Elsevier

Journal of Hepatology

Volume 51, Issue 4, October 2009, Pages 765-777
Journal of Hepatology

Effects of weight loss induced by bariatric surgery on hepatic adipocytokine expression

https://doi.org/10.1016/j.jhep.2009.06.016Get rights and content

Background/Aims

Adipocytokines play a key role in the pathophysiology of non-alcoholic fatty liver diseases (NAFLD). Whereas adiponectin has mainly anti-inflammatory functions, leptin, resistin and pre-B cell enhancing factor (PBEF)/Nampt/visfatin are considered as mainly pro-inflammatory mediators regulating metabolic and immune processes.

Methods

We prospectively examined the effect of weight loss on systemic levels and/or hepatic expression of adiponectin/adiponectin receptors, leptin/leptin receptors, resistin and PBEF/Nampt/visfatin. Severely obese patients underwent laparoscopic adjustable gastric banding (LABG) and serum samples (n = 30) were collected before, and after 6 and 12 months. Paired liver biopsies (before and 6 months after LABG) were obtained from 18 patients.

Results

Bariatric surgery improved insulin resistance, abnormal liver function tests and liver histology. Pronounced weight loss after 6 and 12 months was accompanied by a significant increase in serum adiponectin levels whereas both leptin and PBEF/Nampt/visfatin levels decreased. Resistin serum levels increased after 6 months but fell below baseline values after 12 months. Liver mRNA expression of adiponectin increased slightly after 6 months whereas leptin mRNA expression did not change. Interestingly, weight loss resulted in a significant decrease of hepatic mRNA expression of resistin, PBEF/Nampt/visfatin and both leptin receptor isoforms while expression of type 1 and 2 adiponectin receptor was not affected. Liver immunohistochemistry performed on index and follow-up liver biopsies revealed an increase in adiponectin staining, showed no effect on resistin/leptin positivity, and demonstrated a decrease in PBEF/Nampt/visfatin immunoreactivity.

Conclusions

Weight loss after LABG surgery drives the adipocytokine milieu towards a more anti-inflammatory direction both systemically and in the liver.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a major cause of liver disease worldwide [1], [2]. There is now convincing evidence that NAFLD is part of the metabolic syndrome and insulin resistance (IR) has been identified as a crucial pathophysiologic factor in this disease [3]. Obesity and associated IR are pro-inflammatory states with increased adipose tissue expression of various pro-inflammatory mediators such as tumor necrosis factor-alpha (TNFα) and systemic signs of inflammation [4].

On the basis that NAFLD is part of the metabolic syndrome, weight loss seems to represent a logical treatment modality for NAFLD patients who are overweight or obese [5]. Weight loss, induced by bariatric surgery, improves liver biochemistries and steatosis [6], [7], [8], although some controversy exists from earlier studies about the histologic outcome of such procedures [7], [9]. Among bariatric surgery procedures laparoscopic adjustable gastric banding (LAGB) allows for controlled weight loss without major alterations to the structure and function of the gastrointestinal tract. Compared to alternative surgical procedures, such as biliopancreatic diversion and long limb Roux-en-Y gastric bypass, LAGB has proved to be effective with less perioperative morbidity and mortality [10].

Adipose tissue secretes a variety of bioactive proteins or adipocytokines that have recently gained great interest [11]. This heterogenous group of mediators includes adipocytokines such as adiponectin, leptin, resistin, pre-B-cell enhancing factor (PBEF)/Nampt/visfatin and others [11]. Adiponectin, a major anti-steatotic and anti-inflammatory adipocyte-derived mediator [12], [13] binds to two receptors (ADIPOR1/2) with ADIPOR1 being widely expressed and ADIPOR2 being predominantly confined to the liver [14]. Adiponectin−/− mice show evidence of increased local and systemic TNFα activity [15]. Moreover, adiponectin suppresses inflammation via induction of anti-inflammatory mediators such as IL-10 and IL-1 receptor antagonist (IL-1Ra) [16]. Leptin, the second major adipocytokine, has very diverse immune and metabolic functions. Obesity is associated with high circulating leptin levels and leptin resistance in the central nervous system as leptin fails to correct hyperglycemia in patients with obesity, supporting the idea of “leptin resistance” in these patients [17]. Leptin is in many instances considered the counterpart of adiponectin having mainly pro-inflammatory functions [18]. The leptin receptor (LEPR) exists in at least 6 alternatively spliced forms. The short isoforms of the LEPR (LEPRshort) are expressed by several non-immune tissues and believed to mediate transport and degradation of leptin. The long isoform, known as LEPRb (LEPRlong) is expressed by the hypothalamus, by endothelial cells, macrophages, B and T cells and others [18]. Resistin, initially correlated with IR at least in mice, has been described as a more pro-inflammatory mediator mainly produced by leukocytes [19]. However, even though the pro-inflammatory properties of resistin indicate its role as an inflammatory mediator [20], such a role in humans has not yet been convincingly demonstrated. PBEF/Nampt/visfatin has been recently characterized as a novel adipocytokine [21]. We demonstrated potent pro-inflammatory effects of this adipocytokine in human leukocytes [22]. Elevated serum levels have also been described in states of active inflammation such as sepsis, acute lung injury, rheumatoid arthritis, and inflammatory bowel disease [22], [23], [24], [25]. The aim of the present study was to evaluate liver expression and systemic levels of various adipocytokines before and after weight loss induced by LAGB.

Section snippets

Subjects and preoperative assessment

Selection and preoperative assessment of patients considered for the placement of an adjustable gastric banding device was performed at the Department for General Internal Medicine. Severely obese patients with a body mass index (BMI) of more than 35 kg/m2 who had no significant medical, physical, or psychosocial disabilities were considered to be enrolled into the study. In all patients current and past alcohol intake was less than 20 g per week. Hepatitis B and C serological analyses were

Weight loss

Six months after LAGB surgery we observed a significant weight loss ranging from 6.5 to 49.5 kg corresponding to a mean weight loss of 20.2 ± 1.79 kg in study patients (n = 30). The mean weight loss after 12 months was 25.5 ± 1.80 kg. Patients’ characteristics are shown in Table 2.

Improvement in biochemical and metabolic parameters

The presence of type II diabetes mellitus (TIIDM) as defined by a fasting plasma glucose level of ⩾126 mg/dl [33] was observed in 2 patients before weight loss and in none of the patients after 6 or after 12 months.

Discussion

In this study we describe alterations in both systemic levels and hepatic expression of various adipocytokines. Obesity is associated with decreased levels of circulating adiponectin [39]. Intriguingly, hypoadiponectemia has been shown to be a feature of NAFLD/NASH independent of IR [40]. Besides its anti-lipogenic [12], and insulin-sensitizing properties [13], adiponectin encompasses a wide range of anti-inflammatory activities. Given exogenously, adiponectin showed beneficial effects in

Acknowledgements

The authors thank Sabine Geiger, Barbara Enrich, Karin Salzmann, and Ines Brosch for their perfect technical assistance. Furthermore, we are indebted to nursing staff of the Department of Medicine and the Surgery Unit for their help in performing the study.

This work was supported by the Christian-Doppler Research Society.

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    The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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    These authors contributed equally to this work.

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