Effects of weight loss induced by bariatric surgery on hepatic adipocytokine expression☆
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.
References (68)
- et al.
NASH: from liver diseases to metabolic disorders and back to clinical hepatology
Hepatology
(2002) - et al.
Nonalcoholic fatty liver disease: cytokine–adipokine interplay and regulation of insulin resistance
Gastroenterology
(2006) - et al.
Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis
Surgery
(2004) - et al.
Laparoscopic adjustable gastric banding in the treatment of obesity: a systematic literature review
Surgery
(2004) - et al.
Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes
Biochem Biophys Res Commun
(2004) - et al.
Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial
Gastroenterology
(2008) - et al.
Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions
Am J Gastroenterol
(1999) - et al.
Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells
Am J Pathol
(2006) - et al.
Adiponectin and its receptors in patients with chronic hepatitis C
J Hepatol
(2005) - et al.
Insulin resistance, inflammation, and non-alcoholic fatty liver disease
Trends Endocrinol Metab
(2008)
Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?
Hepatology
Association between nonalcoholic fatty liver, markers of obesity, and serum leptin level in young adults
Am J Gastroenterol
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem Biophys Res Commun
Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin
Gastroenterology
Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease
Clin Gastroenterol Hepatol
Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat
Gastroenterology
Leptin is essential for the hepatic fibrogenic response to chronic liver injury
J Hepatol
Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway
Biochem Biophys Res Commun
Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor
FEBS Lett
Treatment strategies in nonalcoholic fatty liver disease
Nat Clin Pract Gastroenterol Hepatol
Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity
Hepatology
Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes
Diabetes
Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss
Hepatology
Regression of hepatic steatosis in morbidly obese persons after gastric bypass
Am J Clin Pathol
Liver abnormalities in severely obese subjects: effect of drastic weight loss after gastroplasty
Int J Obes Relat Metab Disord
Adipocytokines: mediators linking adipose tissue, inflammation and immunity
Nat Rev Immunol
The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice
J Clin Invest
Endogenous glucose production is inhibited by the adipose-derived protein Acrp30
J Clin Invest
Cloning of adiponectin receptors that mediate antidiabetic metabolic effects
Nature
Diet-induced insulin resistance in mice lacking adiponectin/ACRP30
Nat Med
Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial
JAMA
Leptin in immunology
J Immunol
Role of adiponectin and PBEF/visfatin as regulators of inflammation: involvement in obesity-associated diseases
Clin Sci (Lond)
Role of resistin in obesity, insulin resistance and type II diabetes
Clin Sci (Lond)
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2021, American Journal of SurgeryCitation Excerpt :Lower levels of adiponectin, an antisteatotic and anti-inflammatory adipocyte, were associated with histologic NASH.25 Significant increase in serum adiponectin levels has been observed after substantial weight loss after bariatric surgery.26,27 We have similarly showed a significant increase in mean adiponectin levels in NAFLD patients after SG, corresponding with the improvements in steatosis and NASH score.
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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.