A proportion of obese people are metabolically healthy demonstrating obesity per se does not automatically compromise metabolism. One emerging explanation for this paradox is that ‘fit fat’ people have a greater capacity for adipogenesis than unhealthy counterparts. Higher rates of adipogenesis facilitate adipose tissue expansion by increasing adipocyte cell number (hyperplasia) rather than increasing adipocyte cell size (hypertrophy) raising the possibility that promoting adipogenesis may reduce obesity-related diseases.
We hypothesised that greater understanding of adipogenesis would reveal new therapeutic targets. Using transcriptomic and functional analyses we have identified a novel adipogenic pathway.
Microarray analysis of human preadipocytes treated -/+ the pro-adipogenic factor FGF-1 revealed altered expression of >600 genes. BMP and Activin Membrane-Bound Inhibitor (BAMBI), a modulator of paracrine regulators of adipogenesis including TGFs, BMPs & Wnts, was down-regulated 13-fold by FGF-1 (p<0.01). Loss and gain of function studies (siRNA knockdown and plasmid overexpression) demonstrated BAMBI was a negative regulator of adipogenesis (determined by morphology, lipid accumulation, gene & protein expression, insulin sensitivity, adipokine secretion, all p<0.05) that modulated sensitivity to paracrine factors. Carboxypeptidase X-1 (CPX-1) was up-regulated 22-fold by FGF-1 (p<0.01). CPX-1 lacks catalytic activity but contains a putative collagen binding domain leading us to posit a role in extracellular matrix (ECM) remodelling, an essential process for efficient adipogenesis. We found that CPX-1 protein was secreted and bound collagen. CPX-1 knockdown abolished adipogenesis, altered collagen expression and organization and promoted constitutive activation of FAK, MEK and ERK. These data suggest CPX-1 plays a key role both sensing and regulating ECM. Additional studies revealed CPX-1 acts downstream of BAMBI and independent of, yet complementary to, PPAR.
Collectively these studies identify a novel BAMBI-CPX-1 pathway that modulates ECM remodelling and intracellular signalling independent of the canonical PPAR pathway. Further elaboration of this novel pathway may reveal new therapeutic strategies.
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