Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1).
Preadipocyte factor-1 (Pref-1) is a transmembrane protein highly expressed in preadipocytes. Pref-1 expression is, however, completely abolished in adipocytes. The extracellular domain of Pref-1 undergoes two proteolytic cleavage events that generate 50 and 25 kDa soluble products. To understand the function of Pref-1, we generated transgenic mice that express the full ectodomain corresponding to the large cleavage product of Pref-1 fused to human immunoglobulin-gamma constant region. Mice expressing the Pref-1/hFc transgene in adipose tissue, driven by the adipocyte fatty acid-binding protein (aP2, also known as aFABP) promoter, showed a substantial decrease in total fat pad weight. Moreover, adipose tissue from transgenic mice showed reduced expression of adipocyte markers and adipocyte-secreted factors, including leptin and adiponectin, whereas the preadipocyte marker Pref-1 was increased. Pref-1 transgenic mice with a substantial, but not complete, loss of adipose tissue exhibited hypertriglyceridemia, impaired glucose tolerance, and decreased insulin sensitivity. Mice expressing the Pref-1/hFc transgene exclusively in liver under the control of the albumin promoter also showed a decrease in adipose mass and adipocyte marker expression, suggesting an endocrine mode of action of Pref-1. These findings demonstrate the inhibition of adipogenesis by Pref-1 in vivo and the resulting impairment of adipocyte function that leads to the development of metabolic abnormalities.
Lee
Kichoon
K
Department of Nutritional Sciences and Toxicology, and. Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, USA.
Villena
Josep A
JA
Moon
Yang Soo
YS
Kim
Kee-Hong
KH
Lee
Sunjoo
S
Kang
Chulho
C
Sul
Hei Sook
HS
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002454:Cell Differentiation; D048429:Cell Size; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015870:Gene Expression; D018149:Glucose Intolerance / Q000209:etiology* / Q000378:metabolism; D006130:Growth Disorders / Q000196:embryology / Q000235:genetics; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D018076:DNA, Complementary; C512925:Dlk1 protein, mouse; D007141:Immunoglobulin Fc Fragments; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins