Andreas Schäffler

The Potential of Adiponectin in Driving Arthritis

Articular adipose tissue is a ubiquitous component of human joints, but its local functions are largely unknown. Because recent studies revealed several links between adipose tissue, adipocytokines, and arthritis, we investigated the expression of the adipocytokine adiponectin and its functional role in articular adipose tissue and synovium of patients with different arthritides. In contrast to its protective role in endocrinological and vascular diseases, adiponectin was found to be involved in key pathways of inflammation and matrix degradation in the human joint. The effects of adiponectin in human synovial fibroblasts appear to be highly selective by inducing only two of the main mediators of rheumatoid arthritis pathophysiology, IL-6 and matrix metalloproteinase-1, via the p38 MAPK pathway. Owing to the observation that these effects could be inhibited by different TNF-α inhibitors, adipocytokines such as adiponectin may also be key targets for therapeutic strategies in inflammatory joint diseases. In summary, articular adipose tissue and adipocytokines cannot be regarded as innocent bystanders any more in chronic inflammatory diseases such as arthritis.

Different effects of adiponectin isoforms in human monocytic cells.

Adiponectin (APM) is an adipocyte‐derived adipokine with immunosuppressive, antidiabetic, and antiatherosclerotic properties. Low molecular weight (LMW)‐ and higher molecular weight (HMW)‐APM circulate in the serum and activate different signaling pathways. We were interested to see whether LMW‐APM exerts different effects on monocytic cells compared with the HMW isoform. Therefore, the effects of recombinant LMW‐APM produced in insect cells and the APM from higher eukaryotic cells containing HMW forms on monocytic cells were investigated with respect to apoptosis and inflammation. LMW‐ and HMW‐APM induce apoptosis in nondifferentiated THP‐1 cells, reduce macrophage scavenger receptor (MSR) A mRNA expression, and stimulate phosphorylation of adenosine monophosphate‐activated protein kinase (AMPK). However, HMW‐APM induces the secretion of interleukin (IL)‐6 in human monocytes and THP‐1 cells but does not suppress lipopolysaccharide (LPS)‐induced IL‐6 secretion. In contrast, LMW‐APM reduces LPS‐mediated IL‐6 release and furthermore, stimulates IL‐10 secretion, most likely by reducing the abundance of inhibitor of nuclear factor (NF)‐κB kinase β, leading to a diminished nuclear translocation of NF‐κB p65. Our data indicate that the different APM isoforms do share common effects on monocytic cells but also induce isoform‐specific responses. Although apoptosis, the activation of AMPK, and the reduction of MSR are mediated by all APM isoforms, only LMW‐APM displays anti‐inflammatory properties.

Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes

Background  The adipokine chemerin modulates the function of innate immune cells and may link obesity and inflammation, and therefore, a possible relation of chemerin to inflammatory proteins in obesity and type 2 diabetes (T2D) was analysed. As visceral fat contributes to systemic inflammation, chemerin was measured in portal venous (PVS), hepatic venous (HVS) and systemic venous (SVS) blood of patients with liver cirrhosis.

Mechanisms of Disease: adipocytokines and visceral adipose tissue—emerging role in nonalcoholic fatty liver disease

There is increasing evidence that visceral adipose tissue is a causative risk factor for fatty liver and nonalcoholic steatohepatitis. Adipose tissue-derived secretory proteins are collectively named adipocytokines. Obesity and mainly visceral fat accumulation impair adipocyte function and adipocytokine secretion and the altered release of these proteins contributes to hypertension, impaired fibrinolysis and insulin resistance. This review summarizes recent findings on the role of the adipocytokines adiponectin, leptin and resistin in the context of hepatic insulin resistance, fatty liver and liver fibrosis. Elevated levels of resistin antagonize hepatic insulin action and raise plasma glucose levels. Leptin exerts insulin-sensitizing effects, but obesity has been linked to leptin resistance and low levels of circulating leptin receptor, indicating that high levels of leptin cannot mediate its beneficial effects. Adiponectin improves insulin sensitivity; however, low circulating adiponectin is found in the obese state. Adiponectin is an anti-inflammatory protein, whereas leptin augments inflammation and fibrogenesis. Disturbed adipocytokine secretion might, therefore, promote hepatic steatosis and the development of nonalcoholic steatohepatitis. The beneficial effects of the therapeutic approaches so far tested in the treatment of fatty liver disease and fibrosis might be due to the modulation of these adipocytokines.

