Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1)

J Clin Invest. 2003 Feb;111(4):453-61. doi: 10.1172/JCI15924.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / cytology*
  • Adipocytes / metabolism*
  • Animals
  • Base Sequence
  • Bone and Bones / abnormalities
  • Bone and Bones / embryology
  • Calcium-Binding Proteins
  • Cell Count
  • Cell Differentiation
  • Cell Size
  • DNA, Complementary / genetics
  • Female
  • Gene Expression
  • Glucose Intolerance / etiology*
  • Glucose Intolerance / metabolism
  • Growth Disorders / embryology
  • Growth Disorders / genetics
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pregnancy
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Solubility

Substances

  • Calcium-Binding Proteins
  • DLK1 protein, human
  • DNA, Complementary
  • Dlk1 protein, mouse
  • Immunoglobulin Fc Fragments
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • Repressor Proteins