed
35. Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 2010;59:969–974. Article PubMed
36. Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012;56:1145–1151. Article PubMed
37. Zhou YJ, Zhang ZS, Nie YQ, Cao J, Cao CY, Li YY. Association of adiponectin gene variation with progression of nonalcoholic fatty liver disease: a 4-year follow-up survey. J Dig Dis 2015;16:601–609. Article PubMed
38. Ayonrinde OT, Olynyk JK, Beilin LJ, Mori TA, Pennell CE, de Klerk N, et al. Gender-specific differences in adipose distribution and adipocytokines influence adolescent nonalcoholic fatty liver disease. Hepatology 2011;53:800–809. Article PubMed
39. Feldman A, Eder SK, Felder TK, Kedenko L, Paulweber B, Stadlmayr A, et al. Clinical and metabolic characterization of lean Caucasian subjects with non-alcoholic fatty liver. Am J Gastroenterol 2017;112:102–110. Article PubMed PDF
40. Borel AL, Nazare JA, Baillot A, Almeras N, Tremblay A, Bergeron J, et al. Cardiometabolic risk improvement in response to a 3-yr lifestyle modification program in men: contribution of improved cardiorespiratory fitness vs. weight loss. Am J Physiol Endocrinol Metab 2017;312:E273–E281. Article PubMed
41. Triantafyllou GA, Paschou SA, Mantzoros CS. Leptin and hormones: energy homeostasis. Endocrinol Metab Clin North Am 2016;45:633–645. Article PubMed
42. Abd El-Kader SM, Al-Shreef FM, Al-Jiffri OH. Biochemical parameters response to weight loss in patients with non-alcoholic steatohepatitis. Afr Health Sci 2016;16:242–249. Article PubMed PMC
43. Polyzos SA, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: a systematic review. Metabolism 2016;65:1297–1306. Article PubMed
44. Punthakee Z, Almeras N, Despres JP, Dagenais GR, Anand SS, Hunt DL, et al. Impact of rosiglitazone on body composition, hepatic fat, fatty acids, adipokines and glucose in persons with impaired fasting glucose or impaired glucose tolerance: a sub-study of the DREAM trial. Diabet Med 2014;31:1086–1092. Article PubMed
45. Shargorodsky M, Omelchenko E, Matas Z, Boaz M, Gavish D. Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering? Cardiovasc Diabetol 2012;11:61Article PubMed PMC
46. Matarese G, Procaccini C, De Rosa V, Horvath TL, La Cava A. Regulatory T cells in obesity: the leptin connection. Trends Mol Med 2010;16:247–256. Article PubMed
47. Meek TH, Morton GJ. The role of leptin in diabetes: metabolic effects. Diabetologia 2016;59:928–932. Article PubMed PDF
48. Kakuma T, Lee Y, Higa M, Wang Zw, Pan W, Shimomura I, et al. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci U S A 2000;97:8536–8541. Article PubMed PMC
49. Ferre P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab 2010;12(Suppl 2):83–92. Article PubMed
50. 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. Article PubMed
51. 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. Article PubMed PDF
52. An BQ, Lu LL, Yuan C, Xin YN, Xuan SY. Leptin receptor gene polymorphisms and the risk of non-alcoholic fatty liver disease and coronary atherosclerosis in the Chinese Han population. Hepat Mon 2016;16:e35055. Article PubMed PMC
53. Polyzos SA, Kountouras J, Mantzoros CS, Polymerou V, Katsinelos P. Effects of combined low-dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance, non-invasive indices of steatosis and fibrosis, and adipokine levels in non-alcoholic fatty liver disease: a randomized controlled trial. Diabetes Obes Metab 2017;19:1805–1809. Article PubMed
54. Saryusz-Wolska M, Szymanska-Garbacz E, Jablkowski M, Bialkowska J, Pawlowski M, Kwiecinska E, et al. Rosiglitazone treatment in nondiabetic subjects with nonalcoholic fatty liver disease. Pol Arch Med Wewn 2011;121:61–66. Article PubMed
55. 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. Article PubMed PMC
56. 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. Article PubMed
57. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307–312. Article PubMed PDF
58. Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, et al. Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology 2012;56:2142–2153. Article PubMed
59. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, et al. Regulation of fasted blood glucose by resistin. Science 2004;303:1195–1198. Article PubMed
60. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 2003;88:4848–4856. Article PubMed
61. Fargnoli JL, Sun Q, Olenczuk D, Qi L, Zhu Y, Hu FB, et al. Resistin is associated with biomarkers of inflammation while total and high-molecular weight adiponectin are associated with biomarkers of inflammation, insulin resistance, and endothelial function. Eur J Endocrinol 2010;162:281–288. Article PubMed
62. Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun 2003;309:286–290. Article PubMed
63. Senates E, Colak Y, Yesil A, Coskunpinar E, Sahin O, Kahraman OT, et al. Circulating resistin is elevated in patients with non-alcoholic fatty liver disease and is associated with steatosis, portal inflammation, insulin resistance and nonalcoholic steatohepatitis scores. Minerva Med 2012;103:369–376. PubMed
64. Argentou M, Tiniakos DG, Karanikolas M, Melachrinou M, Makri MG, Kittas C, et al. Adipokine serum levels are related to liver histology in severely obese patients undergoing bariatric surgery. Obes Surg 2009;19:1313–1323. Article PubMed PDF
65. 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. Article PubMed
66. Shen C, Zhao CY, Wang W, Wang YD, Sun H, Cao W, et al. The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis. BMC Gastroenterol 2014;14:39Article PubMed PMC PDF
67. Musso G, Bo S, Cassader M, De Michieli F, Gambino R. Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism. Am J Clin Nutr 2013;98:895–906. Article PubMed PDF
68. Bekaert M, Verhelst X, Geerts A, Lapauw B, Calders P. Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review. Obes Rev 2016;17:68–80.Article
69. Ajmera V, Perito ER, Bass NM, Terrault NA, Yates KP, Gill R, et al. Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease. Hepatology 2017;65:65–77. Article PubMed
70. 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. Article PubMed PMC
71. Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, et al. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol 2007;178:1748–1758. Article PubMed
72. Saxena NK, Anania FA. Adipocytokines and hepatic fibrosis. Trends Endocrinol Metab 2015;26:153–161. Article PubMed PMC
73. Polyzos SA, Kountouras J, Papatheodorou A, Katsiki E, Patsiaoura K, Zafeiriadou E, et al. Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: introduction of CHA index. Ann Hepatol 2013;12:749–757. Article PubMed
74. Genc H, Dogru T, Kara M, Tapan S, Ercin CN, Acikel C, et al. Association of plasma visfatin with hepatic and systemic inflammation in nonalcoholic fatty liver disease. Ann Hepatol 2013;12:548–555. Article PubMed
75. Auguet T, Terra X, Porras JA, Orellana-Gavalda JM, Martinez S, Aguilar C, et al. Plasma visfatin levels and gene expression in morbidly obese women with associated fatty liver disease. Clin Biochem 2013;46:202–208. Article PubMed
76. 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. Article PubMed PMC
77. Kukla M, Ciupinska-Kajor M, Kajor M, Wylezol M, Zwirska-Korczala K, Hartleb M, et al. Liver visfatin expression in morbidly obese patients with nonalcoholic fatty liver disease undergoing bariatric surgery. Pol J Pathol 2010;61:147–153. PubMed
78. Aller R, de Luis DA, Izaola O, Sagrado MG, Conde R, Velasco MC, et al. Influence of visfatin on histopathological changes of non-alcoholic fatty liver disease. Dig Dis Sci 2009;54:1772–1777. Article PubMed PDF
79. Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, et al. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 2007;148:4687–4694. Article PubMed PDF
80. Ress C, Tschoner A, Engl J, Klaus A, Tilg H, Ebenbichler CF, et al. Effect of bariatric surgery on circulating chemerin levels. Eur J Clin Invest 2010;40:277–280. Article PubMed
81. Zabel BA, Silverio AM, Butcher EC. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J Immunol 2005;174:244–251. Article PubMed
82. Krautbauer S, Wanninger J, Eisinger K, Hader Y, Beck M, Kopp A, et al. Chemerin is highly expressed in hepatocytes and is induced in non-alcoholic steatohepatitis liver. Exp Mol Pathol 2013;95:199–205. Article PubMed
83. Sell H, Divoux A, Poitou C, Basdevant A, Bouillot JL, Bedossa P, et al. Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2010;95:2892–2896. Article PubMed PDF
84. Docke S, Lock JF, Birkenfeld AL, Hoppe S, Lieske S, Rieger A, et al. Elevated hepatic chemerin mRNA expression in human non-alcoholic fatty liver disease. Eur J Endocrinol 2013;169:547–557. Article PubMed
85. Kukla M, Zwirska-Korczala K, Hartleb M, Waluga M, Chwist A, Kajor M, et al. Serum chemerin and vaspin in non-alcoholic fatty liver disease. Scand J Gastroenterol 2010;45:235–242. Article PubMed
86. Wolfs MG, Gruben N, Rensen SS, Verdam FJ, Greve JW, Driessen A, et al. Determining the association between adipokine expression in multiple tissues and phenotypic features of non-alcoholic fatty liver disease in obesity. Nutr Diabetes 2015;5:e146. Article PubMed PMC PDF
87. Blaner WS. Retinol-binding protein: the serum transport protein for vitamin A. Endocr Rev 1989;10:308–316. Article PubMed PDF
88. Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab 2007;6:79–87. Article PubMed
89. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 2006;354:2552–2563. Article PubMed
90. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436:356–362. Article PubMed PDF
91. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Schleicher E, et al. High circulating retinol-binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans. Diabetes Care 2007;30:1173–1178. Article PubMed
92. Seo JA, Kim NH, Park SY, Kim HY, Ryu OH, Lee KW, et al. Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease. Clin Endocrinol (Oxf) 2008;68:555–560. Article PubMed PMC
93. Terra X, Auguet T, Broch M, Sabench F, Hernandez M, Pastor RM, et al. Retinol binding protein-4 circulating levels were higher in nonalcoholic fatty liver disease vs. histologically normal liver from morbidly obese women. Obesity (Silver Spring) 2013;21:170–177. Article PubMed
94. Alkhouri N, Lopez R, Berk M, Feldstein AE. Serum retinol-binding protein 4 levels in patients with nonalcoholic fatty liver disease. J Clin Gastroenterol 2009;43:985–989. Article PubMed PMC
95. Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV, Mantzoros CS. Irisin in patients with nonalcoholic fatty liver disease. Metabolism 2014;63:207–217. Article PubMed
96. Perakakis N, Triantafyllou GA, Fernandez-Real JM, Huh JY, Park KH, Seufert J, et al. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 2017;13:324–337. Article PubMed PMC PDF
97. Polyzos SA, Anastasilakis AD, Efstathiadou ZA, Makras P, Perakakis N, Kountouras J, et al. Irisin in metabolic diseases. Endocrine 2018;59:260–274. Article PubMed PDF
98. Aldiss P, Betts J, Sale C, Pope M, Symonds ME. Exercise-induced ‘browning’ of adipose tissues. Metabolism 2018;81:63–70. Article PubMed PMC
99. Sahin-Efe A, Upadhyay J, Ko BJ, Dincer F, Park KH, Migdal A, et al. Irisin and leptin concentrations in relation to obesity, and developing type 2 diabetes: a cross sectional and a prospective case-control study nested in the Normative Aging Study. Metabolism 2018;79:24–32. Article PubMed
100. Qiu S, Cai X, Yin H, Zugel M, Sun Z, Steinacker JM, et al. Association between circulating irisin and insulin resistance in non-diabetic adults: a meta-analysis. Metabolism 2016;65:825–834. Article PubMed
101. Anastasilakis AD, Koulaxis D, Kefala N, Polyzos SA, Upadhyay J, Pagkalidou E, et al. Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. Metabolism 2017;73:1–8. Article PubMed
102. Huh JY, Mantzoros CS. Irisin physiology, oxidative stress, and thyroid dysfunction: what next? Metabolism 2015;64:765–767. Article PubMed
103. Jang HB, Kim HJ, Kang JH, Park SI, Park KH, Lee HJ. Association of circulating irisin levels with metabolic and metabolite profiles of Korean adolescents. Metabolism 2017;73:100–108. Article PubMed
104. Shanaki M, Moradi N, Emamgholipour S, Fadaei R, Poustchi H. Lower circulating irisin is associated with nonalcoholic fatty liver disease and type 2 diabetes. Diabetes Metab Syndr 2017;11(Suppl 1):S467–S472. Article PubMed
105. Petta S, Valenti L, Svegliati-Baroni G, Ruscica M, Pipitone RM, Dongiovanni P, et al. Fibronectin type III domain-containing protein 5 rs3480 A>G polymorphism, irisin, and liver fibrosis in patients with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2017;102:2660–2669. Article PubMed PDF
106. Zhang HJ, Zhang XF, Ma ZM, Pan LL, Chen Z, Han HW, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J Hepatol 2013;59:557–562. Article PubMed
107. Viitasalo A, Atalay M, Pihlajamaki J, Jaaskelainen J, Korkmaz A, Kaminska D, et al. The 148 M allele of the PNPLA3 is associated with plasma irisin levels in a population sample of Caucasian children: the PANIC Study. Metabolism 2015;64:793–796. Article PubMed
108. Polyzos SA, Mantzoros CS. An update on the validity of irisin assays and the link between irisin and hepatic metabolism. Metabolism 2015;64:937–942. Article PubMed
109. 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. Article PubMed
110. Chrusciel P, Sahebkar A, Rembek-Wieliczko M, Serban MC, Ursoniu S, Mikhailidis DP, et al. Impact of statin therapy on plasma adiponectin concentrations: a systematic review and meta-analysis of 43 randomized controlled trial arms. Atherosclerosis 2016;253:194–208. Article PubMed
111. Su JR, Lu ZH, Su Y, Zhao N, Dong CL, Sun L, et al. Relationship of serum adiponectin levels and metformin therapy in patients with type 2 diabetes. Horm Metab Res 2016;48:92–98. Article PubMed PDF
112. Zhuang X, Sun F, Li L, Jiang D, Li X, Sun A, et al. Therapeutic effect of metformin on chemerin in non-obese patients with non-alcoholic fatty liver disease (NAFLD). Clin Lab 2015;61:1409–1414. PubMed
113. Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and HIV-associated lipodystrophy. Metabolism 2015;64:47–59. Article PubMed

Table 1

Circulating Levels of Adipokines in Individuals with Insulin Resistance or with Specific Histological Lesions of Nonalcoholic Fatty Liver Disease (i.e., SS, Hepatic Inflammation, Hepatic Fibrosis)^a

Adipokine	Insulin resistance	SS	Hepatic inflammation	Hepatic fibrosis	Level of evidence
Adiponectin	Decreased [30]	Decreased [30]	Decreased [30]	Decreased compared both to controls and to SS [30]	Meta-analysis
Leptin	Increased [51]	Increased [51]	Increased [51]	Increased compared both to controls and to SS [51]	Meta-analysis
Resistin	Increased [56]	Increased [63] or similar [64]	Increased [63] or similar [64] compared to controls	Increased or similar compared to controls [63,64] or SS [65,66]	Observational studies
Visfatin	Controversial [72]	Increased [75] or similar [73,74]	Increased [75] or similar [73,74]	Increased or similar compared to controls [73,74,75] or SS [76]	Observational studies
Chemerin	Increased [80]	Increased [85]	Increased [85]	Increased [85] or similar [84] compared to controls or SS	Observational studies
RBP-4	Increased [89]	Increased [93]	Increased [93]	Increased [93] compared to controls Similar [93] or lower [94] compared to SS	Observational studies
Irisin	Increased [99]	Increased [95]	Increased [95]	Increased compared to controls [95] or SS [104,105]	Observational studies

SS, simple steatosis; RBP-4, retinol-binding protein 4.

^aCompared to healthy controls unless otherwise stated.

Figure & Data

References

Citations

Citations to this article as recorded by

Lipocalin‐2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high‐fat diet–fed Ob/Ob mice
Kyung Eun Kim, Jaewoong Lee, Hyun Joo Shin, Eun Ae Jeong, Hye Min Jang, Yu Jeong Ahn, Hyeong Seok An, Jong Youl Lee, Meong Cheol Shin, Soo Kyoung Kim, Won Gi Yoo, Won Ho Kim, Gu Seob Roh
Hepatology.2023; 77(3): 888. CrossRef
Effect of Dietary Intervention, with or without Cointerventions, on Inflammatory Markers in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
Renate L. Hall, Elena S. George, Audrey C. Tierney, Anjana J. Reddy
Advances in Nutrition.2023; 14(3): 475. CrossRef
The Anti-Obesity and Anti-Steatotic Effects of Chrysin in a Rat Model of Obesity Mediated through Modulating the Hepatic AMPK/mTOR/lipogenesis Pathways
Ghaleb Oriquat, Inas M. Masoud, Maher A. Kamel, Hebatallah Mohammed Aboudeya, Marwa B. Bakir, Sara A. Shaker
Molecules.2023; 28(4): 1734. CrossRef
Association between caffeine intake and liver biomarkers in non-alcoholic fatty liver disease
Kübra UÇAR, Evrim KAHRAMANOĞLU, Zeynep GÖKTAŞ
Cukurova Medical Journal.2023; 48(1): 177. CrossRef
Changes in liver enzymes are associated with changes in insulin resistance, inflammatory biomarkers and leptin in prepubertal children with obesity
Rosario Valle-Martos, Luis Jiménez-Reina, Ramón Cañete, Rosario Martos, Miguel Valle, María Dolores Cañete
Italian Journal of Pediatrics.2023;[Epub] CrossRef
Fetal programming by androgen excess impairs liver lipid content and PPARg expression in adult rats
Aimé Florencia Silva, Giselle Adriana Abruzzese, María José Ferrer, María Florencia Heber, Silvana Rocío Ferreira, Gloria Edith Cerrone, Alicia Beatriz Motta
Journal of Developmental Origins of Health and Disease.2022; 13(3): 300. CrossRef
Adipose tissue dysfunction and MAFLD in obesity on the scene of COVID-19
Adryana Cordeiro, Amanda Ribamar, Andrea Ramalho
Clinics and Research in Hepatology and Gastroenterology.2022; 46(3): 101807. CrossRef
Comparison of bioelectrical impedance analysis, mass index, and waist circumference in assessing risk for non-alcoholic steatohepatitis
Katherine J.P. Schwenger, Alexander Kiu, Maryam AlAli, Amnah Alhanaee, Sandra E. Fischer, Johane P. Allard
Nutrition.2022; 93: 111491. CrossRef
Unveiling the Role of the Fatty Acid Binding Protein 4 in the Metabolic-Associated Fatty Liver Disease
Juan Moreno-Vedia, Josefa Girona, Daiana Ibarretxe, Lluís Masana, Ricardo Rodríguez-Calvo
Biomedicines.2022; 10(1): 197. CrossRef
Predictive and Diagnostic Value of Serum Adipokines in Pregnant Women with Intrahepatic Cholestasis
Nazan Yurtcu, Canan Soyer Caliskan, Huri Guvey, Samettin Celik, Safak Hatirnaz, Andrea Tinelli
International Journal of Environmental Research and Public Health.2022; 19(4): 2254. CrossRef
Symposium review: Adipose tissue endocrinology in the periparturient period of dairy cows
Susanne Häussler, Hassan Sadri, Morteza H. Ghaffari, Helga Sauerwein
Journal of Dairy Science.2022; 105(4): 3648. CrossRef
Rodent models and metabolomics in non-alcoholic fatty liver disease: What can we learn?
Maria Martin-Grau, Vannina G Marrachelli, Daniel Monleon
World Journal of Hepatology.2022; 14(2): 304. CrossRef
Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients – a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown
Simona Alexandra Iacob, Diana Gabriela Iacob
Frontiers in Endocrinology.2022;[Epub] CrossRef
Protective Roles of Shilajit in Modulating Resistin, Adiponectin, and Cytokines in Rats with Non-alcoholic Fatty Liver Disease
Baran Ghezelbash, Nader Shahrokhi, Mohammad Khaksari, Gholamreza Asadikaram, Maryam Shahrokhi, Sara Shirazpour
Chinese Journal of Integrative Medicine.2022; 28(6): 531. CrossRef
The pathophysiological mechanism between hypopituitarism and nonalcoholic fatty liver disease
Xinhe Zhang, Haoyu Tian, Yiling Li
iLIVER.2022; 1(1): 65. CrossRef
Correlation of Adiponectin Gene Polymorphisms rs266729 and rs3774261 With Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
Yong-Tian Zheng, Tian-Mei Xiao, Chan-Xian Wu, Jin-Yan Cheng, Le-Yu Li
Frontiers in Endocrinology.2022;[Epub] CrossRef
An Overview of the TRP-Oxidative Stress Axis in Metabolic Syndrome: Insights for Novel Therapeutic Approaches
Mizael C. Araújo, Suzany H. S. Soczek, Jaqueline P. Pontes, Leonardo A. C. Marques, Gabriela S. Santos, Gisele Simão, Laryssa R. Bueno, Daniele Maria-Ferreira, Marcelo N. Muscará, Elizabeth S. Fernandes
Cells.2022; 11(8): 1292. CrossRef
Skeletal muscle mass to visceral fat area ratio as a predictor of NAFLD in lean and overweight men and women with effect modification by sex
Yoosun Cho, Yoosoo Chang, Seungho Ryu, Hyun‐Suk Jung, Chan‐won Kim, Hyungseok Oh, Mi Kyung Kim, Won Sohn, Hocheol Shin, Sarah H. Wild, Christopher D. Byrne
Hepatology Communications.2022; 6(9): 2238. CrossRef
The Perirenal Fat Thickness Was Associated with Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus
Yuxian Yang, Shuting Li, Yuechao Xu, Jing Ke, Dong Zhao
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2022; Volume 15: 1505. CrossRef
Non-alcoholic fatty liver disease development: A multifactorial pathogenic phenomena
Aamir Bashir, Ajay Duseja, Arka De, Manu Mehta, Pramil Tiwari
Liver Research.2022; 6(2): 72. CrossRef
Relationship between Liver Stiffness and Steatosis in Obesity Conditions: In Vivo and In Vitro Studies
Francesca Baldini, Mohamad Khalil, Alice Bartolozzi, Massimo Vassalli, Agostino Di Ciaula, Piero Portincasa, Laura Vergani
Biomolecules.2022; 12(5): 733. CrossRef
Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs
Eleftheria Galatou, Elena Mourelatou, Sophia Hatziantoniou, Ioannis S. Vizirianakis
Antioxidants.2022; 11(6): 1060. CrossRef
The epidemiology of non-alcoholic steatohepatitis (NASH) in the United States between 2010-2020: a population-based study
Osama Hamid, Ahmed Eltelbany, Abdul Mohammed, Khaled Alsabbagh Alchirazi, Sushrut Trakroo, Imad Asaad
Annals of Hepatology.2022; 27(5): 100727. CrossRef
Helicobacter Pylori-Induced Gastric Infections: From Pathogenesis to Novel Therapeutic Approaches Using Silver Nanoparticles
Romelia Pop, Alexandru-Flaviu Tăbăran, Andrei Paul Ungur, Andrada Negoescu, Cornel Cătoi
Pharmaceutics.2022; 14(7): 1463. CrossRef
Traumatic brain injury alters the gut-derived serotonergic system and associated peripheral organs
Natosha M. Mercado, Guanglin Zhang, Zhe Ying, Fernando Gómez-Pinilla
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2022; 1868(11): 166491. CrossRef
Detangling the interrelations between MAFLD, insulin resistance, and key hormones
Shreya C. Pal, Mohammed Eslam, Nahum Mendez-Sanchez
Hormones.2022; 21(4): 573. CrossRef
Historical Changes in Weight Classes and the Influence of NAFLD Prevalence: A Population Analysis of 34,486 Individuals
Benjamin Kai Yi Nah, Cheng Han Ng, Kai En Chan, Caitlyn Tan, Manik Aggarwal, Rebecca Wenling Zeng, Jieling Xiao, Yip Han Chin, Eunice X. X. Tan, Yi Ping Ren, Douglas Chee, Jonathan Neo, Nicholas W. S. Chew, Michael Tseng, Mohammad Shadab Siddiqui, Arun J.
International Journal of Environmental Research and Public Health.2022; 19(16): 9935. CrossRef
Adipokines in Non-Alcoholic Fatty Liver Disease: Are We on the Road toward New Biomarkers and Therapeutic Targets?
Vera Francisco, Maria Jesus Sanz, José T. Real, Patrice Marques, Maurizio Capuozzo, Djedjiga Ait Eldjoudi, Oreste Gualillo
Biology.2022; 11(8): 1237. CrossRef
Fatty Liver/Adipose Tissue Dual‐Targeting Nanoparticles with Heme Oxygenase‐1 Inducer for Amelioration of Obesity, Obesity‐Induced Type 2 Diabetes, and Steatohepatitis
Juhyeong Hong, Yong‐Hee Kim
Advanced Science.2022; 9(33): 2203286. CrossRef
Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH
Susanna C. Larsson, Karl Michaëlsson, Marina Mola-Caminal, Jonas Höijer, Christos S. Mantzoros
Metabolism.2022; 137: 155329. CrossRef
Gender differences in the ideal cutoffs of visceral fat area for predicting MAFLD in China
Pingping Yu, Huachao Yang, Xiaoya Qi, Ruixue Bai, Shouqin Zhang, Jianping Gong, Ying Mei, Peng Hu
Lipids in Health and Disease.2022;[Epub] CrossRef
Apelin and chemerin receptors are G protein-coupled receptors involved in metabolic as well as reproductive functions: Potential therapeutic implications?
Anthony Estienne, Alice Bongrani, Pascal Froment, Joëlle Dupont
Current Opinion in Endocrine and Metabolic Research.2021; 16: 86. CrossRef
Metformin dose increase versus added linagliptin in non‐alcoholic fatty liver disease and type 2 diabetes: An analysis of the J‐LINK study
Yasuji Komorizono, Kaori Hosoyamada, Naoko Imamura, Shoko Kajiya, Yasuhiro Hashiguchi, Norio Ueyama, Hirohiko Shinmaki, Nobuyuki Koriyama, Masako Tsukasa, Tetsuro Kamada
Diabetes, Obesity and Metabolism.2021; 23(3): 832. CrossRef
Gender Differences in the Relationships among Metabolic Syndrome and Various Obesity-Related Indices with Nonalcoholic Fatty Liver Disease in a Taiwanese Population
I-Ting Lin, Mei-Yueh Lee, Chih-Wen Wang, Da-Wei Wu, Szu-Chia Chen
International Journal of Environmental Research and Public Health.2021; 18(3): 857. CrossRef
Leptin in Leanness and Obesity
Nikolaos Perakakis, Olivia M. Farr, Christos S. Mantzoros
Journal of the American College of Cardiology.2021; 77(6): 745. CrossRef
Severe insulin resistance syndromes
Angeliki M. Angelidi, Andreas Filippaios, Christos S. Mantzoros
Journal of Clinical Investigation.2021;[Epub] CrossRef
Liver Enzymes Correlate With Metabolic Syndrome, Inflammation, and Endothelial Dysfunction in Prepubertal Children With Obesity
Rosario Valle-Martos, Miguel Valle, Rosario Martos, Ramón Cañete, Luis Jiménez-Reina, María Dolores Cañete
Frontiers in Pediatrics.2021;[Epub] CrossRef
From Nonalcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—New Terminology in Pediatric Patients as a Step in Good Scientific Direction?
Marta Flisiak-Jackiewicz, Anna Bobrus-Chociej, Natalia Wasilewska, Dariusz Marek Lebensztejn
Journal of Clinical Medicine.2021; 10(5): 924. CrossRef
Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives
Christina-Maria Flessa, Ioannis Kyrou, Narjes Nasiri-Ansari, Gregory Kaltsas, Athanasios G. Papavassiliou, Eva Kassi, Harpal S. Randeva
Current Obesity Reports.2021; 10(2): 134. CrossRef
Role of Insulin Resistance in MAFLD
Yoshitaka Sakurai, Naoto Kubota, Toshimasa Yamauchi, Takashi Kadowaki
International Journal of Molecular Sciences.2021; 22(8): 4156. CrossRef
Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non‐alcoholic steatohepatitis
Nikolaos Perakakis, Konstantinos Stefanakis, Michael Feigh, Sanne S. Veidal, Christos S. Mantzoros
Liver International.2021; 41(8): 1853. CrossRef
Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC
Hyunmi Kim, Da Som Lee, Tae Hyeon An, Hyun-Ju Park, Won Kon Kim, Kwang-Hee Bae, Kyoung-Jin Oh
International Journal of Molecular Sciences.2021; 22(9): 4495. CrossRef
Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors
Oriol Juanola, Sebastián Martínez-López, Rubén Francés, Isabel Gómez-Hurtado
International Journal of Environmental Research and Public Health.2021; 18(10): 5227. CrossRef
Serum Visfatin Levels in Nonalcoholic Fatty Liver Disease and Liver Fibrosis: Systematic Review and Meta-Analysis
Abdulrahman Ismaiel, Daniel-Corneliu Leucuta, Stefan-Lucian Popa, Dan L. Dumitrascu
Journal of Clinical Medicine.2021; 10(14): 3029. CrossRef
Possible Hepatoprotective Effect of Tocotrienol-Rich Fraction Vitamin E in Non-alcoholic Fatty Liver Disease in Obese Children and Adolescents
Farah D.R. Al-Baiaty, Aziana Ismail, Zarina Abdul Latiff, Khairul Najmi Muhammad Nawawi, Raja Affendi Raja Ali, Norfilza Mohd Mokhtar
Frontiers in Pediatrics.2021;[Epub] CrossRef
Adipokines in Insulin Resistance: Current Updates
Utpal Jagdish Dongre
Biosciences Biotechnology Research Asia.2021; 18(2): 357. CrossRef
Metabolic Effects of Gastrectomy and Duodenal Bypass in Early Gastric Cancer Patients with T2DM: A Prospective Single-Center Cohort Study
Young Ki Lee, Eun Kyung Lee, You Jin Lee, Bang Wool Eom, Hong Man Yoon, Young-Il Kim, Soo Jeong Cho, Jong Yeul Lee, Chan Gyoo Kim, Sun-Young Kong, Min Kyong Yoo, Yul Hwangbo, Young-Woo Kim, Il Ju Choi, Hak Jin Kim, Mi Hyang Kwak, Keun Won Ryu
Journal of Clinical Medicine.2021; 10(17): 4008. CrossRef
Chromium picolinate balances the metabolic and clinical markers in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled trial
Fateme Kooshki, Fardin Moradi, Arash Karimi, Hamid Reza Niazkar, Manouchehr Khoshbaten, Vahid Maleki, Bahram Pourghassem Gargari
European Journal of Gastroenterology & Hepatology.2021; 33(10): 1298. CrossRef
Specificities of lipotoxicity of free fatty acids and cytokine profile in patients with chronic diffuse liver diseases
V. I. Didenko, I. A. Klenina, О. M. Tatarchuk, O. I. Hrabovska, O. P. Petishko
Regulatory Mechanisms in Biosystems.2021; 13(1): 3. CrossRef
Long-term abuse of a high-carbohydrate diet is as harmful as a high-fat diet for development and progression of liver injury in a mouse model of NAFLD/NASH
Simona Pompili, Antonella Vetuschi, Eugenio Gaudio, Alessandra Tessitore, Roberta Capelli, Edoardo Alesse, Giovanni Latella, Roberta Sferra, Paolo Onori
Nutrition.2020; 75-76: 110782. CrossRef
Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD
Stergios A Polyzos, Nikolaos Perakakis, Chrysoula Boutari, Jannis Kountouras, Wael Ghaly, Athanasios D Anastasilakis, Asterios Karagiannis, Christos S Mantzoros
The Journal of Clinical Endocrinology & Metabolism.2020; 105(3): e390. CrossRef
Inflammatory Mechanisms of HCC Development
Maria Grazia Refolo, Caterina Messa, Vito Guerra, Brian Irving Carr, Rosalba D’Alessandro
Cancers.2020; 12(3): 641. CrossRef
Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
Robert F. Schwabe, Ira Tabas, Utpal B. Pajvani
Gastroenterology.2020; 158(7): 1913. CrossRef
Visceral-to-Subcutaneous Abdominal Fat Ratio Is Associated with Nonalcoholic Fatty Liver Disease and Liver Fibrosis
Chan-Hee Jung, Eun-Jung Rhee, Hyemi Kwon, Yoosoo Chang, Seungho Ryu, Won-Young Lee
Endocrinology and Metabolism.2020; 35(1): 165. CrossRef
