Selective inhibition of forebrain or hindbrain leptin receptors modifies the response to peripheral leptin

Abstract

Previously we showed that peripheral infusions of physiological doses of leptin increase body fat in chronically decerebrate rats, in which the forebrain is surgically dissociated from the hindbrain. This study tested whether inhibition of leptin receptors (ObR) in the vicinity of either the 3rd or the 4th ventricle modified changes in food intake and body weight caused by peripheral leptin injections. Rats were food deprived during the light cycle and received 3rd ventricle injections of 0, 1.5, 2.5, 3.0 or 3.5 ug of leptin mutein protein (mutein), an ObR antagonist, 30 minutes before an i.p. injection of either PBS or 2.5 mg leptin/kg. Leptin inhibited 36 hour food intake and weight gain in rats receiving 0, 1.5 or 2.5 ug mutein, whereas 3.0 and 3.5 ug mutein increased weight gain and prevented any effect of leptin on either intake or weight gain. In a second study of similar design rats received 4th ventricle injections of 0, 0.75 or 1.5 ug mutein 30 minutes before an i.p. injection of 2.5 mg leptin/kg. Leptin inhibited 24 hour, but not 36 hour, food intake of rats receiving 0 ug mutein. Both doses of mutein inhibited weight gain and food intake and these effects were exaggerated and prolonged by leptin. These observations support those made in decerebrate rats and suggest that ObR in the brainstem oppose the feeding and energy expenditure responses to activation of forebrain ObR. Supported by NIH grant DK053903.