Innate immunity and adipose tissue biology

The understanding of the role of adipose tissue has changed from a lipid storage organ to an endocrine and immunologically active organ. Here, we summarize the evidence for an important role of adipose tissue in innate immunity. The review focuses on the expression and function of Toll-like receptors (TLRs) in adipocytes and on the role of adipose tissue macrophages. The dual activation of TLR4 in adipocytes by lipopolysaccharide and fatty acids represents a molecular gate that connects innate immunity with metabolism. Dichotomic molecules derived from ancient precursor molecules control metabolism and immune function. Visceral adipose tissue is infiltrated by macrophages in obesity, and there is local crosstalk between these two types of cells, leading to an inflammatory transformation of adipose tissue.

Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.

Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼

CTRP family: linking immunity to metabolism

3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378–85)

Adiponectin represents an independent cardiovascular risk factor predicting serum HDL-cholesterol levels in type 2 diabetes

It is well known that infectious and inflammatory diseases such as sepsis and severe inflammatory response syndrome are accompanied by metabolic alterations such as insulin resistance. Conversely, metabolic diseases such as visceral obesity and type 2 diabetes are characterized by high levels of proinflammatory cytokines. Metabolism and immunity are linked by proteins of dual function. Adiponectin, a member of the C1q/TNF-related protein (CTRP) family, has attracted much interest because of its anti-inflammatory and insulin-sensitizing effects. To date, 15 additional CTRP family members have been identified that might also play a role in metabolism and immunity. This review focuses on the biochemistry and pleiotropic physiological functions of CTRPs as new molecular mediators connecting inflammatory and metabolic diseases.

Profiling adipocytokine secretion from creeping fat in Crohn's disease

Low levels of high‐density lipoprotein (HDL)‐cholesterol represent an independent cardiovascular risk factor and, besides reduced physical activity, mechanisms leading to decreased HDL‐cholesterol levels are not known. We aimed to test the hypothesis, that adiponectin provides a missing link between type 2 diabetes and low levels of HDL‐cholesterol, independent from common metabolic risk factors. 523 patients with type 2 diabetes were investigated for adiponectin serum levels and parameters of lipid metabolism. Even after correction for age, gender, BMI and fasting insulin concentration, serum levels of adiponectin were highly significant (P<0.0001) and positively (regression analysis: r=0.86) associated with HDL‐cholesterol levels in type 2 diabetes. Conclusion: adiponectin seems to predict HDL‐cholesterol levels in patients with diabetes mellitus type 2. Low levels of adiponectin are associated with low levels of HDL‐cholesterol independently from common metabolic risk factors and therefore represent an independent cardiovascular risk factor in type 2 diabetes. Thus, adiponectin is a potentially new drug target in the treatment of dyslipidaemia.

Innate Immunity and Adipocyte Function: Ligand‐specific Activation of Multiple Toll‐like Receptors Modulates Cytokine, Adipokine, and Chemokine Secretion in Adipocytes

Background: Adipose tissue is recognized as a compartment secreting highly active molecules. Creeping fat represents a characteristic feature of Crohns disease (CD). Proinflammatory or anti‐inflammatory adipose‐derived secretory products, now generally called adipocytokines, may play a role in the pathogenesis of CD. Materials and Methods: Adipose tissue specimens were obtained from creeping fat contiguous to the involved intestine of 10 patients with CD. Mesenteric adipose tissue specimens resected from 13 patients with colon cancer (CC) and from 7 patients with diverticulitis served as controls. Three fat tissue specimen per well and 6 to 8 wells per patient were incubated ex vivo for 24 h. The release of adiponectin, resistin, leptin, interleukin‐6, macrophage colony‐stimulating factor, monocyte chemotactic protein‐1, and migration inhibitory factor was measured by ELISA. The expression of AdipoR1 and AdipoR2 receptors was investigated by real‐time quantitative polymerase chain reaction in a subset of adipose tissues. Results: The secretion of adiponectin and macrophage colony‐stimulating factor, as well as leptin and migration inhibitory factor, was significantly upregulated in CD compared with CC and diverticulitis or CC only, respectively. Resistin, interleukin‐6, and monocyte chemotactic protein‐1 were not specifically induced in CD but were associated with unspecific inflammation. Adiponectin receptor expression was not different in CC, CD, or diverticulitis. Steroid treatment in CD patients had differential effects on the ex vivo secretion of adipocytokines. Conclusions: A specific secretion pattern of proinflammatory and anti‐inflammatory adipocytokines indicates the significance of adipose tissue in intestinal inflammation in CD. Future investigations of this intestinal compartment may provide novelinsights into the pathophysiological role of creeping fat and CD.