1523-P: A Leptin-Mediated Interoceptive Network between the Brain and Brown Adipose Tissue

Obesity is attributed to 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). Previously, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. Unexpectedly, in this study, we observed that iBAT leptin expression displayed a distinct circadian pattern and fluctuated with nutritional and ambient temperature. These observations suggest a vital role of iBAT leptin in the regulation of energy homeostasis. To explore this idea, we performed gain and loss of function experiments by overexpressing (LEPOE) or knocking down (LEPKD) leptin selectively in UCP1+ cells of iBAT, respectively. We found that LEPOE reduced food intake while LEPKD increased it in normal and fasting-induced feeding conditions. Notably, LEPOE/LEPKD selectively increased/decreased 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 found that the leptin receptor is highly expressed in the iBAT-associated sensory nerve (iBAT-SN). Moreover, iBAT-specific leptin infusion activated leptin signaling in the iBAT-SN and subsequently stimulated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Conversely, chemical ablation of iBAT-SN increased food intake and blunted hypothalamic POMC activation induced by iBAT-specific leptin infusion. These findings indicate that iBAT possesses a structural and functional basis for paracrine leptin signaling via iBAT-SN, which cross-talks with POMC neurons to modulate energy homeostasis. Our results support an unappreciated metabolic role of iBAT leptin in energy homeostasis.