Abstract
Leptin is an adipocyte-derived hormone with pleiotropic functions affecting appetite and mood. While leptin’s role in the regulation of appetite has been extensively studied in hypothalamic neurons, its function in the hippocampus, where it regulates mood-related behaviors, is poorly understood. Here, we show that the leptin receptor (LepRb) colocalizes with brain-derived neurotrophic factor (BDNF), a key player in the pathophysiology of major depression and the action of antidepressants, in the dentate gyrus of the hippocampus. Leptin treatment increases, whereas deficiency of leptin or leptin receptors decreases, total Bdnf mRNA levels, with distinct expression profiles of specific exons, in the hippocampus. Epigenetic analyses reveal that histone modifications, but not DNA methylation, underlie exon-specific transcription of the Bdnf gene induced by leptin. This is mediated by stimulation of AKT signaling, which in turn activates histone acetyltransferase p300 (p300 HAT), leading to changes in histone H3 acetylation and methylation at specific Bdnf promoters. Furthermore, deletion of Bdnf in the dentate gyrus, or specifically in LepRb-expressing neurons, abolishes the antidepressant-like effects of leptin. These findings indicate that leptin, acting via an AKT-p300 HAT epigenetic cascade, induces exon-specific Bdnf expression, which in turn is indispensable for leptin-induced antidepressant-like effects.
Highlights
Leptin is produced and secreted from adipocytes [1], circulates in the blood [2], and is transported across the blood–brain barrier [3]
While mRNA levels of Bdnf exons II and III remained unchanged, exons I, IV, and VI transcripts were found to increase 2 h after leptin treatment (5 mg/kg) (treatment: F(1,155) = 52.8300, P < 0.001; exon: F(4,155) = 2.8020, P = 0.0278; treatment × exon interaction: F(4,155) = 2.8020, P = 0.0278; exons I: P < 0.001; exons II: P = 0.0511; exons III: P > 0.9999; exons IV: P < 0.001; exons VI: P < 0.001) (Fig. 3b). These results suggest that Bdnf transcripts containing exons I, IV, and VI are responsible for leptin-induced upregulation of total Bdnf gene expression in the hippocampus
MRNA levels for total Bdnf and exons IV and VI varied across the estrous cycle with higher levels in the proestrus phase (Fig. 4a). These results suggest that basal expression levels of total Bdnf and specific exons and their responses to leptin treatment are estrous cycle-dependent, which could be partially due to a dynamic change in endogenous leptin and LepRb across the estrous cycle [63]
Summary
Leptin is produced and secreted from adipocytes [1], circulates in the blood [2], and is transported across the blood–brain barrier [3]. We and others have shown that circulating leptin levels are reduced in chronic stress animal models of depression [15,16,17], whereas systemic and intracerebroventricular injections of leptin produce antidepressant-like behavioral effects [15, 18,19,20]. Direct infusion of leptin into the dentate gyrus of the hippocampus induces an antidepressant-like effect, similar to the effect observed after systemic injection [15]. Deletion of LepRb in the dentate gyrus results in depression-like behaviors and attenuates leptin’s antidepressant-like effects [13, 22]. Blockade of leptin signaling in the dentate gyrus attenuates the antidepressant-like effects of leptin [14] These findings support an important role of the hippocampus in mediating leptin’s actions on mood-related behavior.
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