Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment

Background: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. Aim: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. Methods: Eighteen patients with active acromegaly were studied at the time of diagnosis and >= 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, beta-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). Results: Total FGF21, active FGF21 and beta-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (mu g/L) were markedly reduced after treatment [105.6 +/- 29.4 vs 62.2 +/- 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and Delta FAP correlated positively with Delta Procollagen Type I (P < 0.000) and Type III (P < 0.000). Conclusion: 1) Circulating FGF21 and beta-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover.