Role of wnt5a in metabolic inflammation in humans.

Isabelle Relling, Gül Akcay, Daniela Fangmann, Carina Knappe, Dominik Maria Schulte, Katharina Hartmann, Nike Müller, Kathrin Türk, Astrid Dempfle, Andre Franke, Stefan Schreiber, Matthias Laudes
Year of publication:
Journal title abbreviated:
J. Clin. Endocrinol. Metab.
Journal title long:
The Journal of clinical endocrinology and metabolism
Impact factor:
Common nutrition-associated diseases like obesity and type 2 diabetes are linked to chronic low-grade inflammation. The secreted glycopeptide wnt5a has been implicated in metabolic inflammation in rodent models suggesting a potential novel treatment target. So far data on the role of wnt5a in human physiology yielded conflicting results.In the present study we measured wnt5a serum concentrations in a cross-sectional cohort of n=896 human subjects to gain deeper insights into wnt5a physiology.Wnt5a serum concentrations were measured by ELISA and related to several phenotyping/genotyping data. In vitro experiments were performed in THP-1 macrophages to examine potential molecular mechanisms.Wnt5a levels were found to be significantly positively correlated to IL-6 and triglyceride levels. Diabetic subjects revealed elevated wnt5a levels and a significant correlation of wnt5a levels with fasting plasma glucose concentrations. While wnt5a levels were not influenced by common single-nucleotide-polymorphisms in the human wnt5a gene, environmental factors significantly altered wnt5a concentrations: (1) wnt5a levels were reduced in subjects with high nutritional load of the long-chain eicosatetraenoic acid independent of the total caloric intake/overall composition of the macronutrients and (2) wnt5a levels were lower in humans with a high gut microbiome α-diversity. In vitro experiments revealed that stimulation of the IL-6 receptor or the long-chain fatty acid receptor GPR40 directly affect wnt5a expression in human macrophages.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.