Identification of Carboxypeptidase X-1 (CPX-1) as a novel regulator of human adipogenesis — ASN Events
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  3. Identification of Carboxypeptidase X-1 (CPX-1) as a novel regulator of human adipogenesis

Identification of Carboxypeptidase X-1 (CPX-1) as a novel regulator of human adipogenesis (#158)

Yu-Hee Kim 1 2 , Louise J Hutley 1 , Julie A Webster 1 , Xiao Luo 1 , Choaping Ng 1 , Johannes B Prins 1 , Jonathan P Whitehead 1
  1. Mater Medical Research Institute, South Brisbane, QLD, Australia
  2. University of Queensland Diamantina Institute , Brisbane, Australia

The prevalence of Type 2 Diabetes (T2D) is increasing at an alarming rate mirroring the global increase in obesity. An important protagonist driving the association of T2D and obesity is dysregulation of adipose tissue function. Accumulating evidence suggests this dysregulation occurs as a result of inappropriate expansion via hypertrophy of existing adipocytes rather than hyperplasia and differentiation of preadipocytes. Thus, strategies to increase the latter, termed adipogenesis, are of therapeutic interest.

Our previous work demonstrated that FGF-1 is a potent adipogenic factor. Here we describe the identification and characterization of Carboxypeptidase X-1 (CPX-1) as a novel downstream effector of FGF-1. The function of CPX-1 is unknown. It lacks catalytic activity but contains a putative collagen binding domain. We hypothesized that CPX-1 is involved in remodelling of the extracellular matrix (ECM), a process that is essential for efficient adipogenesis.

We identified putative FGF-1 effectors by performing transcriptomic analysis of primary human preadipocytes treated -/+ FGF-1. Levels of CPX-1 mRNA were increased over 20-fold by FGF-1 (p<0.05, n=3). Results were confirmed at the mRNA / protein level by qRT-PCR / Western blot of human SGBS preadipocytes which revealed that induction of CPX-1 is transient. Biochemical analysis demonstrated that CPX-1 is secreted from cells in an N-glycosylation dependent manner and in vitro assays showed recombinant CPX-1 binds collagen. Inhibition of CPX-1 induction, using siRNA, abolished adipogenesis as determined by morphology, lipid accumulation, gene / protein expression and functional studies (all p<0.05). Picrosirius red staining revealed altered collagen organization in CPX-1-/- cells. Intriguingly, constitutive overexpression compromised adipogenesis suggesting coordinated expression of CPX-1 is critical for adipogenesis. Further studies revealed that CPX-1 acts downstream of BAMBI1 and independent of, yet complementary to, PPARgamma. 

These studies identify CPX-1 as a novel regulator of adipogenesis that may provide novel strategies for therapeutic intervention

  1. Luo X, Hutley LJ, Webster JA, Kim YH, Liu DF, Newell FS, Widberg CH, Bachmann A, Turner N, Schmitz-Peiffer C, Prins JB, Yang GS, Whitehead JP. Identification of BMP and Activin Membrane-Bound Inhibitor (BAMBI) as a Potent Negative Regulator of Adipogenesis.