Serum HGF is elevated in obese individuals. This study examined the contribution of excess adipose tissue to increased circulating HGF levels in obesity. Serum HGF was measured by ELISA before and after weight loss due to bariatric surgery or a 24-h fast. At 6.1 ± 0.1 mo following surgery, BMI (50.6 ± 1.6 vs. 35.1 ± 1.3 kg/m²; P < 0.0001) and serum HGF were significantly decreased (1,164 ± 116 vs. 529 ± 39 pg/ml, P < 0.001). A 24-h fast did not change serum HGF, but serum leptin was significantly reduced (67.7 ± 7.1 vs. 50.3 ± 8.3 ng/ml, P = 0.02). HGF secretion in vitro from adipocytes of obese (BMI 40.3 ± 2.8 kg/m²) subjects was significantly greater (80.9 ± 10.4 vs. 21.5 ± 4.0 pg/10⁵ cells, P = 0.008) than release from adipocytes of lean (BMI 23.3 ± 1.4 kg/m²) subjects. HGF mRNA levels determined by real-time RT-PCR were not different in adipocytes from lean (BMI 24.0 ± 0.8 kg/m²) and obese (45.7 ± 3.0 kg/m²) subjects, but serum HGF was significantly elevated in the obese individuals studied (787 ± 61 vs. 489 ± 49 pg/ml, P = 0.001). TNF-α (24 h treatment) significantly increased HGF release from subcutaneous adipocytes 23.6 ± 8.3% over control (P = 0.02). These data suggest that elevated serum HGF in obesity is in part attributable to excess adipose tissue and that this effect can be reversed by reducing adipose tissue mass through weight loss. Increased HGF secretion from adipocytes of obese subjects may be due to posttranscriptional events possibly related to adipocyte size and stimulation by elevated TNF-α in the adipose tissue of obese individuals.