Leptin in the Hindbrain Facilitates Phosphorylation of STAT3 in the Hypothalamus

Abstract

Leptin receptors (ObRb) in the forebrain and hindbrain are each independently recognized as important mediators of leptin‐induced changes in energy balance. We recently used sub‐threshold doses of leptin to show that chronic activation of both hypothalamic and brainstem ObRb is required to reduce body fat. The objective of this study was to identify selectively activated brain nuclei in rats receiving chronic infusions of sub‐threshold leptin in both forebrain and hindbrain. Male Sprague Dawley rats were fitted with 3rd and 4th ventricle cannulas. Alzet pumps were used to infuse either saline (S) or leptin (L) (0.1 µg/24h in 3rd, 0.6 µg/24h in 4th) for 6 days, resulting in four treatment groups SS, SL, LS, LL (3th‐4th). There was no effect of leptin in single ventricle infused groups (LS, SL) compared to controls (SS). Double ventricle infused rats (LL) showed a 50% inhibition of food intake, 30% loss in body fat, and an increase in ObRb activation marker phosphorylated STAT3 (pSTAT3‐ir) in the arcuate nucleus (Arc), ventromedial (VMH), dorsomedial (DMH) and posterior hypothalamus compared to other groups. No differences in pSTAT3‐ir were observed in midbrain or brainstem nuclei despite a 6 fold higher infusion of leptin into the 4th ventricle than the 3rd. Delta Fos B‐ir, a chronic neuronal activation marker, showed that multiple brain nuclei were chronically activated due to the process of infusion, but only the Arc, VMH, DMH and ventral tuberomammillary nucleus showed a significant increase in LL rats compared to other groups. These data imply that the simultaneous activation of both forebrain and hindbrain ObRb is required to reduce body fat and that leptin in the hindbrain facilitates phosphorylation of STAT3 in hypothalamic areas involved in the control of energy balance.