Integrated Effects of Leptin in the Forebrain and Hindbrain

Abstract

Obesity develops because of a sustained positive shift in energy balance. The hormone leptin was identified as a key negative feedback signal in energy balance regulation, yet it has been ineffective in reversing human obesity. Leptin injection studies in experimental animals have identified leptin receptors (ObRb) in the forebrain and hindbrain as critical and independent mediators of leptin responses. We hypothesized that under near physiological conditions; activation of ObRb in both these areas is required to reduce body fat. We used a male Sprague Dawley double cannulation rat model (3rd and 4th ventricle) and infused either saline (S) or sub-threshold doses of leptin (L) for 12 days (0.1μg leptin/24h in 3rd, 0.6μg leptin/24h in 4th) in different combinations SS, SL, LS, LL (3rd-4th), to test for integration of forebrain and hindbrain responses. There was no effect of leptin in single ventricle infused groups (LS, SL) compared to controls (SS). Rats with sub-threshold leptin infusions into both ventricles (LL) showed a 60% reduction in energy intake that reversed after day 6 and a 20% weight loss which stabilized at day 6. Body fat of LL rats was decreased by 30% in 6 days, and 50% after 12 days despite correction of energy intake. LL rats displayed normal activity and maintained normal energy expenditure despite weight loss. We further investigated which brain nuclei are involved in this integrated response using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) as a marker of ObRb activation and delta FosB (ΔFosB) as a marker of chronic neuronal activation. The weight loss in LL rats was associated with a significant increase in pSTAT3 and ΔFosB within multiple hypothalamic nuclei, including the arcuate, ventromedial and dorsomedial nuclei, with no changes in activation of brainstem nuclei. Our results suggest that under near physiologial conditions, the simultaneous activation of both forebain and hindbrain ObRb is required for leptin to reduce body fat and this is facilitated by leptin in the hindbrain promoting activation of pSTAT3 in the hypothalamus. This provides a new perspective on the physiological role of leptin and could lead to new strategies to treat obesity.