The role of leptin in human lipid and glucose metabolism: the effects of acute recombinant human leptin infusion in young healthy males.

BACKGROUND: Obese and lean humans treated with leptin have not experienced convincing weight-loss results compared with the dramatic weight losses observed in obese rodents. OBJECTIVE: We sought to investigate the effect of acutely elevating leptin to concentrations observed in obese individuals on muscle and adipose tissue metabolism and muscle signaling in healthy lean males. DESIGN: Healthy, lean, postabsorptive males were infused with either recombinant human leptin (rhleptin; n = 8) or saline (control; n = 8) for 4 h, which elicited leptin concentrations of ~ 20 and ~ 1 ng/mL, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism in vivo were assessed before, during, and 2 h after cessation of the infusion. Skeletal muscle biopsy specimens were obtained to quantify changes in signal transducers and activators of transcription-5'AMP-activated protein kinase (STAT-AMPK) signaling. RESULTS: During the infusion of rhleptin, no differences in either systemic, skeletal muscle, or adipose tissue glucose or fat metabolism were observed. These observations were made despite increased activation of STAT (~ 17-fold) and AMPK (1.43-fold) after 1 h of rhleptin infusion. After the rhleptin infusion, an increase in systemic palmitate and fat oxidation was observed (P < 0.0003), which likely was caused by a concomitant increase in skeletal muscle palmitate oxidation (P < 0.02). This was observed despite lowered leptin concentrations and basal skeletal muscle STAT-AMPK signaling. CONCLUSIONS: Elevating circulating leptin concentrations to concentrations comparable with those of obese individuals increases human in vivo skeletal muscle signaling through the AMPK pathway and causes an increase in skeletal muscle fatty acid oxidation. Abdominal adipose tissue was unaffected by the acute physiologic increase in leptin concentrations.

IL-6 selectively stimulates fat metabolism in human skeletal muscle.

Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ∼40 and ∼1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis in muscle could account for the systemic changes. Skeletal muscle signaling increased after 1 h of rhIL-6 infusion, indicated by a fourfold increase in the phosphorylated signal transducer and activator of transcription (STAT) 3-to-STAT3 ratio, whereas no changes in phosphorylated AMP-activated protein kinase or acetyl-CoA carboxylase levels could be observed. Our findings suggest that an acute increase in IL-6 at a normophysiological level selectively stimulates lipolysis in skeletal muscle, whereas adipose tissue is unaffected.