Alpha-syntrophin deficiency protects against non-alcoholic steatohepatitis associated increase of macrophages, CD8+ T-cells and galectin-3 in the liver
Lisa Rein-Fischboeck, Elisabeth M. Haberl, Ganimete Bajraktari, Susanne Feder, Rebekka Pohl, Elke Eggenhofer, Christa Buechler
Experimental and Molecular Pathology.2020; 113: 104363. CrossRef
Targeting of Secretory Proteins as a Therapeutic Strategy for Treatment of Nonalcoholic Steatohepatitis (NASH)
Kyeongjin Kim, Kook Hwan Kim
International Journal of Molecular Sciences.2020; 21(7): 2296. CrossRef
Non-Alcoholic Fatty Liver Disease Treatment in Patients with Type 2 Diabetes Mellitus; New Kids on the Block
Vasilios G. Athyros, Stergios A. Polyzos, Jiannis Kountouras, Niki Katsiki, Panagiotis Anagnostis, Michael Doumas, Christos S. Mantzoros
Current Vascular Pharmacology.2020; 18(2): 172. CrossRef
High body mass index hinders fibrosis improvement in patients receiving long‐term tenofovir therapy in hepatitis B virus‐related cirrhosis
Young Eun Chon, Kyu Sik Jung, Yeonjung Ha, Mi Na Kim, Joo Ho Lee, Seong Gyu Hwang, Sang Hoon Ahn, Do Young Kim, Kwang‐Hyub Han, Jun Yong Park
Journal of Viral Hepatitis.2020; 27(11): 1119. CrossRef
The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease
Nikolaos Perakakis, Konstantinos Stefanakis, Christos S. Mantzoros
Metabolism.2020; 111: 154320. CrossRef
The Selective Peroxisome Proliferator‐Activated Receptor Gamma Modulator CHS‐131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis
Nikolaos Perakakis, Aditya Joshi, Natia Peradze, Konstantinos Stefanakis, Georgia Li, Michael Feigh, Sanne Skovgard Veidal, Glenn Rosen, Michael Fleming, Christos S. Mantzoros
Hepatology Communications.2020; 4(9): 1302. CrossRef
Osteocalcin and osteoprotegerin levels and their relationship with adipokines and proinflammatory cytokines in children with nonalcoholic fatty liver disease
Doaa El Amrousy, Dalia El-Afify
Cytokine.2020; 135: 155215. CrossRef
The effect of saffron supplementation on some inflammatory and oxidative markers, leptin, adiponectin, and body composition in patients with nonalcoholic fatty liver disease: A double‐blind randomized clinical trial
Farnaz Kavianipour, Naheed Aryaeian, Marjan Mokhtare, Reyhanesadat Mirnasrollahiparsa, Leila Jannani, Shahram Agah, Sodabeh Fallah, Nariman Moradi
Phytotherapy Research.2020; 34(12): 3367. CrossRef
Hepatic Lipidomics and Molecular Imaging in a Murine Non-Alcoholic Fatty Liver Disease Model: Insights into Molecular Mechanisms
Ricardo Rodríguez-Calvo, Sara Samino, Josefa Girona, Neus Martínez-Micaelo, Pere Ràfols, María García-Altares, Sandra Guaita-Esteruelas, Alexandra Junza, Mercedes Heras, Oscar Yanes, Xavier Correig, Lluis Masana
Biomolecules.2020; 10(9): 1275. CrossRef
The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling
Samukelisiwe C. Shabalala, Phiwayinkosi V. Dludla, Lawrence Mabasa, Abidemi P. Kappo, Albertus K. Basson, Carmen Pheiffer, Rabia Johnson
Biomedicine & Pharmacotherapy.2020; 131: 110785. CrossRef
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Na Xie, Lu Zhang, Wei Gao, Canhua Huang, Peter Ernst Huber, Xiaobo Zhou, Changlong Li, Guobo Shen, Bingwen Zou
Signal Transduction and Targeted Therapy.2020;[Epub] CrossRef
Neurochemical regulators of food behavior for pharmacological treatment of obesity: current status and future prospects
Gayane Sargis Vardanyan, Hasmik Samvel Harutyunyan, Michail Iosif Aghajanov, Ruben Sargis Vardanyan
Future Medicinal Chemistry.2020; 12(20): 1865. CrossRef
Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases
Maite Martínez-Uña, Yaiza López-Mancheño, Carlos Diéguez, Manuel A. Fernández-Rojo, Marta G. Novelle
International Journal of Molecular Sciences.2020; 21(24): 9368. CrossRef
Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression
Ming-Ling Chang, Zinger Yang, Sien-Sing Yang
International Journal of Molecular Sciences.2020; 21(21): 8308. CrossRef
CHANGES IN CARBOHYDRATE METABOLISM AND ADIPOCYTOKINES UNDER THE INFLUENCE OF TREATMENT OF PATIENTS WITH ALCOHOLIC CIRRHOSIS OF THE LIVER IN COMBINATION WITH OBESITY USING ADAMETHIONINUM AND ARGININE GLUTAMATE
N. R. Matkovska
Medical and Clinical Chemistry.2020; (3): 17. CrossRef
Effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Ex quo et quo vadimus?
