Intracerebroventricular administration of insulin and glucose inhibits the anorectic action of leptin in rats.
ABSTRACT Obese individuals with glucose intolerance present with high serum levels of glucose, insulin, and leptin. These substances are potent inhibitors of feeding in the brain. Obese subjects still present with over-feeding despite elevation of the above factors. To elucidate the mechanism of this paradox, the effects of insulin and glucose on the anorectic action of leptin in the hypothalamus were examined. Adult male Sprague-Dawley rats (weighing 285-320 g) were pretreated with intracerebroventricular injection of insulin, glucose, or saline, followed by leptin (7.5 microg) or phosphate-buffered saline (PBS) injection into the third cerebral ventricle (icv). The cumulative food intakes were measured 24 hr after leptin icv. The tyrosine phosphorylation of signal transducer and activator transcription factor 3 (STAT3) in the hypothalamus was determined by Western blotting. In rats pretreated with saline and stimulated with leptin (saline/LEPTIN group), food intake diminished to about 50% of that of the saline/PBS group (P < 0.005). Food intake in the insulin/LEPTIN group was significantly higher compared with the saline/LEPTIN group (P < 0.005) and reached the level seen in the saline/PBS group. Similar data were obtained in glucose pretreatment experiments. Insulin and glucose icv resulted in reduction of leptin-induced STAT3 tyrosine phosphorylation compared with saline. Infusion of insulin and glucose icv did not alter peripheral blood glucose levels in all groups. High insulin or glucose levels in the brain could result in leptin resistance as manifested by food intake, which is probably due to the attenuation of STAT3 phosphorylation downstream the leptin receptor.
Article: Glucose injection reduces neuropeptide Y and agouti-related protein expression in the arcuate nucleus: a possible physiological role in eating behavior.[show abstract] [hide abstract]
ABSTRACT: Evidence suggests that neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC) are modulated by glucoregulatory hormones and involved in maintaining normal eating patterns and glucose homeostasis in states of energy deficiency. This study investigated whether these peptides respond to glucose itself under conditions, e.g., before the nocturnal feeding cycle, when carbohydrate stores are low. After removal of food 3 h before dark onset, Sprague-Dawley rats were given a single, intraperitoneal (i.p.) injection of saline or 10% glucose (0.13 g/kg) and were sacrificed at different intervals, from 3.5 to 90 min later, for measurements of circulating hormones and metabolites or of NPY and AgRP mRNA in the ARC. With no change in insulin, leptin, or triglycerides, glucose injection produced a 1.8-mM rise in circulating glucose during the first 15 min, followed by a 30-60% reduction in NPY and AgRP mRNA at 30 and 60 min post-injection. A similar effect was observed with intraventricular administration of 5% glucose. At 90 min, however, this suppressive effect of i.p. glucose relative to saline was lost and actually reversed into a 50% increase in NPY and AgRP, possibly attributed to a decline in circulating glucose followed by a 50% rise in corticosterone at 60 min. These biphasic shifts over a 90-min period may reflect mechanisms underlying natural eating patterns at the onset of the nocturnal cycle, when spontaneous meals are approximately 90 min apart and rich in carbohydrate, glucose levels are low, and corticosterone and ARC peptides naturally peak.Molecular Brain Research 05/2005; 135(1-2):69-80. · 2.00 Impact Factor