Objective: Regulation of growth hormone (GH) receptor expression and hence tissue GH sensitivity may be important for the conflicting results found in treatment studies with recombinant growth hormone in chronic heart failure (CHF). Growth hormone-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor and is closely related to measures of body composition and, specifically, to size of visceral fat tissue. Leptin, the adipocyte specific (ob) gene product, has been proposed as the signal linking adipose tissue and GHBP/GH-receptor expression. CHF has recently been shown to be a hyperleptinaemic and insulin-resistant state regardless of aetiology. This study aimed to examine the influence of leptin on GHBP in CHF patients with and without cardiac cachexia compared with healthy control subjects. Methods: We studied 47 male patients with CHF (mean age 61±2 years, New York Heart Association (NYHA)-class 2.7±0.1, left ventricular ejection fraction (LVEF) 28±2%, peak oxygen consumption 16.8±0.9 ml/kg/min) and 21 male healthy controls of similar age. Of the CHF patients, 19 were cachectic (cCHF; non-oedematous weight loss >7.5% over at least 6 months) and 28 non-cachectic (ncCHF; similar for age and LVEF). Insulin sensitivity was assessed by an intravenous glucose tolerance test using the minimal model approach. Results: Compared with healthy controls, patients had elevated levels of leptin (7.6±0.7 vs 4.8±0.7 ng/ml, P <0.05), insulin (76.2±8.9 vs 41.4±6.0 pmol/l, P < 0.01), and reduced insulin sensitivity (2.43±0.2 vs 3.48±0.3 min-1.μU.ml-1.104, P < 0.005) but similar GHBP levels (901±73 vs 903±95 pmol/l). Leptin levels were increased in ncCHF (9.11±1.0ng/ml, P = 0.001) but were not different from normal in cCHF (5.32±0.7 ng/ml, P > 0.5). After correction for total body fat mass, both ncCHF and cCHF were hyperleptinaemic (41.8±3.8 and 37.9±0.38 vs 24.4±2.1 ng/ml/100g, ANOVA P = 0.001). In both patients and controls there was a direct correlation between leptin levels and GHBP (r = 0.70 and r = 0.71 respectively, both P < 0.0001). This relationship was stronger than between GHBP and several parameters of body composition (body mass index (BMI), total and regional body fat mass or % body fat) and held true when sub-groups were tested individually (ncCHF r = 0.62, P < 0.001; cCHF r = 0.79, P < 0.0001). In multivariate regression analysis in all CHF patients, serum leptin levels emerged as the strongest predictor of GHBP, independent of age, BMI, total and regional fat mass or % body fat, fasting insulin level and insulin sensitivity. Conclusion: Fat mass corrected leptin levels are elevated in CHF patients with and without cachexia. Reduced total fat mass may account for lower leptin levels in cachectic CHF patients compared with non cachectic patients. Leptin strongly predicts GHBP levels in CHF regardless of its hyperleptinaemic state or severely altered body composition as in cardiac cachexia. Leptin could be the signalling link between adipose tissue and GHBP/GH receptor expression in CHF.