155-OR: Brown Adipose Tissue Leptin Feedback Regulates Feeding Behavior

Obesity is a consequence of chronic disruption in energy homeostasis. This phenomenon is controlled by systemic and local signals such as leptin, a nutrient-sensitive signal secreted primarily by the white adipose tissue (WAT) . In contrast, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. In this study, unexpectedly, we observed overnight fasting decreased leptin expression in iBAT, and 2-hour refeeding was able to restore the iBAT leptin levels. This nutritional status-dependent fluctuation suggests a vital role of iBAT leptin in the acute regulation of energy homeostasis. Consistently, we found that mice with leptin selectively overexpressed in the UCP1-positive cells of iBAT (LEP-OEiBAT/UCP1) showed reduced fast-induced food intake. This hypophagia phenotype was associated with increased satiation as reflected by decreased meal numbers and increase postmeal interval. Notably, LEP-OEiBAT/UCP1 selectively increased the mRNA expression of leptin in the iBAT without affecting circulating leptin levels, indicating a possible paracrine role of iBAT leptin. In supporting this point of view, we showed that chemical ablation of sensory nerves (SS) in iBAT significantly increased fast-induced food intake, associated with altered meal frequency. Additionally, we also found that iBAT-specific infusion of leptin increased Stat3 phosphorylation (pStat3) in the upstream iBAT-innervating sensory neurons, suggesting leptin-mediated sensory detection. Notably, the increased pStat3 was associated with neural activation in the arcuate nucleus of the hypothalamus in the brain, and chemical ablation of iBAT SS blunted this stimulation. Our results support a model that feeding-induced iBAT leptin modulates iBAT-specific sensory inputs to the brain to regulate food intake and feeding patterns.