Low-dose peripheral leptin infusion produces selective activation of ventromedial hypothalamic and hindbrain STAT3

Previous studies have shown that very low dose, acute, single peripheral leptin injections fully activate arcuate nucleus signal transducer and activator of transcription 3 (STAT3), but ventromedial hypothalamus (VMH) pSTAT3 continues to increase with higher doses of leptin that inhibit food intake. The lowest dose that inhibited intake increased circulating leptin 300-fold whereas food intake is inhibited by chronic peripheral leptin infusions that only double circulating leptin. This study examined whether the pattern of hypothalamic pSTAT3 was the same in leptin-infused rats as in leptin-injected rats. Male Sprague-Dawley rats received intraperitoneal infusions of 0, 5, 10, 20, or 40 µg leptin/day for 9 days. The highest dose of leptin increased serum leptin by 50-100%, inhibited food intake for 5 days, but inhibited weight gain and retroperitoneal fat mass for 9 days. Energy expenditure, respiratory exchange ratio, and brown fat temperature did not change. pSTAT3 was quantified in hypothalamic nuclei and the nucleus of the solitary tract (NTS) when food intake was inhibited and when it had returned to control levels. There was no effect of leptin on pSTAT3 in the medial or lateral arcuate nucleus or in the dorsomedial nucleus of the hypothalamus. VMH pSTAT3 was increased only at day 4 when food intake was inhibited, but NTS pSTAT3 was increased at both 4 and 9 days of infusion. These results suggest that activation of leptin VMH receptors contributes to the suppression of food intake, but that hindbrain receptors contribute to a sustained change in metabolism that maintains a reduced weight and fat mass.NEW & NOTEWORTHY Low-dose, chronic peripheral infusions of leptin produced an initial, transient inhibition of food intake that correlated with signal transducer and activator of transcription 3 (STAT3) activation in the ventromedial hypothalamus (VMH) and nucleus of the solitary tract (NTS). When intake normalized, but weight remained suppressed, the NTS was the only area that remained activated. These data suggest that leptin's primary function is to reduce body fat, that hypophagia is a means of achieving this and that different areas of the brain are responsible for the progressive response.