ESPE Abstracts

Background and aim: Pediatric patients with germline mutations in phosphatase and tensin homolog (Pten) frequently develop aberrant adipose tissue growth/lipomas. In severe cases this can have adverse effects on organ function and quality of life. Due to the lack of understanding the basis of lipoma development, no systemic treatment options are available. We therefore aimed to characterize an already described lipoma bearing mouse model with conditional knockout of Pten in osteoprogenitor cells (Pten cKO). Surprisingly, these mice did not develop lipomas, but showed an age-dependent decrease in adipose tissue weight.

Methods: We compared metabolic characteristics and adipose tissue histology of Pten cKO and control mice. We analyzed insulin signalling pathway activation on protein level, gene expression of adipogenesis markers as well as the serum proteome of Pten cKO and control mice. Wnt induced signalling protein (Wisp1) and Leptin serum levels were quantified by ELISA.

Results: We found an age-dependent loss of fat mass in Pten cKO mice affecting the inguinal (ing) as well as gonadal (gon) white adipose tissue (WAT) depots, with no effect on brown adipose tissue. Other metabolically active organs were not affected and no change in body weight was observed. Further exploration of adipose tissue histology revealed distinct morphological differences between Pten cKO mice and controls, with adipocytes of Pten cKO mice being significantly smaller compared to control adipocytes, but also showing a broader spectrum of adipocyte size. We did not detect any changes in gene and protein expression of Pten in the WAT depots of Pten cKO mice compared to controls. On protein level, ingWAT and gonWAT of Pten cKO mice showed a 0.6fold and 0.5fold decrease, respectively (ingWAT: P = 0.03, n = 4 per group; gonWAT: P = 0.005, n = 9 Cre negative and n = 5 Pten cKO) in Akt phosphorylation. On mRNA level we observed a 0.5fold reduction of the proliferation marker Pcna (ingWAT: P = 0.01, n = 5 Cre negative and n = 4 Pten cKO; gonWAT: P = 0.03, n = 5 Cre negative and n = 4 Pten cKO). Systemically, we found that Wisp1 was significantly increased in male and female Pten cKO mouse serum compared to controls. In line with WAT macroscopic changes, serum leptin levels showed a trend towards reduction.

Conclusion: Knockout of Pten in osteoprogenitor cells leads to alterations in adipose tissue composition and loss of adipose tissue, which is potentially due to increased Wisp1 serum levels. This points to a novel bone-adipose tissue communication axis mediated by loss of Pten induced expression of Wisp1.