Serum GLP-1 and Thrombospondin-2 predict improved metabolism and attenuated liver fibrogenesis in severely obese patients undergoing an intensive weight loss (Kiel Intervention Cohort)

Background: Glucagon-like peptide-1 (GLP-1) is one of the most promising biological targets in weight loss therapy due to its involvement in the central regulation of food intake and satiety. Still, the qualities of GLP-1 are not fully understood. Thrombospondin-2 (TSP-2) is a novel key serum fibrosis marker that reflects fibrosis and especially the dynamics of liver fibrogenesis in patients with fatty liver disease. Therefore, we investigated serum GLP-1 and TSP-2 levels in association to multimodal weight loss therapy with special regard to liver inflammation and fibrogenesis upon lifestyle intervention.

Material and Methods: The Kiel Intervention Cohort is constituted of 180 patients with severe obesity who underwent a multimodal intensive interdisciplinary weight loss program for 6 months at the University Medical Center Schleswig-Holstein. At baseline, after 10 weeks of VLCD, and after another 16-week of a normo-caloric maintenance phase, serum concentrations of GLP-1 were measured using a valid commercial ELISA, and those of TSP-2 using a validated in-house ELISA for TSP-2. GLP-1 and TSP-2 were correlated with anthropometric and clinical laboratory parameters including liver enzymes, and -elastography.

Results: A significant decrease of BMI (-16.8±6.2 kg/m2) was achieved by the weight loss therapy, which, aside from other metabolic improvements, significantly correlated with a decrease in GLP-1. This was pronounced during fasting and remained stable during maintenance. Interestingly, a similar correlation and course was observed for the fibrogenesis marker TSP-2. There was also a significant correlation between GLP-1 und TSP-2 at baseline. However, when assessing individual GLP-1 and TSP-2 courses, a lot of variation can be noted, indicating the need for differentiated further analyses. Indeed, sex-specific differences were apparent with men having higher GLP-1 and TSP-2 values than women. Furthermore, when stratifying participants into quartiles of baseline GLP-1 levels (Overall range: 3.66 – 600.94 pg/ml), an approximation of GLP-1 but not consistent decrease can be observed for these groups. In terms of structural liver improvements, liver enzymes, stiffness assessed by liver elastography, and TSP-2 show similarly decreasing courses during weight loss. Still, when comparing these measures, deviations in risk estimation become apparent which reflect in the absence of correlation between elastography and BMI.

Conclusion and Outlook: Our results confirm the modulation of both the metabolic parameter GLP-1 and of obesity related liver fibrogenesis via the matricelluar fibrosis marker TSP-2 through multimodal weight loss therapy. Notably, both parameters correlated with baseline BMI and efficient weight loss, but showed only a mild correlation, indicating that improved metabolism will not always result in attenuated (liver) fibrogenesis. Further analyses will include changes in body composition, metabolic status and inflammatory activity.