Integrated effects of leptin in the forebrain and hindbrain of male rats.

Leptin receptors (ObRs) in the forebrain and hindbrain have been independently recognized as important mediators of leptin responses. It is unclear how leptin activity in these areas is integrated. We tested whether both forebrain and hindbrain ObRs have to be activated simultaneously to change energy balance and to maintain metabolic homeostasis. Previous studies used acute leptin injections in either the third ventricle (1-5 μg) or the fourth ventricle (3-10 μg); here we used 12-day infusions of low doses of leptin in one or both ventricles (0.1 μg/24 h in third, 0.6 μg/24 h in fourth). Male Sprague Dawley rats were fitted with third and fourth ventricle cannulas, and saline or leptin was infused from Alzet pumps for 6 or 12 days. Rats that received leptin into only the third or the fourth ventricle were not different from controls that received saline in both ventricles. By contrast, rats with low-dose leptin infusions into both the third and fourth ventricle showed a dramatic 60% reduction in food intake that was reversed on day 6, a 20% weight loss that stabilized on day 6, and a 50% decrease in body fat at day 12 despite the correction of food intake. They displayed normal activity and maintained energy expenditure despite weight loss, indicating inappropriately high thermogenesis that coincided with increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the brainstem. Altogether, these findings show that with low doses of leptin, chronic activation of both hypothalamic and brainstem ObRs is required to reduce body fat.