BackgroundObesity is associated with macrophage infiltration of adipose tissue. These inflammatory cells affect adipocytes not only by classical cytokines but also by the secreted glycopeptide wnt5a. Healthy adipocytes are able to release the wnt5a inhibitor sFRP5. This protective effect, however, was found to be diminished in obesity. The aim of the present study was to examine (1) whether obese human subjects exhibit increased serum concentrations of wnt5a and (2) whether wnt5a and/or sFRP5 serum concentrations in obese subjects can be influenced by caloric restriction.Methodology23 obese human subjects (BMI 44.1±1.1 kg/m2) and 12 age- and sex-matched lean controls (BMI 22.3±0.4 kg/m2) were included in the study. Obese subjects were treated with a very low-calorie diet (approximately 800 kcal/d) for 12 weeks. Body composition was assessed by impedance analysis, insulin sensitivity was estimated by HOMA-IR and the leptin-to-adiponectin ratio and wnt5a and sFRP5 serum concentrations were measured by ELISA. sFRP5 expression in human adipose tissue biopsies was further determined on protein level by immunohistology.Principal FindingsPro-inflammatory wnt5a was not measurable in any serum sample of lean control subjects. In patients with obesity, however, wnt5a became significantly detectable consistent with low grade inflammation in such subjects. Caloric restriction resulted in a weight loss from 131.9±4.0 to 112.3±3.2 kg in the obese patients group. This was accompanied by a significant decrease of HOMA-IR and leptin-to-adiponectin ratio, indicating improved insulin sensitivity. Interestingly, these metabolic improvements were associated with a significant increase in serum concentrations of the anti-inflammatory factor and wnt5a-inhibitor sFRP5.Conclusions/SignificanceObesity is associated with elevated serum levels of pro-inflammatory wnt5a in humans. Furthermore, caloric restriction beneficially affects serum concentrations of anti-inflammatory sFRP5 in such subjects. These findings suggest a novel regulatory system in low grade inflammation in obesity, which can be influenced by nutritional therapy.

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Objective: In the present study, we examined the effect of a very low-calorie diet(VLCD)-based obesity program on human gut microbiome diversity and metabolism during weight loss and weight maintenance. Methods: Obese subjects underwent 3 months of VLCD followed by 3 months of weight maintenance. A lean and an obese control group were included. The microbiome was characterized by performing high-throughput dual-indexed 16S rDNA amplicon sequencing. Results: At baseline, a significant difference in the Firmicutes/Bacteroidetes ratio between the lean and obese individuals was observed (p = 0.047). The VLCD resulted in significant alterations in gut microbiome diversity from baseline to 3 months (p = 0.0053). Acinetobacter represented an indicator species for the observed effect (indicator value = 0.998, p = 0.006). Metabolic analyses revealed alterations of the bacterial riboflavin pathway from baseline to 3 months (p_nom = 0.0078). These changes in diversity and bacterial metabolism induced by VLCD diminished during the weight maintenance phase, despite sustained reductions in body weight and sustained improvements of insulin sensitivity. Conclusion: The present data show that a VLCD is able to beneficially alter both gut microbiome diversity and metabolism in obese humans, but that these changes are not sustained during weight maintenance. This finding might suggest that the microbiome should be targeted during obesity programs.

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Our data suggest that wnt5a is important in linking inflammation to metabolism. The nutrition and the microbiome might be interesting targets to prevent and/or treat wnt5a-mediated metabolic inflammation.

SummarySepsis and type 2 diabetes exhibit insulin resistance as a common phenotype. In type 2 diabetes we and others have recently provided evidence that alterations of the proinflammatory wingless-related integration site (wnt)-5a/antiinflammatory secreted frizzled-related protein (sFRP)-5 system are involved in the pathogenesis of insulin resistance. The aim of the present study was to investigate whether this novel cytokine system is dysregulated in human sepsis, which may indicate a potential mechanism linking inflammation to metabolism. In this single-centre prospective observational study, critically ill adult septic patients were examined and proinflammatory wnt5a and wnt5a inhibitor sFRP5 were measured in serum samples by enzyme-linked immunosorbent assay (ELISA) at admission to the intensive care unit (ICU) and 5 days later. Sixty sepsis patients were included, and 30 healthy individuals served as controls. Wnt5a levels were found to be increased significantly in septic patients compared to healthy controls (2·21 ± 0·33 versus 0·32 ± 0·03 ng/ml, P < 0·0001). In contrast, sFRP5 was not altered significantly in septic patients (19·72 ± 3·06 versus 17·48 ± 6·38 ng/ml, P = 0·07). On admission to the ICU, wnt5a levels exhibited a significant positive correlation with the leucocyte count (rs = 0·3797, P = 0·004). Interestingly, in patients recovering from sepsis, wnt5a levels declined significantly within 5 days (2·17 ± 0·38-1·03 ± 0·28 ng/ml, P < 0·01). In contrast, if sepsis was worsening, wnt5a levels increased in the same time-period by trend (2·34 ± 0·59-3·25 ± 1·02 ng/ml, P > 0·05). sFRP5 levels did not change significantly throughout the study period. The wnt5a/sFRP5 system is altered in human sepsis and might therefore be of interest for future studies on molecular pathophysiology of this common human disease.