Phosphorylation of STAT3 in hypothalamic nuclei is stimulated by lower doses of leptin than are needed to inhibit food intake.

This experiment investigated which hypothalamic nuclei were activated by a dose of leptin that inhibited food intake. Foodnot intake, energy expenditure, respiratory exchange ratio (RER), and intrascapular brown adipose tissue (IBAT) temperature were measured in male and female Sprague Dawley rats for 36 h following an intraperitoneal injection of 0, 50, 200, 500, or 1,000 µg leptin/kg with each rat tested with each dose of leptin in random order. In both males and females, RER and 12-h food intake were inhibited only by 1,000 µg leptin/kg, but there was no effect on energy expenditure or IBAT temperature. At the end of the experiment, phosphorylated signal transducer and activator of transcription 3 (pSTAT3) immunoreactivity was measured 1 h after injection of 0, 50, 500, or 1,000 µg leptin/kg. In male rats, the lowest dose of leptin produced a maximal activation of STAT3 in the Arc and nucleus of the solitary tract (NTS). There was no response in the dorsomedial hypothalamus, but there was a progressive increase in ventromedial nucleus of the hypothalamus (VMH) pSTAT3 with increasing doses of leptin. In female rats, there was no significant change in Arc and pSTAT3 NTS activation was maximal with 500 mg leptin/kg, but only the highest dose of leptin increased VMH pSTAT3. These results suggest that the VMH plays an important role in the energetic response to elevations of circulating leptin but do not exclude the possibility that multiple nuclei provide the appropriate integrated response to hyperleptinemia. The results of this experiment show that doses of leptin too small to inhibit food intake produce a maximal response to leptin in the arcuate nucleus. By contrast the VMH shows a robust response that correlates with inhibition of food intake. This suggests that the VMH plays an important role in the energetic response to hyperleptinemia.