Membrane-Tethered Delta-Like 1 Homolog (DLK1) Restricts Adipose Tissue Size by Inhibiting Preadipocyte Proliferation

Adipocyte renewal from preadipocytes has been shown to occur throughout life and to contribute to obesity, yet very little is known about the molecular circuits that control preadipocyte expansion. The soluble form of the preadipocyte factor (also known as pref-1) delta-like 1 homolog (DLK1S) is known to in-hibit adipogenic differentiation; however, the impact of DLK1 isoforms on preadipocyte proliferation remains to be determined. We generated preadipocytes with different levels of DLK1 and examined differentially affected gene pathways, which were functionally tested in vitro and confirmed in vivo. Here, we dem-onstrate for the first time that only membrane-bound DLK1 (DLK1M) exhibits a substantial repression effect on preadipocyte proliferation. Thus, by independently manipulating DLK1 isoform levels, we established that DLK1M inhibits G1-to-S-phase cell cycle progression and thereby strongly inhibits preadipocyte proliferatio