Editors' ChoicePhysiology

The fat Wnt where?

Sci. Signal.  17 Feb 2015:
Vol. 8, Issue 364, pp. ec36
DOI: 10.1126/scisignal.aaa9044

Cardiovascular disease and type 2 diabetes are associated with fat accumulation in specific white adipose tissue (WAT) depots in the body. The adipocytes in distinct fat depots differ in their secretion of hormones and cytokines and in fatty acid storage and metabolism. Wnt signaling has been implicated in adipogenesis and in regional differences in adipocyte identity and metabolism. Wnt signaling inhibits adipogenesis and instead promotes osteoblastogenesis. Whereas patients with loss-of-function mutations in the Wnt coreceptor LRP5 develop osteoporosis and have an increased risk for developing type 2 diabetes, patients with gain-of-function mutations in LRP5 have abnormally high bone mass. Loh et al. found that gain-of-function LRP5 mutations were also associated with preferential accumulation of fat in the lower body, increased insulin sensitivity, and reduced inflammation in WAT. Conversely, a loss-of-function allele of LRP5 was associated with increased upper-body fat accumulation. In subcutaneous fat samples from lean and obese volunteers, LRP5 was more abundant at both the transcript and protein levels in abdominal fat than in gluteal fat, and expression of LRP5 in gluteal fat negatively correlated with systemic insulin resistance and inflammation. In vitro experiments with immortalized human WAT precursors from gluteal and abdominal fat depots indicated that knocking down LRP5 or pharmacologically reducing canonical (β-catenin–dependent) Wnt signaling inhibited proliferation of both gluteal and abdominal adipocytes, inhibited differentiation of gluteal adipocytes, and promoted differentiation of abdominal adipocytes. Thus, Wnt signaling dose-dependently and region-specifically affects the proliferation and differentiation of WAT. Increased Wnt signaling stimulates the proliferation and differentiation of abdominal adipocytes, whereas reduced Wnt signaling less potently induces proliferation and favors the differentiation of gluteal adipocytes.

N. Y. Loh, M. J. Neville, K. Marinou, S. A. Hardcastle, B. A. Fielding, E. L. Duncan, M. I. McCarthy, J. H. Tobias, C. L. Gregson, F. Karpe, C. Christodoulides, LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion. Cell Metab. 21, 262–272 (2015). [PubMed]