Christoph F. Ebenbichler

Adiponectin and its receptors in non-alcoholic steatohepatitis

Background: Adiponectin, an adipocyte derived polypeptide, has been shown to alleviate steatosis and inflammation in mice with non-alcoholic fatty liver disease. Aim: In the present study, we wished to define liver expression of adiponectin and its receptors in morbidly obese patients undergoing bariatric surgery. Patients with non-alcoholic steatohepatitis (NASH) or simple steatosis were investigated to test whether dysregulation of this system might be involved in these disorders. Patients and methods: Liver mRNA expression of adiponectin and its recently cloned receptors RI and RII (adipoRI and adipoRII) were analysed by fluorescence based real time polymerase chain reaction in 13 patients with NASH and nine with simple steatosis. Adiponectin and adipoRII protein expression were assessed by immunohistochemistry in a subgroup of patients. Results: Adiponectin and adipoRII mRNA expression were significantly reduced in liver biopsies of patients with NASH compared with simple steatosis while no difference was found in adipoRI mRNA expression. In NASH, adipoRII mRNA expression was negatively correlated with serum aspartate aminotransferase levels, serum alanine aminotransferase levels, and grade of fibrosis. Liver adiponectin protein expression was mainly found in endothelial cells of portal vessels and liver sinusoids whereas adipoRII expression was seen in hepatocytes only. Adiponectin and adipoRII staining were lower in biopsies of subjects with NASH compared with simple steatosis. Conclusion: Reduced hepatic expression of adiponectin and adipoRII might be of pathophysiological relevance in non-alcoholic fatty liver diseases.

A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (∼63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

Metabolic side effects of antipsychotic medication.

The use of second‐generation antipsychotics (SGAs) is associated with metabolic side effects including weight gain, diabetes mellitus and an atherogenic lipid profile. These adverse effects are not only the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus leading to increased morbidity and mortality but may also impair the patients adherence to treatment.

Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention

Background: Human adipose tissue expresses and releases proinflammatory cytokines and these measures of chronic inflammation have recently been associated with obesity.Hypothesis: To test whether the proinflammatory state is reversible in subjects undergoing weight loss by surgical measures.Subjects and Methods: Twenty morbidly obese women participated in this prospective study. Subjects were examined for fat mass, high-sensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) before and 1 y after Swedish adjustable gastric banding.Results: Anthropometric measures displayed a significant reduction of the body mass index (BMI) from 41.6±5.4 to 30.8±6.1 kg/m2 and the fat mass from 53.9±10.3 to 29.8±12.1 kg (mean±s.d.). Hs-CRP levels decreased significantly from 1.33±1.21 mg/dl in pre-gastric banding subjects to 0.40±0.61 mg/dl in post-gastric banding subjects, respectively. IL-6 and TNF-α levels did not differ significantly between pre- and post-gastric banding subjects.Conclusions: We speculate that in these patients the marked reduction in C-reactive protein might be beneficial in reducing their cardiovascular risk and is not solely mediated by IL-6 and TNF-α.

Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor α expression

Objective Severe obesity is a chronic inflammatory disease where various cytokines/adipocytokines play a key role. Pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumour necrosis factor-α (TNFα) are produced by human adipose tissue dependent on the degree of obesity. Mouse studies suggest a key role of adipose tissue-derived IL-6 in hepatic insulin resistance via modification of liver suppressor of cytokine signalling 3 (SOCS-3) expression. Design and methods We examined the effect of excessive weight loss on systemic levels, subcutaneous and visceral adipose tissue and liver expression of IL-6 and TNFα in 20 severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB). Furthermore, we studied liver expression of SOCS3, an important regulator of insulin resistance, and fat tissue expression of the anti-inflammatory adipocytokine adiponectin and its receptors. Serum and tissue samples were collected before and 6 months after LAGB surgery. Results IL-6/TNFα mRNA expression before weight loss were similar in subcutaneous and visceral adipose tissue and much higher compared to hepatic expression. Subcutaneous adipose tissue mRNA expression of both pro-inflammatory cytokines, but especially of IL-6 decreased dramatically after extensive weight loss whereas expression of adiponectin and its receptors increased. Weight loss also led to a significant reduction in liver IL-6 expression, whereas liver TNFα mRNA expression did not change. IL-6 and C-reactive protein serum levels decreased after weight loss whereas TNFα serum levels were below the detection limit before and after surgery. These effects were paralleled by reduced hepatic SOCS3 expression and improved insulin resistance 6 months after LAGB surgery. Conclusion Expression of IL-6 and TNFα mRNA is more pronounced in adipose compared to liver tissue in patients with severe obesity. Our results highlight excessive weight loss as a successful anti-inflammatory strategy.

Postprandial state and atherosclerosis

Accumulating evidence suggests that triglyceride-rich lipoproteins are an independent risk factor for atherosclerosis. This epidemiological evidence first emerged as a result of studying postprandial lipaemia that characterized the metabolic capacity of triglycerides in the postabsorptive state, that is, under challenge. Studies of postprandial lipaemia were helpful to explain several effects of triglyceride-rich lipoproteins on cholesteryl-ester-rich lipoproteins. From these studies it became apparent that peculiarities of cholesteryl-ester-rich lipoproteins, such as small LDL and small HDL, which have been associated with risk for atherosclerosis, were caused by impaired triglyceride metabolism.

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

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.

Interaction of several complement proteins with gp120 and gp41, the two envelope glycoproteins of HIV-1.

ObjectiveTo study the binding of human complement proteins to gp41 and gp120 of HIV-1. MethodsThe interaction of complement proteins with gp41 and gp120 and their effect on the gp41-gp120 complex in enzyme-linked immunosorbent assays (ELISA) and on stably transfected Schneider-2 cells expressing a gp41-gp120 complex was investigated. The molecular basis of these interactions was analysed by computer-supported sequence analysis. Resultgp41 strongly binds human complement regulatory proteins factors H and properdin, and weakly binds factors I and B. The binding occurs with recombinant soluble (rs) gp41 fixed on ELISA plates as well as gp41-gp120 complex expressed on Schneider-2 cells. The basis for this binding potential might be an amino-acid (aa) sequence of gp41 displaying homologies to sites in human C3. rgp120 also binds C3(H20), a C3b-like form of C3, and C4b. These binding features of gp120 can be explained by homology of constant region (CR) 4 in gp120 to sites in C4b binding protein. Additionally, CR1 in gp120 exhibits a weak similarity to human properdin. Preincubation of rsgp41 with either factor H or properdin, and of rgp120 with C3b or C4b affected the interaction between rsgp41 and rgp120. Incubation of Schneider-2 cells, expressing a functional gp41-gp120 complex, with factor H reduced the detectable amount of gp120. This effect was similar to that induced by soluble CD4. ConclusionThese results strongly suggest that HIV-1 envelope proteins interact with human complement proteins. Additionally, C3b-like features of gp41 and the C3b/C4b binding structures in gp120 may affect the non-covalent association between gp41 and gp120.

Pronounced postprandial lipemia impairs endothelium-dependent dilation of the brachial artery in men.

OBJECTIVE Pronounced postprandial lipemia has been established as a risk factor for cardiovascular disease, but reports regarding its effect on endothelial function have been controversial. In the present study the influence of a standardized fatty meal with its ensuing postprandial lipemia of highly varying magnitude on endothelium-dependent dilation (EDD) was investigated. METHODS In 17 healthy, normolipidemic men EDD of the brachial artery was quantified in two series of three measurements each. In both series initial measurements were performed at 08:00 h after an overnight fast followed by measurements at 12:00 and 16:00 h, in the first series with continued fasting and in the second following the ingestion of a standardized fatty test meal 4 and 8 h postprandially. RESULTS Measurements of EDD in the fasting state revealed the recently appreciated diurnal variation with higher values in noon and afternoon hours compared with morning values (2.5+/-1.6% at 08:00, 7.5+/-2.7% at 12:00, and 7.0+/-2.1% at 16:00 h, P<0.001 by analysis of variance). Postprandial EDD values measured at 12:00 h were, at the average, lower than fasting EDD values measured at 12:00 h and correlated inversely with the magnitude of postprandial triglyceridemia (r=-0.81, P<0.001). In multivariate analysis, higher postprandial lipemia was associated with impaired postprandial EDD (P<0.001) independent of fasting triglycerides, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol, insulin, age and body mass index. CONCLUSION We conclude that pronounced postprandial lipemia is associated with transient impairment of endothelial function. Our findings support the notion that impaired triglyceride metabolic capacity plays an important role in atherogenesis.

Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss.

Morbid obesity is associated with a state of chronic inflammation. Interleukin-1 family (IL-1F) cytokine members are produced by human adipose tissue in obesity. Whereas certain IL-1F members such as IL-1β or IL-18 are potently proinflammatory, others such as IL-1 receptor antagonist (IL-1Ra) or IL-37 (formerly IL-1F7) are antiinflammatory. The NLRP3 inflammasome plays a key role in the processing of bioactive IL-1β and IL-18. We investigated the effect of excessive weight loss on subcutaneous adipose tissue and liver expression of IL-1α, IL-1β, IL-18, IL-1Ra, IL-37 and NLRP3. Twenty-one severely obese patients undergoing laparoscopic adjustable gastric banding were studied. Tissue samples were collected before and 6 months after laparoscopic adjustable gastric banding surgery. mRNA expression of all studied IL-1F members, but especially of IL-37, was much higher in subcutaneous/visceral adipose tissue compared with their liver expression. Subcutaneous adipose tissue mRNA expression of IL-1β decreased significantly after extensive weight loss; expression of IL-18 and IL-1Ra did not change, whereas IL-37 expression increased. Weight loss led to a significant reduction in liver IL-1β, IL-18 and IL-1Ra expression, whereas hepatic IL-37 mRNA expression remained stable. Adipose/liver NLRP3 inflammasome and IL-1α expression were not affected by weight loss. Tissue expression of IL-1β, IL-18 and IL-37 were significantly higher in subcutaneous/visceral adipose tissue compared with the liver. In conclusion, expression of IL-1F members is more pronounced in adipose compared with liver tissue in patients with severe obesity. Excessive weight loss changes the adipose and liver expression profile of IL-1F members toward a more antiinflammatory direction.