Niki Katsiki, Nikolaos Perakakis, Christos Mantzoros
Metabolism.2019; 98: iii. CrossRef
Role of Soluble Adiponectin Receptor 2 in Non-Alcoholic Fatty Liver Disease in Children
Gulsah Kaya Aksoy, Reha Artan, Cihat Aksoy, Sebahat Özdem, Atike Atalay, Aygen Yılmaz
Pediatric Gastroenterology, Hepatology & Nutrition.2019; 22(5): 470. CrossRef
Determinants of ectopic liver fat in metabolic disease
Anja Bosy-Westphal, Wiebke Braun, Viktoria Albrecht, Manfred J. Müller
European Journal of Clinical Nutrition.2019; 73(2): 209. CrossRef
Involvement of the hepatic branch of the vagus nerve in the regulation of plasma adipokine levels in rats fed a high-fructose diet
Naoto Hashimoto, Manabu Wakagi, Katsunari Ippoushi, Yuko Takano-Ishikawa
The Journal of Nutritional Biochemistry.2019; 71: 90. CrossRef
Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease
Ines C.M. Simoes, Justyna Janikiewicz, Judith Bauer, Agnieszka Karkucinska-Wieckowska, Piotr Kalinowski, Agnieszka Dobrzyń, Andrzej Wolski, Maciej Pronicki, Krzysztof Zieniewicz, Paweł Dobrzyń, Marcin Krawczyk, Hans Zischka, Mariusz R. Wieckowski, Yaiza P
Nutrients.2019; 11(12): 2871. CrossRef
Childhood obesity: increased risk for cardiometabolic disease and cancer in adulthood
Susann Weihrauch-Blüher, Peter Schwarz, Jan-Henning Klusmann
Metabolism.2019; 92: 147. CrossRef
Effects of moderate-intensity continuous training and high-intensity interval training on serum levels of Resistin, Chemerin and liver enzymes in Streptozotocin-Nicotinamide induced Type-2 diabetic rats
Parastesh Mohammad, Khosravi Zadeh Esfandiar, Saremi Abbas, Rekabtalae Ahoora
Journal of Diabetes & Metabolic Disorders.2019; 18(2): 379. CrossRef
Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics
Stergios A. Polyzos, Jannis Kountouras, Christos S. Mantzoros
Metabolism.2019; 92: 82. CrossRef
The Latest Insights into Adipokines in Diabetes
Won Kon Kim, Kwang-Hee Bae, Sang Chul Lee, Kyoung-Jin Oh
Journal of Clinical Medicine.2019; 8(11): 1874. CrossRef
Postprandial leptin and adiponectin in response to sugar and fat in obese and normal weight individuals
M. A. Larsen, V. T. Isaksen, E. J. Paulssen, R. Goll, J. R. Florholmen
Endocrine.2019; 66(3): 517. CrossRef
First demonstration of protective effects of purified mushroom polysaccharide-peptides against fatty liver injury and the mechanisms involved
Shuang Zhao, Shuman Zhang, Weiwei Zhang, Yi Gao, Chengbo Rong, Hexiang Wang, Yu Liu, Jack Ho Wong, Tzibun Ng
Scientific Reports.2019;[Epub] CrossRef
Applying Non-Invasive Fibrosis Measurements in NAFLD/NASH: Progress to Date
Somaya Albhaisi, Arun J. Sanyal
Pharmaceutical Medicine.2019; 33(6): 451. CrossRef
Adiponectin rs2241766 and rs266729 gene polymorphisms in non-alcoholic fatty liver disease
Aida A. Mahmoud, Hoda M. Moghazy, Laila M. Yousef, Asmaa N. Mohammad
Gene Reports.2019; 15: 100381. CrossRef
Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: A proof of concept study
Nikolaos Perakakis, Stergios A. Polyzos, Alireza Yazdani, Aleix Sala-Vila, Jannis Kountouras, Athanasios D. Anastasilakis, Christos S. Mantzoros
Metabolism.2019; 101: 154005. CrossRef
Association between Helicobacter pylori infection and nonalcoholic fatty liver
Rongqiang Liu, Qiuli Liu, Ying He, Wenqing Shi, Qianhui Xu, Qing Yuan, Qi Lin, Biao Li, Lei Ye, Youlan Min, Peiwen Zhu, Yi Shao
Medicine.2019; 98(44): e17781. CrossRef
CHANGES IN CARBOHYDRATE METABOLISM IN PATIENTS WITH ALCOHOLIC CIRRHOSIS OF THE LIVER ASSOCIATED WITH NON-ALCOHOLIC FATTY LIVER DISEASE DEPENDING ON THE STAGE OF DECOMPENSATION
Nataliia Matkovska, Nataliia Virstiuk, Uliana Balan
International Academy Journal Web of Scholar.2019; (6(36)): 17. CrossRef
Non-alcoholic fatty liver disease and colorectal cancer: A marker of risk or common causation?
Niki Katsiki, Dimitri P. Mikhailidis, Christos Mantzoros
Metabolism.2018; 87: A10. CrossRef
Critical Roles of microRNAs in the Pathogenesis of Fatty Liver: New Advances, Challenges, and Potential Directions
Chenggui Miao, Zhongwen Xie, Jun Chang
Biochemical Genetics.2018; 56(5): 423. CrossRef
Alpha-syntrophin dependent expression of tubulin alpha 8 protein in hepatocytes
Lisa Rein-Fischboeck, Ganimete Bajraktari, Rebekka Pohl, Susanne Feder, Kristina Eisinger, Wolfgang Mages, Elisabeth M. Haberl, Christa Buechler
Journal of Physiology and Biochemistry.2018; 74(4): 511. CrossRef
Pathogenesis of Nonalcoholic Steatohepatitis and Hormone-Based Therapeutic Approaches
Kook Hwan Kim, Myung-Shik Lee
Frontiers in Endocrinology.2018;[Epub] CrossRef
Helicobacter pyloriand extragastric diseases: A review
Antonietta Gerarda Gravina, Rocco Maurizio Zagari, Cristiana De Musis, Lorenzo Romano, Carmelina Loguercio, Marco Romano
World Journal of Gastroenterology.2018; 24(29): 3204. CrossRef
Thiazolidinedione induces a therapeutic effect on hepatosteatosis by regulating stearoyl‑CoA desaturase‑1, lipase activity, leptin and resistin
Hessah Al‑Muzafar, Kamal Amin
Experimental and Therapeutic Medicine.2018;[Epub] CrossRef
Impact of weight cycling on CTRP3 expression, adipose tissue inflammation and insulin sensitivity in C57BL/6J mice
Xin Li, Li Jiang, Miao Yang, Yu‑Wen Wu, Jia‑Zhong Sun
Experimental and Therapeutic Medicine.2018;[Epub] CrossRef
Analysis of non‑alcoholic fatty liver disease microRNA expression spectra in rat liver tissues
Jiao Nie, Chang‑Ping Li, Jue‑Hong Li, Xia Chen, Xiaoling Zhong
Molecular Medicine Reports.2018;[Epub] CrossRef