Keratinocyte growth factor promotes preadipocyte proliferation via an autocrine mechanism

Abstract

Keratinocyte growth factor (KGF; also known as FGF-7) is a well-characterized paracrine growth factor for tissue growth and regeneration. However, its role in adipose tissue, which is known to undergo tremendous expansion in obesity, is virtually unknown. Given that we previously identified KGF as one of the up-regulated growth factors in adipose tissue of an early-life programmed rat model of visceral obesity, the present study was undertaken to examine the hypothesis that KGF promotes adipogenesis. Using 3T3-L1 and rat primary preadipocytes as in vitro model systems, we demonstrated that (1) KGF stimulated preadipocyte proliferation in a concentration-dependent manner with a maximal effect at 2.5 ng/ml (approximately 2-fold increase); (2) KGF mRNA was highly expressed in rat adipocytes and preadipocytes as well as 3T3-L1 cells; (3) treatment of preadipocytes with a neutralizing antibody against KGF and siRNA-mediated knockdown of KGF led to a 50% reduction in their proliferative capacity; (4) KGF activated the protein kinase Akt, and the PI3 kinase inhibitor LY294002 blocked KGF stimulation of preadipocyte proliferation; and (5) KGF did not promote differentiation of preadipocytes to mature adipocytes. Together, these results reveal adipocytes and their precursor cells as novel sites of KGF production. Importantly, they also demonstrate that KGF promotes preadipocyte proliferation by an autocrine mechanism that involves activation of the PI3K/Akt signaling pathway. Aberrant KGF expression may have consequences not only for normal adipose tissue growth but also for the pathogenesis of obesity.