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 (DLK1(S)) is known to inhibit 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 demonstrate for the first time that only membrane-bound DLK1 (DLK1(M)) exhibits a substantial repression effect on preadipocyte proliferation. Thus, by independently manipulating DLK1 isoform levels, we established that DLK1(M) inhibits G1-to-S-phase cell cycle progression and thereby strongly inhibits preadipocyte proliferation in vitro. Adult DLK1-null mice exhibit higher fat amounts than wild-type controls, and our in vivo analysis demonstrates that this may be explained by a marked increase in preadipocyte replication. Together, these data imply a major dual inhibitory function of DLK1 on adipogenesis, which places DLK1 as a master regulator of preadipocyte homeostasis, suggesting that DLK1 manipulation may open new avenues in obesity treatment.
Laboratory of Molecular and Cellular Cardiology, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, and the Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark.
Sussi B
SB
Mortensen
Charlotte H
CH
Jensen
Mikael
M
Schneider
Mads
M
Thomassen
Torben A
TA
Kruse
Jorge
J
Laborda
Søren P
SP
Sheikh
Ditte C
DC
Andersen
D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis; D050154:Adiposity; D000818:Animals; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D048429:Cell Size; D002478:Cells, Cultured; D005260:Female; D016193:G1 Phase; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012995:Solubility
D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering