Evidence that tumor necrosis factor-alpha-induced hyperinsulinemia prevents decreases of circulating leptin during fasting in rats.
Administration of tumor necrosis factor-alpha (TNF-alpha) acutely increases leptin gene expression and circulating leptin concentrations in rodents and humans. Since TNF-alpha also induces hyperinsulinemia, and because insulin is a potent stimulator of leptin production, we hypothesized that elevated plasma insulin mediates TNF-alpha-induced increases of circulating leptin. To test this hypothesis, rats were made insulin-deficient with streptozotocin (STZ) and treated with subcutaneous implants that released insulin at a constant rate and thereby "clamped" insulin levels. STZ-diabetic and nondiabetic rats were injected with TNF-alpha or vehicle; plasma leptin, insulin, and glucose concentrations were measured during an initial 12-hour postinjection period of fasting and after a subsequent 12-hour period of refeeding. Food intake during the 12 hours after fasting was assessed as a physiologic correlate of changes in leptin concentrations. In nondiabetic rats, TNF-alpha increased plasma insulin (P =.016) and prevented the fasting-induced decrease of circulating leptin (P =.004) over the initial 12 hours compared with vehicle. Food intake during the refeeding period was 30% lower (P =.008) when the nondiabetic animals were injected with TNF-alpha. In contrast, TNF-alpha did not affect leptin concentrations in STZ-diabetic animals with clamped plasma insulin levels or their food intake during the refeeding period. These results suggest that TNF-alpha-induced hyperinsulinemia likely mediates the stimulatory effect of TNF-alpha on circulating leptin in vivo. Elevated leptin levels may in turn contribute to the effect of TNF-alpha to decrease food intake.
Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis 95616, USA.
Edward A
EA
Medina
Kent L
KL
Erickson
Kimber L
KL
Stanhope
Peter J
PJ
Havel
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000188:drug therapy; D004435:Eating; D005215:Fasting / Q000097:blood*; D006946:Hyperinsulinism / Q000097:blood* / Q000139:chemically induced*; D007328:Insulin / Q000097:blood / Q000172:deficiency / Q000627:therapeutic use; D020738:Leptin / Q000097:blood*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha